Psilocybin, the active ingredient in magic mushrooms, has already drawn abundant interest for its therapeutic potential in a variety of contexts, notably its potential to help folks quit smoking cigarettes and manage mental health conditions. Now, researchers at the University of Heidelberg have evidence that the psychedelic could be effective to stave off cravings for alcohol and curb alcohol use disorder (AUD).
The research article was published in the journal Science Advances, and the study’s leaders focused on the promising effects of psilocybin stemming from the compound’s ability to restore expression of a specific glutamate receptor known as mGLuR2. Reduced expression of that specific receptor causes alcohol craving and impairments in “executive functions,” they demonstrated in the study, and ultimately, it can impact self-control and decision-making.
“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,” said Dr. Marcus Meinhardt, first author of the study.
To observe the potential benefits psilocybin could offer in the equation, the team exposed rats to alcohol vapor that intoxicated them at similar levels seen in people with clinical alcohol addiction. Over seven weeks, long-lasting behavioral changes and molecular changes in the brain occurred and the rats became dependent on alcohol, according to researchers.
The first approach was to fully knock out all the mGLuR2 receptors in a rat’s brain from birth, which they achieved using a mutant rat line that has this deficit from birth. The other approach uses a targeted, gene-editing approach that aims to remove the mGLuR2 neurons from mature rats’ addictions pathways.
Each approach produced different results. The targeted approach reduced cognitive flexibility in a similar way to expended alcohol exposure. The full knockout didn’t affect the rat’s behavioral performance. Meinhardt explained that the team suspected the finding was 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, ‘OK, there are no mGluR2 left, then we have to compensate for that.’”
After establishing this, researchers then dosed the rats with one of two different doses of psilocybin to determine if it would be effective to reduce relapse. The team 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.
Injections of 1 mg/kg or 2.5/kg would stimulate a hallucinogenic response if scaled up to a human and were able to increase mGLuR2-related gene expression, which ultimately reduced alcohol-seeking behavior.
Both doses were effective, compared to a control treatment, according to the team.
“Our preclinical results provide support for mGLuR2 as a molecular target for treating reduced cognitive flexibility, craving and relapse responses in alcohol-dependent patients,” the study noted.
Looking toward the future and potential for clinical treatments of AUD on people, the researchers propose a number of key steps. First, they suggested performing an experimental medicine trial in alcohol-dependent patients to demonstrate improved cognitive flexibility, in response to a single administration of psilocybin.
“Such a trial would benefit from an enrichment strategy based on the FDG-PET biomarker described here,” the team said.
Second, they suggest performing a cue-elicited craving study in alcohol-dependent patients in the MRI scanned to demonstrate normalized, functional connectivity in brain areas which are known to be involved in neuronal cue reactivity, following a single application of psilocybin.
“In the case that both proposed human experimental studies yield positive results, a randomized controlled trial (RCT) for testing the anti-relapse properties of psilocybin is indicated,” they concluded.
Though, as promising as this initial study may be, researchers acknowledged that it is unlikely that even this is a magic solution for AUD, since there are so many contributing factors to addictive behaviors, emphasizing the need for further research.