Magic Mushroom Compound Reduces Excessive Drinking in Rat Study

A pre-clinical study in rats suggests that the psychedelic compound psilocybin might reverse excessive consumption of alcohol and genetic markers of altered brain chemistry seen in alcohol use disorder (AUD).

Changes in AUD

AUD, a medical condition that often emerges after years of excessive drinking, involves fundamental alterations to brain circuitry and disruption to executive function that can persist long after a person with AUD has stopped drinking.

Current treatments for AUD have limited effectiveness and there is a desperate need for better solutions. A new focus on the molecular mechanisms of AUD could provide a solution.

“In alcohol use disorder you see a lot of cell loss and degeneration of brain tissue. Then, on a network level, when you look at activity of different networks, you see that many networks that are related to executive function, they are mainly downregulated, but highly increased when, for example, they are challenged by specific cues such as smell of alcohol,” says Dr. Marcus Meinhardt, first author of a new study on AUD published in Science Advances and a researcher at the Central Institute of Mental Health in Mannheim, Germany, which is associated with the University of Heidelberg.

Meinhardt and colleagues investigated how alcohol addiction affects the frontal cortex in a rat model of AUD. The team wanted to examine the molecular action of the psychedelic mushroom-derived compound psilocybin, which is currently being investigated for treating a host of psychiatric and behavioral disorders, including addiction.

Despite the drug’s use in clinical trials, the mechanism by which the psilocybin might combat addictions like AUD is not yet clear. One molecular target that could link psilocybin and AUD is a type of brain receptor called a metabotropic glutamate receptor (mGluR). “It’s stimulated by the neurotransmitter glutamate and it’s a kind of gatekeeper for the release of glutamate from the synapse,” explains Meinhardt. When mGluRs are activated, they clamp down on glutamate release. Excessive glutamate release, says Meinhardt, is seen when a person with AUD experiences cravings. Could a loss of mGluRs be permitting this binge-fueling glutamate overload?

mGLuRs are not targeted by psilocybin, which directly affects another type of receptor called  5-HT_2A that responds to the mood-boosting brain chemical serotonin. There is ample evidence, however, that the two receptors closely interact. Extended activation of 5-HT_2A has been shown to cause a desensitization that increases signaling via mGLuRs, and blocking certain mGluRs stops the head twitch behavior exhibited by rats when they are given psilocybin.

A subtype of mGLuRs, called mGluR2s, are also highly represented in brain areas, like the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), that play a role in addictive behaviors. Collectively, this makes the receptor an excellent target for research exploring the molecular mechanisms of addiction.

Changes to cognitive flexibility

In their study, Meinhardt and colleagues showed that rats that were chronically exposed to high levels of alcohol showed a reduced cognitive flexibility, an indicator of the impaired executive function humans with AUD show. The cognitive flexibility test involves a behavioral task where the rules are suddenly switched mid-game, forcing the rats involved to learn new rules on the fly. A similar approach is used in a human behavioral task called the Wisconsin card sorting test.

These alterations to behavior were accompanied by structural changes in the rats’ prefrontal cortices. The researchers wanted to see whether reduced signaling through mGluR2 receptors could explain these changes. To do so, they took two genetic approaches: a sledgehammer and a stiletto.

More than one way to alter brain signaling

The first approach was to completely knockout all mGluR2 receptors in a rat’s brain from birth, something the researchers achieved by using a mutant rat line that has this deficit from birth. The other approach used a targeted gene editing approach that aimed to remove mGLuR2 neurons specifically from mature rats’ addiction pathways.

The two approaches produced drastically different results. While the targeted approach reduced cognitive flexibility in a similar way to extended alcohol exposure, the global knockdown, unexpectedly, didn’t affect the rats’ behavioral performance. Meinhardt explained that the team suspected this finding may be due to the plastic mammalian brain: “This global knockout is already present in early development, and since the brain is very plastic, during development, the brain can adapt to many, many processes. So, the idea is that receptors such as the mGluR3, which is very similar to the mGluR2, might take over the job of the mGluR2 when the brain says, 'Okay, there are no mGluR2 left, then we have to compensate for that',” he says.

Psilocybin cuts alcohol seeking

Further pursuing the targeted approach, Meinhardt’s team first showed that the alterations made rats who had not previously been exposed to alcohol seek it out by pressing a lever in their cage that would release it. They then showed that injections of 1 mg/kg or 2.5 mg/kg of psilocybin, doses that would stimulate a hallucinogenic response if scaled up to a human, were able to increase mGluR2-related gene expression and reduce alcohol seeking behavior.

In their final experiment, the team acknowledged that there is unlikely to be a magic bullet for AUD, given that there are many contributing factors to addictive behaviors. How can we work out which patients might benefit from therapy targeting mGluR2?  Meinhardt’s team used an imaging technique called fluorodeoxyglucose (FDG)-positron emission tomography (PET) to examine brain activity after stimulating mGluR2s.The imaging showed that the whole brain's use of glucose was reduced in alcohol-dependent rats after mGluR2 activation. This difference might also be applicable to identify human AUD patients that could benefit from related treatments, as it could act as a biomarker indicating patients who have impaired mGluR2.

Meinhardt says his team’s next steps are to look into the mechanisms that might explain psilocybin effects: “How does it work? What does psilocybin really do on a cellular level? What are the processes that lead to these alterations of gene expression, and is this an effect that is long lasting?”

The arrow of scientific progress doesn’t always point in one direction. While basic studies in pre-clinical models like rodents usually precede clinical findings, one issue Meinhardt’s study highlighted was the relative scarcity of pre-clinical studies of psychedelics, despite a growing number of clinical trials. Meinhardt, for one, has his fingers crossed that other labs will get in on the act soon. “I really hope that that more labs also get interested so that we can really generate cumulative evidence for these drugs for general mental health,” he concluded.

Reference:

Meinhardt, WM, Pfarr, S, Fouquet, G, et al. Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism. Sci. Adv. 2021; 7. eabh2399.