Depression: Psychedelic is better than serotonin – 02/25/2023 – Marcelo Leite

In 2021, the World Health Organization estimated that 280 million people suffered from depression in the world, one of the main causes of the 700 thousand suicides that occur each year. With the Covid pandemic, the crowd of depressed people may have grown to 350 million.

To make matters worse, at least a third of patients find no benefit from existing antidepressants. Hence the interest in recent years for studies —still preliminary, covering a few patients— with psychedelic substances as a quick solution alternative for so many unassisted people.

The earliest clinical trials involve psilocybin from poorly termed “magic” mushrooms. It’s biochemistry, not sorcery. Improvements already appear with the first dose of the possible drug, which, if approved by regulatory agencies as psychotherapy support, should not be used continuously.

Promising but equally limited results have come out of small trials with ayahuasca and its psychoactive component, dimethyltryptamine (DMT). A pioneering, placebo-controlled study tested three dozen volunteers with resistant depression at the Federal University of Rio Grande do Norte (UFRN).

Nobody really knows what causes depression, besides, of course, the hardships of life. The brain of the depressed person seems to suffer from retraction of connections in areas important for the control of emotions, such as the frontal cortex, but the reason for this is mysterious.

One hypothesis blamed the brain’s deficit of serotonin, the so-called “happiness hormone.” Great enthusiasm arose in 1986 when fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI) that increases the concentration of the neurotransmitter in the synapses, came on the market.

The improvement in communication between neurons relieves many depressed people, but not all, as already mentioned. Serotonin, even in greater amounts, cannot directly induce the formation of new connections (neuroplasticity), which would give the mind more flexibility to deal with everyday sadness.

That’s where psychedelics come in. After half a century of bad fame and prohibition, several studies —including at UFRN— have shown its impact on neuroplasticity. This would explain the antidepressant benefits seen on the first day, whereas SSRIs can take weeks to show an effect.

It turns out that psychedelics act on the same neuronal serotonin receptors, especially 5HT2A. It remained an enigma that one substance, serotonin, is incapable of inducing new connections and that others, psychedelics, by activating the same cellular switches, manage to take the additional antidepressant step.

A piece of the puzzle fell into place on the 17th, with an article in Science magazine by David Olson’s group, from the University of California at Davis. Olson is also the founder of the company Delix Therapeutics.

The team showed that psychedelics like DMT from ayahuasca manage to penetrate neurons and trigger 5HT2A receptors inside the cells, not just those positioned on the membrane. Penetration would be essential to trigger neuroplasticity and subjective effects such as psychedelic trips.

Much remains to be explained. If there are receptors for psychedelics deep inside neurons, it must be because the body itself produces its own consciousness-altering drugs. Indeed, it is already known that there is endogenous DMT in the brain, such as endorphins and endocannabinoids.

Why? For what? And, even more: what is the explanation for compounds with such power to modify perception and even combat depression being secreted in the leaves of plants such as chacrone (DMT), in the body of mushrooms (psilocybin) and even in that of frogs (5 -MeO-DMT)?

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