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Psilocybin reduces excessive drinking in rats

A pre-clinical study in rats has shown that the psychedelic compound psilocybin can reverse excessive alcohol consumption and genetic markers of altered brain chemistry seen in alcohol use disorder.

Alcohol use disorders

Although alcohol consumption is popular in many cultures, it is an important cause of morbidity and mortality worldwide. It accounts for 5.3% of all deaths annually. Some individuals are excessive drinkers and eventually can develop an alcohol use disorder (AUD). AUD involves a pattern of compulsive heavy alcohol use and a loss of control over alcohol intake. Clinical presentation is highly heterogenous but typically involves deficits in executive function e.g., working memory, motivation and regulation of emotions. Despite the availability of four approved pharmacological treatments for AUD, these treatments have limited effectiveness and their prescription rates are low. This demonstrates the need for alternative options in the treatment of AUD.

One such option is the use of psychedelics. In recent years, despite a long hiatus, psychedelic drugs have emerged as a possible new therapeutic source. Psychedelics have been shown to promote effects on GPCR signalling as well as downstream effectors, secondary messengers and gene expression. A key mechanism is its effects on serotonin 2A receptor (5-HT2A), more specifically, 5-HT2A receptor desensitisation. This leads to reduced signalling in downstream pathways. Despite the use of the magic mushroom compound psilocybin in clinical trials, the mechanisms by which it might combat addictions like AUD is not yet clear.

A common molecular mechanism

In a recent study, published in Science Advances, researchers established rat models of AUD to test the hypothesis that mGluR2/3 dysfunction in the prefrontal cortex could comprise a common molecular mechanism for deficits seen in several behavioural domains. Group II metabotropic glutamate receptors (mGluR2/3) have received growing attention in addiction research due to their abundance in the pathway from the medial prefrontal cortex (mPFC) to the nucleus accumbens. These regions are known to mediate drug craving and relapse as well as cognitive flexibility. The team also sought to determine whether this mGluR2 dysfunction in the mPFC could be restored by psychedelic treatment. Although mGluRs are not directly targeted by psilocybin, mGluRs closely interact with 5-HT2A receptors.

The researchers were able to demonstrate a causal link between reduced prefrontal mGluR2 function and impaired executive control and alcohol craving. When they generated a neuron-specific prefrontal mGluR2 knockdown in rats, they found that the rats presented with a phenotype of reduced cognitive flexibility and excessive alcohol seeking. However, virally restoring mGluR2 levels in these mice rescued these behaviours. The team also found that psilocybin was capable of restoring mGluR2 expression and reducing relapse behaviour.

Finally, the paper reported a putative biomarker – fluorodeoxyglucose (FDG) positron emission tomography (PET) – to identify mGluR2 treatment-responsive individuals. They found that the brain’s use of glucose was reduced in alcohol-dependent rates after mGLuR2 activation.

The team hope to further explore the mechanisms that might explain psilocybin’s effects at the cellular and gene levels.

Image credit: canva