Twenty-five milligrams of psilocybin — a psychoactive compound found in magic mushrooms — can effectively treat depression when combined with psychotherapy, a study published last week in The New English Journal of Medicine found.
In 2018, the mental health company COMPASS Pathways received “breakthrough status” for psilocybin, allowing them to manufacture a synthetic version of the compound and test it in clinical trials. In their latest study, researchers at universities in the United Kingdom, Europe, and the United States, as well as COMPASS Pathways, tested different doses of that synthetic compound in people with treatment-resistant depression. The results are promising — and cautionary.
Background — Over the past two decades, research into the therapeutic potential of psychedelic drugs like psilocybin, LSD, Ketamine, and MDMA has skyrocketed. While Ketamine is the only one of these drugs to have FDA approval for depression, studies into all four drugs have yielded promising results. What’s less well understood, though, is how long the antidepressant effects of these drugs last.
What they did — The researchers split participants with treatment-resistant depression into three groups — each group received different amounts of COMP360, COMPASS’ proprietary synthetic psilocybin. One group received one milligram of COMP360, which served as the control group, one group received 10 milligrams, and the last group received 25 milligrams of the drug. All groups had preparation sessions with a mental health professional, as well as two follow-up sessions.
Guy Goodwin, Chief Medical Officer for COMPASS and Professor Emeritus of Psychiatry at The University of Oxford, and one of the researchers on the study explains how COMP360 is, and isn’t, different from psilocybin found in Psilocybe cubensis, also known as magic mushrooms.
“The actual psilocybin molecule in Psilocybe mushrooms and in COMP360 is the same,” Goodwin tells Inverse. “The formulation as a crystalline form guarantees the dose, which cannot be exactly done for mushrooms.”
Further, psilocybin isn’t the only psychoactive compound in mushrooms, so using only psilocybin allows the researchers to understand how that compound affected the participants without interference from other psychoactive substances.
What they found — The researchers found that while both 10 milligrams and 25 milligrams produced psychoactive effects, only the 25-milligram dose produced significant antidepressant effects compared to the one-milligram dose.
After one 25-milligram dose of Comp360 psilocybin, alongside psychotherapy, one in three participants no longer met the diagnostic criteria for depression at three weeks, and one in five sustained that improvement through week 12.
While the 10-milligram dose didn’t produce the same kind of antidepressant effects, Goodwin says the study still checks an important box necessary for eventual regulatory approval of the drug. Both the 10-milligram dose and the 25-milligrams produced psychedelic effects, but only the 25-milligram dose had a sustained antidepressant effect. That kind of dose-increased response relationship is important, Goodwin says, because regulators want to see that psilocybin behaves like other drugs in that respect.
Digging into the details — While this and other psilocybin studies are promising regarding treatment-resistant depression, there are serious reasons to proceed with some caution. The authors note that some participants in the study experienced increased suicidal ideation or suicidality from baseline to week three of the study. In the 25-milligram group, 14 percent experienced a worsening suicidal state; in the 10-milligram group and 1-milligram group, those numbers were 17 percent and nine percent, respectively.
While any increase in suicidal ideation or suicidality demands careful consideration and vigilance, Goodwin stresses that such increases are not uncommon in studies evaluating possible treatments for intractable depression and don’t necessarily mean the psilocybin is responsible for the rise.
“Suicidal ideas are very common in depression, especially in the difficult-to-treat group...The percent increases are not very surprising when viewed through that lens and not systematically different between the study arms,” he says. “Unfortunately, suicidality represents a feature of depression, hence the need always to be cautious, but it is unlikely to be related to COMP360 treatment as such.”
It also underscores the need for mental health professionals on staff throughout the treatment.
What it means for the future — This study corroborates the antidepressant effects of psilocybin that other studies have found. Researchers are still trying to understand precisely why psilocybin is effective for treatment-resistant depression when so many other pharmacological interventions are not.
There’s some evidence to suggest that the drug allows different parts of the brain to interact with each other. Previous studies suggest this is the opposite of the rigidity and negative thinking loop often experienced by people with depression. A landmark 2016 study in the Journal of Psychopharmacology found that psilocybin treatment produced “immediate, substantial, and sustained” relief from anxiety and depression in cancer patients. A 2021 study published in JAMA Psychiatry evaluating psilocybin combined with psychotherapy in people with treatment-resistant depression found that 71 percent of participants had a clinically significant response to the treatment and that at week four, 51 percent of participants were in remission from the disorder.
Goodwin believes the outcomes from this phase 2 trial are promising.
“About 20 percent of the group who received 25 milligrams had a stable response over the full 12 weeks,” he says. “We regard this as very promising in this patient group who have failed multiple previous treatments.”
For the Phase three trial, Goodwin says researchers will be evaluating “two administrations of COMP360 3 weeks apart.”
That Phase three trial “is the prelude to a submission for regulatory approval for use of COMP360 in treatment-resistant depression,” he says.
If you or someone you know is having thoughts of suicide, call or text 988 or go to https://988lifeline.org/chat/ to connect with a trained crisis counselor. You can also go to https://afsp.org/suicide-prevention-resources for additional resources.
