How psychedelic drugs can treat depression

Hallucinogenic mushrooms hold promise of medical benefits, but we are only now beginning to understand how they might help treat depression.

Up to 30% of people with depression do not respond to antidepressant treatment. This may be due to biological differences between patients and because the reaction to drugs often takes a long time – which leads some people to give up on treatment.

Therefore, there is an urgent need to expand the set of drugs available to treat people with depression.

In recent years, attention has turned to psychedelics such as psilocybin – the active compound in “magic mushrooms”.

Although a series of clinical trials have shown that psilocybin can quickly treat depression, including in cancer patients, little is known about how this substance acts directly in the brain.

But two recent studies, published in The New England Journal of Medicine and Nature Medicine, shed some light on this mysterious process.

Psilocybin is a hallucinogen that alters the brain’s reaction to a substance called serotonin. When broken down by the liver (into “psilocin”), it causes an altered state of consciousness and perception in users.

Previous studies using functional magnetic resonance imaging (FMRI) of the brain have shown that psilocybin appears to reduce activity in the medial prefrontal cortex, an area of ​​the brain that helps regulate a number of cognitive functions, including attention, control inhibition, habits and memory. The compound also reduces connections between this region and the posterior cingulate cortex, which may participate in the regulation of memory and emotions.

The active connection between these two brain regions is normally a feature of the brain’s “default mode network”. This network is active when we rest and focus internally, perhaps reminiscing about the past, envisioning the future, or thinking about ourselves or others.

By reducing network activity, psilocybin may well be removing the constraints of the inner self. There are users who report having an “open mind”, with greater perception of the world around them.

Interestingly, mental rumination – the state of being “stuck” in negative thoughts, especially about oneself – is a hallmark of depression. And we know that patients with higher levels of negative rumination tend to exhibit more Default Mode Network (RMP) activity compared to other resting networks. They literally start to react less to the world around them.

But it remains to be seen whether it is the symptoms of depression that cause this change in activity or whether people with a more active default mode network are more prone to depression.

The most convincing evidence of how psilocybin works comes from a randomized double-blind study (the gold standard of clinical studies) that compared a group of people with depression treated with psilocybin with another who received the existing antidepressant escitalopram – something that has never been done before. had been tried before.

The exam was further analyzed using FMRI images of the brain and the results were compared with the FMRI findings from another recent clinical examination.

Just one day after the first dose of psilocybin, FMR measurements revealed a general increase in connectivity between the various brain networks, which are typically reduced in people with major depression. And the standard mode network was simultaneously reduced while connectivity between it and the other networks increased, confirming earlier smaller studies.

The substance caused a greater increase in connectivity in some people than in others. But studies have shown that people with the greatest increase in connection between networks also had a significant improvement in symptoms six months later.

The brains of people who took escitalopram showed no change in connectivity between standard mode and other brain networks six weeks after starting treatment. It is possible that this drug may bring about changes later on, but the rapid onset of psilocybin’s antidepressant effects means it may be ideal for people who do not respond to existing antidepressants.

The study proposes that the observed effect may occur because psilocybin has a more concentrated action than escitalopram on brain receptors known as “serotonergic 5-HT2A receptors”. These receptors are activated by serotonin and are active throughout all networked brain regions, including the default mode network.

We already know that the level of binding of these receptors to psilocybin causes psychedelic effects, but the exact way in which this activation generates changes in network connectivity remains to be explored.

The end of traditional antidepressants?

These findings raise the question of whether altering the activity of brain networks is necessary for the treatment of depression.

Many people who take traditional antidepressants still report improvement in their symptoms without it. And indeed, the study showed that six weeks after starting treatment, both groups had reduced symptoms.

According to some depression rating scales, psilocybin had the greatest effect on overall mental well-being. And a greater proportion of patients treated with psilocybin exhibited a clinical reaction compared with those treated with escitalopram (70% versus 48%).

In addition, more patients in the psilocybin group still had a reduction in symptoms after six weeks (57% versus 28%). The fact that some patients did not respond to psilocybin or relapsed after treatment only demonstrates how difficult the treatment of depression can be.

Another important point is that mental health professionals assisted both treatment groups during and after the study. The success of psilocybin largely depends on the environment in which it is administered. In other words, using it for self-medication is a bad idea.

In addition, patients for psilocybin-assisted therapy were carefully selected based on their history to avoid the risk of psychosis and other harmful effects.

Regardless of the caveats, these studies are incredibly promising and could expand the treatment options available to patients with depression. And internalized negative thought processes are not specific to depression. In due course, other disorders such as addiction and anxiety may also benefit from psilocybin-assisted therapy.

*Clare Tweedy is a professor of neuroscience at the University of Leeds, UK.

This article was originally published on the academic news site The Conversation and republished under a Creative Commons license. read here the original version (in English).

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