A ground-breaking study conducted by INSERM’s Groupe de Recherches sur l’Alcool et les Pharmacodépendances (GRAP) opens up new therapeutic perspectives for the treatment of alcohol addiction with psilocybin, the active compound in hallucinogenic mushrooms. Published in the scientific journal Brain, their work confirms the potential of psilocybin to combat alcohol addiction, while shedding light on the molecule’s hitherto unknown mechanisms of action. A highly promising scientific breakthrough for curbing the scourge of alcohol addiction with psychedelics.
Psilocybin reduces alcohol self-administration through selective activation of the left nucleus accumbens
The results of a study conducted by Inserm and UPJV scientists show that psilocybin administration in mouse models of alcohol addiction reduces alcohol consumption by half. These data confirm the value of studying this molecule in the treatment of alcohol dependence.
To explain these effects and better understand the underlying mechanisms, researchers measured the expression of certain genes known to be involved in alcohol addiction in the brain’s nucleus accumbens. The nucleus accumbens plays a central role in addiction, notably by relaying the pleasurable effects of drugs and the motivation to consume them.
The results surprisingly reveal a cerebral lateralization in the effects of psilocybin, with a modification of the expression of certain genes, either up or down, and which is different according to the left or right side of the brain.
These initial results prompted researchers to explore the specific role of the left or right nucleus accumbens by injecting psilocybin directly into either the left or right nucleus accumbens.
Psilocybin injected into non-alcoholic rats induced specific changes in the brain, notably a decrease in the expression of serotonin 5HT-2A receptors only in the left nucleus accumbens. Unexpectedly, increased expression of the BDNF gene, associated with brain plasticity, was observed only in the right nucleus accumbens.
When psilocybin is injected directly into the left nucleus accumbens, it reduces alcohol consumption by half, but has no effect when injected into the right nucleus accumbens.
A better understanding of the mechanism involved in psilocybin’s beneficial effects on alcohol consumption
Prof. Naassila’s team went a step further to decipher psilocybin’s biological mechanism. We know that psilocybin’s hallucinogenic effects are linked to its action on serotonin 5-HT2A receptors. In this work, the researchers showed that these receptors were over-expressed after psilocybin treatment. Then, to really demonstrate that psilocybin’s effects on alcohol consumption are linked to a specific effect on serotonin 5-HT2A receptors - they tested the effect of blocking these receptors.
And indeed, infusion of ketanserin, a 5HT-2A receptor blocker, directly into the left nucleus accumbens prevents psilocybin from reducing alcohol consumption. Blocking in the right nucleus accumbens, on the other hand, is not effective.
The study also highlights another well-known potential mechanism in addiction. Psilocybin administration increases the expression of dopamine D2 receptors in the nucleus accumbens of alcohol-dependent rats. Since we already know that in alcohol addiction, both animals and humans show a decrease in D2 receptor expression, these results could also explain how psilocybin counteracts the mechanisms of addiction, by restoring the expression of these receptors.
This groundbreaking discovery of the lateralization of psychedelic effects in the treatment of alcohol addiction opens up new avenues of research. The next steps will be to map this lateralization more precisely, and to check whether it can be generalized to other psychedelics (LSD, DMT, etc.).
According to Prof. Mickael Naassila: "These results are highly original, as they demonstrate that psilocybin acts differently on gene expression depending on the cerebral hemisphere. And that in the brain, it is particularly the nucleus accumbens, but the one located in the left hemisphere, which seems to be involved in the effects of reducing alcohol consumption".
