Decades of heavy drinking dramatically reshapes gene activity in brain areas governing impulse control and decision-making, a new study reveals. It’s a biological explanation for why breaking free from alcohol addiction feels so impossibly hard—and it suggests potential new avenues for treatment.
Brain Changes Linked to Long-Term Alcohol Use
Researchers pinpointed specific gene expression imbalances tied to alcohol use disorder, offering clues to relapse vulnerability.
- Chronic alcohol consumption alters gene expression in the prefrontal cortex and nucleus accumbens.
- The endocannabinoid system, crucial for reward and motivation, is significantly impacted.
- Changes in CB1 receptor gene expression are linked to increased relapse risk.
- Alterations in CB2 receptor gene expression may weaken the brain’s defenses against alcohol-induced damage.
“Alcohol use disorder is one of the leading causes of disease and death worldwide, yet despite its enormous social and health impact, available treatment options remain limited,” explains Jorge Manzanares, a professor at Miguel Hernández University of Elche (UMH). “Understanding what changes in the brain after decades of alcohol consumption is essential for developing more effective therapies,” he added.
Q: How does long-term alcohol use affect the brain?
A: The study shows that chronic alcohol consumption causes significant changes in gene expression within key brain regions, particularly those involved in reward processing, impulse control, and decision-making, ultimately impacting an individual’s vulnerability to relapse.
The Endocannabinoid System’s Role
To investigate, researchers analyzed post-mortem brain tissue from individuals who had consumed alcohol chronically for an average of 35 years. Their focus was the endocannabinoid system—a complex network influencing reward, motivation, and addictive behaviors. This system, which regulates pleasure, mood, memory, and stress response, comprises receptors (including CB1 and CB2), endogenous ligands, and enzymes like FAAH and MGLL. “This system acts as a fine-tuned modulator of brain activity and plays a central role in reward and motivation,” Manzanares explained.
While previous research suggested a link between alcohol and the endocannabinoid system, detailed evidence from human brain tissue was lacking. This study provides a clearer picture of how chronic alcohol use alters the expression of key endocannabinoid genes in brain regions critical to addiction.
Focus on the Mesocorticolimbic System
The research team examined two key components of the mesocorticolimbic system: the prefrontal cortex, responsible for judgment, planning, and decision-making, and the nucleus accumbens, a central hub for reward processing and habit formation.
Compared to control samples from individuals without addiction, brain tissue from those with alcohol use disorder exhibited marked gene expression imbalances. Expression of the CB1 receptor gene increased by 125% in the prefrontal cortex and by 78% in the nucleus accumbens. “CB1 is closely linked to reinforcement of addictive behaviors and relapse risk,” explained María Salud García-Gutiérrez, a UMH professor and first author of the study.
Conversely, expression of the CB2 receptor gene decreased by approximately 50% in both brain regions. “Because CB2 has neuroprotective and anti-inflammatory functions, its reduction suggests a weakening of the brain’s defenses against alcohol-induced damage,” García-Gutiérrez noted.
Uncovering Changes in GPR55 and FAAH
The study also revealed alterations in GPR55, a receptor previously considered an “orphan” due to uncertainty about its natural ligand. GPR55 expression increased by 19% in the prefrontal cortex but dropped by 51% in the nucleus accumbens. This marks the first documentation of changes in GPR55 gene expression in humans with alcohol use disorder.
Researchers also detected region-specific changes in FAAH, the enzyme responsible for breaking down anandamide, an endocannabinoid involved in anxiety and reward. FAAH gene expression was reduced in the prefrontal cortex but increased by 24% in the nucleus accumbens, potentially altering endocannabinoid availability and signaling.
The researchers utilized brain tissue samples from the New South Wales Tissue Resource Centre in Australia, a key strength of the study. All samples came from individuals with chronic alcohol use disorder who did not consume other illicit drugs, allowing researchers to isolate the specific effects of alcohol on the human brain. “This approach provides a much clearer picture of how alcohol alone reshapes gene expression in brain regions central to addiction,” García-Gutiérrez explained.
The authors believe these findings help explain the increased relapse vulnerability and impaired executive control observed in individuals with alcohol use disorder. Identifying which components of the endocannabinoid system are altered, and where in the brain these changes occur, could pave the way for more targeted and personalized therapeutic strategies.
Reference: García‐Gutiérrez MS, Torregrosa AB, Navarrete F, Aracil‐Fernández A, Rubio G, Manzanares J. Endocannabinoid system gene expression in mesocorticolimbic brain regions of individuals with alcohol use disorder: A descriptive study. Addiction. 2025:add.70293. doi: 10.1111/add.70293
