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Small, Landmark Trial Sees Magic Mushroom Compound Perform as Well as Antidepressants

15 APRIL 2021

In an ongoing search for new ways to tackle depression, researchers have compared psilocybin, the active compound of magic mushrooms, against a well-established antidepressant in a small phase II trial.

 

Promisingly, the results show that psilocybin was at least as effective as the common antidepressant when used alongside psychological therapy.

It's still very early research. But previous studies have suggested psilocybin doesn't produce nearly as many side effects as antidepressants and its effects are almost immediate.

Trialing the most common type of antidepressants, selective serotonin reuptake inhibitors (SSRIs), on the other hand, can be a nauseating experience for many of us, involving brain zaps, lethargy and emotional turbulence.

Many patients end up feeling worse before it can finally be established if the drug is even working, which can take up to six weeks.

After that, ongoing side-effects of antidepressants can include fatigue or insomnia, dizziness, weight gain, and loss of libido, among a long list.

The drug's positive effects can then wear out for some people over time, leaving the frustrating side effects to contend with on top of a new wave of deteriorating mental health. For other people, SSRIs never work to begin with.

But there could be other options on the horizon.

Closely guided by mental health professionals, 59 volunteers with depression were split into two groups. One group was given the antidepressant escitalopram (often sold under the brand names Lexapro, Cipralex, and others) daily, with extremely weak doses of psilocybin provided twice, three weeks apart.

 

For the second group, the doses of psilocybin were much stronger, and placebos were given in place of escitalopram. Both groups also received psychological support throughout the trial.

Neither the volunteers or the research team, led by Imperial College London neuroscientist Robin Carhart‑Harris, knew which group would receive which treatment.

After six weeks, the volunteer's self-reported scores of depression suggest the magic mushroom ingredient was just as effective as the antidepressant. While the psilocybin group did report a slightly greater improvement than the escitalopram group, the researchers point out it was not at a statistically significant level.

They also suspect that because the SSRI has a delayed effect, if the trial had gone on for longer they may have seen an even greater improvement in depression scores for escitalopram, too.

Before anyone rushes out to self medicate, Carhart-Harris cautions the volunteers also had guided psychotherapy to help them through any hallucination experiences.

"We strongly believe that the … psychotherapy component is as important as the drug action," he told The Guardian.

"With a psychedelic it is more about a release of thought and feeling that, when guided with psychotherapy, produces positive outcomes."

 

While five patients taking the SSRI either reduced or stopped their doses entirely because of the negative effects they were experiencing, none in the psilocybin group did. But due to the hallucinogenic effects of psilocybin, volunteers with a family history of psychosis were excluded from the trial, which likely biased the trial sample towards those who wouldn't have significant side effects.

"The percentages of patients who had anxiety, dry mouth, sexual dysfunction, or reduced emotional responsiveness were higher in the escitalopram group than in the psilocybin group," the team wrote in their paper.

The most common side effect experienced by those taking the psilocybin was a transient headache after they received the active doses. This was also observed in a pilot study some of the same researchers worked on in 2016.

In a New England Journal of Medicine commentary that accompanies the paper, psychiatrist Jeffrey Lieberman from Columbia University cautions that while this "is an evidentiary milestone in the development of psychedelic drugs" there's still a lot we don't yet know like, such as what exactly psilocybin does to our physiology. 

 

Like common antidepressants, the active substance in magic mushrooms works on the serotonin pathways in our brains. Rodent studies have shown psilocybin binds to a serotonin receptor called 5-hydroxytryptamine type 2A, which is part of a chain of biochemical reactions implicated in depression.

While SSRIs lead to a kind of emotional blunting, psilocybin appears to do the opposite - fMRI scans have supported patients' reports that the magic mushroom compound seems to increase emotional connections, but exactly how this happens is still unclear.

However, we also still don't fully understand yet how the changes SSRIs make to serotonin levels in our brains work to alleviate depression or anxiety.

While the results call for further investigation, we must be cautious about reading too much into them given the small sample size and the fact many of the participants belonged to the same demographic of highly educated white males. The results were also self-reported, which means they're hard to objectively compare.

And given the controversial history of magic mushrooms, Lieberman is wary about the resources the drug has attracted and how this is distorting the usual procedures for drug development. He also raises valid concerns about the hallucination effects of the drug.

"How do we explain mystical, ineffable, and potentially transformative experiences to patients, particularly if they are in a vulnerable state of mind?" he asks.

However, another recent study suggests this aspect of psilocybin's effects is not required for its antidepressant benefits, and other researchers have been looking into synthesizing psychedelics for mental health treatments without causing hallucinations.

With almost 800 million people with mental health disorders worldwide, those of us relying on external help with our brain chemistry eagerly await more research in the hope of easier treatment options.

The new research was published in The New England Journal of Medicine.