Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism

In this study in rats, a deficiency in mGluR2 function (receptor for the neurotransmitter glutamate) was identified as a common mechanism for increased alcohol-seeking behaviour and impaired cognitive flexibility in rodent models of alcohol use disorder (AUD). Psilocybin was shown to restore prefrontal mGluR2 levels and reduce relapse behaviour. Researchers suggest a biomarker approach to target this neuronal mechanism, implying that psilocybin can treat AUD physiologically as well as psychologically, as other research has suggested.


“Alcohol-dependent patients commonly show impairments in executive functions that facilitate craving and can lead to relapse. However, the molecular mechanisms leading to executive dysfunction in alcoholism are poorly understood, and new effective pharmacological treatments are desired. Here, using a bidirectional neuromodulation approach, we demonstrate a causal link between reduced prefrontal mGluR2 function and both impaired executive control and alcohol craving. A neuron-specific prefrontal mGluR2 knockdown in rats generated a phenotype of reduced cognitive flexibility and excessive alcohol seeking. Conversely, virally restoring prefrontal mGluR2 levels in alcohol-dependent rats rescued these pathological behaviors. In the search for a pharmacological intervention with high translational potential, psilocybin was capable of restoring mGluR2 expression and reducing relapse behavior. Last, we propose a FDG-PET biomarker strategy to identify mGluR2 treatment-responsive individuals. In conclusion, we identified a common molecular pathological mechanism for both executive dysfunction and alcohol craving and provided a personalized mGluR2 mechanism-based intervention strategy for medication development for alcoholism.”

Authors: Marcus W. Meinhardt, Simone Pfarr, Gregory Fouquet, Cathrin Rohleder, Manuel Meinhardt, Janet Barroso-Flores, Rebecca Hoffman, Konstantin Wagner, Bernd Neumaier, Dusan Bartsch, Rainer Spanagel & Wolfgang H. Sommer


The exact nature of mental health disorders remains speculative at best, with both physiological and psychological factors involved in the aetiology of these disorders. Psychedelics are helping to treat these disorders although the manner in which they act remains unknown. Psychedelics can cause people to have intense psychological experiences all while inducing structural changes in the brain by promoting neurophysiological mechanisms like neuroplasticity.

In the present study, researchers sought to understand the molecular mechanisms underlying cognitive impairment and executive dysfunction associated with alcohol use disorder (AUD). Based on previous research, the researchers hypothesized that deficits of mGluR2 receptors in the medial prefrontal cortex may underlie the behavioural changes seen in AUD and that these changes could be treated using psilocybin. To test their hypothesis, researchers treated AUD rats using psilocybin.

This is what they saw in the rodents:

  • Using advanced genetic tools and pharmacologically validated rat models of AUD, the researchers provide evidence that a mGluR2 deficit is both necessary and sufficient for diminished cognitive flexibility and increased drug craving.
  • Psilocybin administration was capable of restoring mGluR2 deficit in alcohol-dependent rats and thus could decrease relapse behaviour and may also positively impact cognitive flexibility.
  • The authors describe a novel FDG-Positron Emission Tomogrpahy (PET) biomarker strategy to identify mGluR2 treatment responsive individuals. Such a technique may contribute to enhancing therapeutic outcomes in patients with AUD.

The findings of the present study provide support for mGluR2 as a molecular target for treating reduced cognitive flexibility, craving, and relapse responses in alcohol-dependent patients. However, as this study was conducted using rodent models such findings may not translate to humans.

Clinical research is needed in order to determine this effect. Nonetheless, the findings support the use of psilocybin to treat AUD both psychologically, as previous research has suggested, and physiologically.

Summary of Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism


Alcohol use disorder (AUD) is a pattern of compulsive heavy alcohol use and a loss of control over alcohol intake. It is often accompanied by deficits in executive functions, which may contribute to craving and subsequent relapse in abstinent patients.

Psychedelic drugs, including the tryptamine psilocybin, have emerged as a new possible source of innovation in medicine. However, unexpectedly little preclinical research has been conducted so far. Psychedelics have been shown to promote effects on G protein – coupled signal transduction, downstream effectors, second messengers, and gene expression. This may explain why psychedelics have sustained effects in humans. The metabotropic glutamate receptor subtype 2 (mGluR2) is thought to be an important target of drug-induced neuroadaptations, and its down-regulation and reduced function may comprise a common molecular mechanism for deficits in several behavioral domains.

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