Magic mushroom study suggests psilocybin may reverse alcohol-induced brain damage

After half a century of blocks to research on psychedelics’ potential for treating alcohol use disorder, today’s scientists are finally catching up to the pioneering work of their predecessors. In a new study, researchers show that one psychedelic, psilocybin, essentially repairs the part of the brain responsible for alcohol cravings, hinting at a potential new treatment for the disorder.

What’s new — The study, published Wednesday in the journal Science Advances, builds off work begun in the late 1950s, when researchers Humphry Osmond and Abram Hoffer, two early LSD researchers, gave the drug to alcoholics and found that a year later, 40 to 45 percent of alcoholics who received the drug were still sober; a remarkable feat for a condition with high rates of relapse.

The consumption of alcoholic beverages is responsible for 5.3 percent of deaths worldwide every year, and treatments that reduce or eliminate cravings for alcohol are desperately needed.

In the new study, the researchers hone in on why these drugs work at the neurobiological level, pinpointing a specific glutamate receptor in brain cells affected by alcohol use — when this receptor is damaged, it has a harmful effect on brain function. When treated with psilocybin, however, mice used to mimic alcohol use disorder showed repaired glutamate receptor function. What’s more, the researchers identify a biomarker in the study that may ultimately help doctors determine who might benefit most from psilocybin treatment in humans.

Here’s the background — To understand the new study’s findings, we need to zoom in on the neurobiology that is its focus. In the brain, a region called the prefrontal cortex is responsible for cognitive control functions like attention, impulse control, and cognitive flexibility. Previous research demonstrates neurons in the prefrontal cortex are especially vulnerable to the negative effects of chronic, intermittent, alcohol use.

Marcus Meinhardt, a co-author of the new study, says that in the past, his team identified a specific type of glutamate receptor affected by ethanol, basically pure alcohol. This receptor is called metabotropic glutamate receptor subtype 2, or mGluR2 for short.

Glutamate plays an essential role in maintaining brain function, so when glutamate receptors are damaged, the work of the neurotransmitter goes awry. To make matters worse, alcohol suppresses glutamate production, so there is less of the neurotransmitter to go around, too.

Meinhardt tells Inverse this suggests that mGluR2 loss “may be a major consequence of alcohol dependence and a key pathophysiological mechanism mediating increased propensity to relapse.”

While LSD and psilocybin are different drugs, they work very similarly in the brain: They are both “serotonergic psychedelics;” which means they target a specific serotonin receptor in the brain. Previous studies have shown this serotonin receptor and mGluR2 can modulate each others’ functions, leading the researchers to hypothesize psilocybin may act on mGluR2.

What they did — In the new study, Meinhardt and his colleagues exposed mice to alcohol vapor to intoxicate them to similar levels as people with chronic alcohol use disorder experience for seven weeks. Over that period, the researchers monitored the mice’s behavior as well as molecular changes in their brains.

They then separated the alcohol-dependent mice into three groups and then gave two groups psilocybin:

• Lower dose psilocybin
• Higher dose psilocybin
• Control group

What they found — As hypothesized, mGluR2 expression was reduced in the brains of alcohol-dependent mice. That reduction was consistent with lower executive function and increased alcohol cravings.

In other words, becoming dependent on alcohol resulted in changes in the brains of mice — specifically in mGluR2 expression — and made the mice want more alcohol and less able to resist alcohol (in addition to a reduction in other executive functions).

People who study alcohol addiction often call it “progressive;” without intervention, alcohol use disorder can get worse over time. The brains of these alcohol-dependent mice may illustrate precisely why that is, revealing how executive functions — like self-control, emotion regulation, memory, decision making, and cognitive flexibility — are eroded by chronic alcohol misuse.

This syncs with defining features of alcohol use disorder, Meinhardt says: a pattern of compulsive heavy alcohol use and a loss of control over alcohol intake, as well as “deficits in executive functions.”

But here’s where it gets both hopeful and exciting: In both groups of mice that received psilocybin, mGluR2 expression was restored following the treatment. This change was evident in the mice’s behavior, too: The psilocybin group relapsed roughly 45 percent less compared to the control mice.

That result mirrors what the LSD researchers found back in the 1950s. After a dose of LSD — a structurally and functionally very similar compound to psilocybin — 40 to 45 percent of alcoholics were still abstinent a year later.

What it means for the future— Studies in rodents always need to be taken with a grain of salt. We are humans, and what happens in rodents isn’t always consistent with what happens in mice.

But we do know that humans with alcohol use disorder have decreased mGluR2 expression and that psilocybin and LSD have shown promise as treatments for alcohol use disorder in both rodent models and in humans, although the research is still scant in the latter.

If further validated, Meinhardt says, the team’s findings could “also be used in humans to identify patients with reduced mGluR2 receptor, that may preferably respond to psilocybin treatment.” In other words, this may not only present a new treatment strategy but also be useful in determining before embarking on any future therapy who is most likely to benefit from the treatment in the first place.

Abstract: 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 for reduced prefrontal mGluR2 function and both impaired executive control and alcohol craving. By neuron-specific prefrontal knockdown of mGluR2 in rats, we 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 those individuals who respond to mGluR2-based interventions. 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 of alcoholism.