Psychedelic psilocybin cuts cravings and boosts key brain functions in rat models of alcohol use disorder

Alcohol accounts for about 3 million deaths worldwide annually, and there are only four approved drugs to treat alcohol use disorder. Psilocybin, the active ingredient in magic mushrooms, has drawn interest as a potential remedy for the disorder, and now a team of German researchers is backing up the idea with intriguing preclinical data.

Researchers at the University of Heidelberg treated rat models of alcohol addiction with psilocybin and found that the psychedelic was effective at staving off cravings, they reported in the journal Science Advances. 

The promising effects of psilocybin stem from the compound's ability to restore expression of a specific glutamate receptor known as mGluR2, the researchers explained. Reduced expression of the receptor causes both alcohol cravings and impairments in "executive functions," such as self-control and decision-making, they demonstrated in the study. 

The team started by exposing the rats to alcohol vapor that made them intoxicated at similar levels seen in people with clinical alcohol addiction. Long-lasting behavioral changes and molecular changes in the brain occurred as the rats became dependent on alcohol over seven weeks, the researchers reported. 

RELATED: Psilocybin clears biggest depression test yet, but Compass stock falls amid chatter about adverse events, durability

The researchers gave the rats one of two different doses of psilocybin to see whether the magic mushroom ingredient was effective at reducing relapses. They found that both doses were effective compared to a control treatment, the team said in a statement. 

Little is understood about the molecular mechanisms that contribute to the crumbling of executive function in alcohol use disorder, the researchers said. That led them to perform the tests, which found that lower levels of mGluR2 expression in a certain region of the cortex trigger alcohol-seeking behavior and impaired cognitive flexibility in the animal model. 

The team then set out to see whether psilocybin could restore the receptor's expression and tamp down the desire to seek out alcohol while also restoring flexibility in cognition. In addition to reducing cravings, the treatment lessened alcohol-seeking behavior in the rat models and reduced the risk of relapse, they reported.

The Heidelberg team's research comes amid a wave of investor interest in psychedelics as treatments for depression, addiction and other conditions. Alcohol use disorder is the focus of Journey Colab's lead drug candidate, which is derived from a psychedelic compound found in some cacti. The startup snagged $12 million in September to move the drug into clinical trials next year.

As for psilocybin, it's being tested in several diseases, including depression. Compass Pathways reported earlier this month that its psilocybin candidate showed improved symptoms in people with treatment-resistant depression in a phase 2b trial.

Hurdles remain, though, including a federal law that has hampered research in the field, ethics concerns, intellectual property challenges and a stigma surrounding psychedelics. What's more, Compass' trial raised concerns about suicidal ideation in some patients and the durability of the treatment. 

The German team mapped out a strategy for testing psilocybin in people with alcohol dependency. As part of their study, they used positron emission tomography to identify a biomarker they believe could be used to identify people who might benefit from interventions targeting the mGluR2 receptor.

They suggested starting by enrolling patients identified with the biomarker into a trial of psilocybin and using MRI scans to track improvements in "functional connectivity" in the brain after a single dose, they wrote. If such improvements are observed, a longer controlled trial could be designed to test whether psilocybin reduces alcohol cravings and prevents relapses, they proposed.