For some years now, scientists have been investigating how psilocybin, the psychedelic compound in magic mushrooms, can ease the symptoms of depression.

More evidence of the link has arrived with a phase 2, double-blind trial involving 233 participants, the largest study on this subject carried out so far in terms of sample size.

The volunteers all had treatment-resistant depression, which means at least two antidepressant treatments haven't worked to relieve major depressive disorders.

Led by mental health care company COMPASS Pathways, the clinical trials lasted 12 weeks and were conducted over 22 sites across 10 different countries in Europe and North America.

For the purposes of the study, the participants were split into three groups. One group received a single dose of 25 mg of a synthetic form of psilocybin called COMP360, modeled on the psychedelic compound found in magic mushrooms, A second group received 10 mg, and the final group (acting as the control) received 1 mg. None of the volunteers knew which dose they received.

"This study, which is by far the largest clinical trial on the use of psilocybin for treatment-resistant depression to date, demonstrated that a single 25 mg dose of psilocybin reduces the severity of participants' symptoms in comparison to a 1 mg control dose," says psychiatrist James Rucker, from King's College London in the UK.

However, there was no substantial difference between the 10 mg group and the 1 mg group.

It wasn't all good news, though. Within the 25 mg group, 84 percent of volunteers reported side effects such as headache, nausea, and dizziness in the three months after the drug was taken, while a handful experienced more severe adverse effects, including two reporting self-harm and two of suicidal ideation.

Fewer participants in the other two groups expressed having similar experiences, with around three-quarters in each also describing the less severe effects. Only one percent of those taking 1 mg of COMP360 experienced the more severe side effects.

The researchers note future studies need to be vigilant in light of the side effects, though are confident the progress of the subjects was positive.

The psilocybin was administered in dedicated rooms designed to put the participants at ease, and a therapist was present until the psychedelic effects wore off and individuals were allowed to leave (which took between six and eight hours).

Over the following weeks, the Montgomery-├ůsberg Depression Rating Scale was used to assess any change in the symptoms of depression in the people involved in the trial. Questions used by the scale cover mood, tension, sleep and appetite.

"These findings are a positive step in the right direction," says Rucker. "Our task now is to investigate psilocybin for treatment-resistant depression in larger trials with more participants, comparing it both to placebo and to established treatments."

The researchers are now ready to move ahead to a phase 3 trial, where the psilocybin will be compared against the best treatments currently available for depression. That should tell us more about whether this magic mushroom compound is ready to be used at scale.

Researchers suspect the hallucinogenic properties of psilocybin alters brain connectivity in some way, though it's still not clear exactly how that happens. Previous studies have also shown that the psilocybin compound could be effective in treating alcohol addiction.

Another added bonus from this study has been the opportunity to improve how psilocybin treatments are given to patients, with guidelines drawn up for therapists to help them manage the initial hallucinations and other effects of the drug.

"As part of the training program, a therapy manual was developed to enable the standardization of the psychological support across sites and therapists around the world," says psychologist Nadav Liam Modlin, from King's College London.

The research has been published in the New England Journal of Medicine.

If this story has raised concerns or you need to talk to someone, please consult this list to find a 24/7 crisis hotline in your country, and reach out for help.