Opinion – Psychedelic Turn: How psilocybin unties depression’s knot for at least 3 weeks

The psychic suffering of people with serious depression looks like a Gordian knot: the more they pull on the thought, the more the mental grip tightens. This Monday’s article (11) in the journal Nature Medicine reveals how the psychedelic psilocybin manages to loosen the depressive bond and keeps it slippery for three weeks, something that available antidepressants are incapable of.

Psilocybin is the consciousness and perception modifying substance present in “magic mushrooms” of the genus psilocybe. In scientific studies, the compound of synthetic origin is used for better dosage control.

It is yet another study by the Center for Psychedelic Research at Imperial College London under the leadership of David Nutt and Robin Carhart-Harris (RCH is now at the University of California at San Francisco). One of the co-authors is the Brazilian Bruna Giribaldi, a young researcher at Imperial.

This time they analyzed maps of brain activity from 60 patients at baseline and after three weeks, in two experiments, with functional magnetic resonance imaging. The images showed a decrease in the segregation between brain networks, that is, increased communication between them.

One of these networks is the default mode, known by the acronym DMN, active in introspection states. Others relevant to depression, such as the executive network (EN), involved in cognitive control, and the salience network (SN), important in the alternation of attention between the external and internal worlds.

Disturbances in the action and interaction of these networks seem to be at the origin of the most severe forms of depression, as in patients who do not respond to treatment. They are trapped in a closed circle of negative thoughts, rumination, which in turn would be associated with an increase in modularity, that is, in segregation between networks.

The two clinical trials in which the resonance images were obtained had already attracted attention. In the first one, from 2016, all the volunteers knew they would take psilocybin, as did the researchers (this is what is called an “open label” trial). In the other, a 2021 randomized double-blind trial, the psychedelic drug was compared with the antidepressant escitalopram.

In both cases, psilocybin-treated participants had immediate improvement in depression symptoms and sustained it for weeks. More importantly, the study in Nature Medicine now shows that, in parallel, modularity between brain networks has also decreased,

In other words, there was more communication between them, possibly opening gaps in the rumination circle. The same was not observed in the resonances of those who only took escitalopram (Lexapro), whose antidepressant effect usually takes weeks to manifest.

“It’s increased flexibility across networks,” explains Carhart-Harris in an e-mail message. “Think of modularity as segregation of modules, so if it goes down, there’s less segregation.” He believes that the same mechanism could be mobilized, depending on new research, against disorders such as anorexia and chemical dependence.

“The finding is more about the change in the global landscape, in which the panorama becomes more open and flexible. It is important not to get stuck thinking about a single network here. The merit of the analysis and the result is to take a ‘meta’ look about total brain function [whole-brain function].”

The general increase in flexibility could explain the immediate effect of psilocybin, even better news when it turns out that the correlation persists even after three weeks. This is what David Nutt, mentor of RCH, highlighted in a statement from Imperial College:

“These findings are important because, for the first time, we’ve found that psilocybin works differently from conventional antidepressants — making the brain more flexible and fluid, less entrenched in the negative thought patterns associated with depression. This supports our initial predictions and confirms that psilocybin could be a real alternative approach to depression treatments.”

“While these results are encouraging,” the authors caution, “previous trials evaluating psilocybin for depression have taken place under controlled clinical conditions, employing a regulated, laboratory-formulated dose, and have involved extensive psychological support before, during, and after dosing, provided by mental health professionals.”

In other words, no resorting to self-medication. Trying to cut the Gordian knot of depression without outside help can be frustrating, if not risky.

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To learn more about the history and new developments of science in this area, including in Brazil, look for my book “Psiconautas – Travels with Brazilian Psychedelic Science”