The most compelling evidence that psilocybin works comes from a randomized, double-blind, controlled trial (the gold standard of clinical studies) that compared a group of depressed people taking psilocybin with those taking escitalopram, a existing antidepressant – something that has never been done before. The trial was further analyzed using fMRI brain scans, and the results were compared to other fMRI results from another recent clinical trial.
Just a day after the first dose of psilocybin, fMRI measurements revealed an overall increase in connectivity between different brain networks, which is typically reduced in people with severe depression. The default mode network was simultaneously reduced, while connectivity between it and other networks was increased, confirming previous smaller studies.
The dose increased connectivity more in some people than in others. But the studies showed that people who had the most connection between networks also had the greatest improvement in their symptoms six months later.
The brains of people taking escitalopram, on the other hand, showed no change in connectivity between the default mode and other brain networks six weeks after starting treatment. Escitalopram may cause changes later. But the rapid onset of psilocybin’s antidepressant effect means it may be ideal for people who don’t respond to existing antidepressants.
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The study suggests that the observed effect may be due to the fact that psilocybin has a more concentrated action on receptors in the brain called “serotonin 5-HT2A receptors” than escitalopram. These receptors are activated by serotonin and are active in all brain areas of the network, including the default mode network. We already know that the level of psilocybin binding to these receptors leads to psychedelic effects. Exactly how their activation leads to changes in network connectivity, however, remains to be explored.
The end of traditional antidepressants?
This raises the question of whether altered activity of brain networks is necessary to treat depression. Many people taking traditional antidepressants still report improvement in their symptoms without them. In fact, the study showed that six weeks after starting treatment, both groups reported improvement in their symptoms.
On some depression rating scales, however, psilocybin had the greatest effect on overall mental well-being. And a greater proportion of patients treated with psilocybin showed a clinical response compared to those treated with escitalopram (70% versus 48%). More patients in the psilocybin group were also still in remission at six weeks (57% vs. 28%). The fact that some patients still do not respond to psilocybin, or relapse after treatment, shows how difficult it can be to treat depression.
Additionally, mental health professionals supported both treatment groups during and after the trial. The success of psilocybin is highly dependent on the environment in which it is consumed. This means it’s a bad idea to use it for self-medication. Additionally, patients were carefully selected for psilocybin-assisted therapy based on their history to avoid the risk of psychosis and other adverse effects.
Regardless of the caveats, these studies are incredibly promising and bring us closer to expanding the treatment options available for patients with depression. Moreover, internalized negative thought processes are not specific to depression. In due course, other disorders, such as addiction or anxiety, might also benefit from psilocybin-assisted therapy.
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