Psychedelics indicate clues to antidepressants – 06/13/2023 – Virada Psychedelica

The renaissance of psychedelic substances for medicine, whose flagship is their antidepressant effect, runs the risk of collapsing into fainting. A study by the University of Helsinki (Finland) gives new life to the strategy of developing medicines, based on them, that do away with the alteration of consciousness, the infamous “trip”.

Eero Castrén’s group includes the participation of Plinio Casarotto, graduated in pharmacy at the Federal University of Paraná. Also participating in the study published last week in the journal Nature Neuroscience were Brazilians Caroline Biojone and Cassiano Diniz.

His experiments with rodents suggest that the therapeutic benefit comes more from the neuroplasticity (formation of new brain connections) induced by psychedelics rather than the psychedelic experience itself. More than that, still: the two effects seem independent of each other.

Several clinical tests with psilocybin from “magic” mushrooms and with dimethyltryptamine (DMT) from ayahuasca have shown good results against depression. Before prohibition in the 1970s war on drugs, these substances and others like LSD were investigated to treat this disorder and others, such as chemical dependency, but under crackdowns the topic became kryptonite.

In the last two decades, these studies have returned and started to use more refined investigative techniques, such as double-blind assays, molecular biology and brain imaging. The group with an epicenter in Helsinki focused on receptors on mouse neurons for two compounds, serotonin and BDNF.

Serotonin, already called the “hormone of happiness”, acts on receptors of the 5HT class. Psychedelics are similar to it and fit well, specifically one of them, 5HT2a, considered to trigger the alteration of consciousness and visuals that characterize lysergic and quetal trips.

BDNF is the acronym in English for brain-derived neurotrophic factor, active in the formation of connections between neurons. This neuroplasticity is considered as a probable biochemical mechanism behind the therapeutic mental effect of psychedelics, as new connections would open alternative ways to reprocess traumas and negative ideas.

The Finnish team had already demonstrated that conventional antidepressants such as fluoxetine, as well as the anesthetic ketamine (or ketamine), which has been used against depression, act on the BDNF receptor known as TrkB. But these drugs are not psychedelics in the strong sense, as they do not act on the 5HT2a receptor.

What’s new about the study in Nature Neuroscience is that it reveals that the psychedelics LSD and psilocybin not only act on TrkB, too, but do so more efficiently. The chemical affinity between the key (psychedelic) and the lock (receptor), in the case of the LSD-TrkB pair, is up to a thousand times greater than that of fluoxetine or ketamine.

Furthermore, the assays showed that this affinity is independent of its action on the 5HT2a receptor. In other words, in principle it would be possible to obtain the desired plasticity with innovative drugs that would not launch the patient on a psychedelic trip – an alternative, perhaps, for those who do not want to have this experience, or cannot (such as people prone to psychotic breaks).

“Our findings open an avenue for structure-based design of high-affinity TrkB-selective ligands that have rapid and long-lasting antidepressant action but are potentially devoid of hallucinogenic activity,” the authors wrote in another section of the journal.

“The differences in the way these substances bind and stabilize the TrkB receptor provide a new direction for experimental investigations, with the potential to lead to the development of new drugs that combine the high efficacy of psychedelics with the safety of conventional antidepressants”, concurs the Brazilian neuroscientist Stevens Rehen, from UFRJ and Instituto Usona (Wisconsin, USA), when commenting on the article, in which he had no participation.

Such drugs could also become medications for other psychiatric and neurological disorders, such as substance abuse or stroke, in which increased plasticity could be beneficial, Castrén and colleagues add. They caution, however: “It is unclear whether a similar separation between the antidepressant and hallucinogenic effects of LSD is present in humans.”

Physiologist Nicole Galvão-Coelho, from the Federal University of Rio Grande do Norte, who also did not participate in the article, agrees with this reservation about species, in other ways. The correlation of BDNF levels with antidepressant response is a very popular explanation, but she points out that this does not always happen and that there is a great distance between animal models of depression and the exuberant manifestation of the disorder in people.

She has doubts about the therapeutic potential of future psychedelics for severely depressed patients with treatment-resistant disorders and many complex traumas. In those cases, the psychedelic experience and subsequent therapy would remain important to the clinical outcome, she believes.

Casarotto, who in the meantime left bench research in Helsinki and now works as a scientific editor at the Cell Press group, says that he was afraid to work with psychedelic receptors because there were many groups working in the field. However, after publishing evidence in 2021 that classic antidepressants had a low affinity for TrkB (an idea by Biojone, to whom Casarotto is married), the group had a competitive platform to investigate other molecules, such as psychedelics.

Although the data point in the direction of “parapsychedelics” (compounds inspired by them, but incapable of causing the classic alteration of consciousness), the strategy of David Olson at the University of California and by Cao Dongmei and Wang Sheng at the Institute of Biochemistry and Cell Biology from Shanghai, Casarotto views the proposal with caution, the same one he reserves for the notion that the “journey” and its integration through psychotherapy are essential for therapeutic gain.

“It’s too premature to assume that now”, he points out. “Extrapolating from our data, [moduladores de TrkB] they have no effect per se, they need neuronal activity and therefore external inputs. But between what the data indicate and the conclusion that the therapy is essential there is a big difference.”

For the Brazilian, clinical studies on the antidepressant effect of psychedelics suffer a lot from bias. Among other reasons, because it is very difficult to maintain the double-blind system, the gold standard of clinical trials – the participants almost always know whether they took a placebo or not.

“I see very passionate discussions, especially on Twitter, on this subject. Passion, ideology and science do not mix. “

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NOTICE TO NAVIGATORS – Psychedelics are still experimental therapies and certainly do not constitute a panacea for all psychic disorders, nor should they be the object of self-medication. Speak with your therapist or doctor before venturing into the area.

On the tendency to legalize the therapeutic and adult use of psychedelics in the US, see the article “Cogumelos Livres” in the December 2022 issue of Piauí magazine.

To learn more about the history and new developments of science in this area, including in Brazil, look for my book “Psiconautas – Viagens com a Ciência Psychedelica Brasileira”.