Summary: Lower brain levels of FAAH, the enzyme that breaks down the endocannabinoid anandamide (which activates the cannabinoid 1 receptor), may help sustain excessive alcohol use and increase vulnerability to alcohol use disorder (AUD).
Source: Elsevier
Heavy drinking during young adulthood raises the risk of developing alcohol use disorder (AUD), the most common substance use disorder worldwide, but not every young person who drinks heavily will develop AUD.
Previous research has identified that differences in how individuals experience alcohol—such as sensitivity to its stimulating versus sedating effects—and physiological responses can predict drinking patterns and the likelihood of progressing to AUD. However, the brain mechanisms underlying why some young heavy drinkers develop persistent harmful drinking while others do not remain poorly understood. Greater clarity about these neural factors could inform prevention and early intervention strategies.
A new peer-reviewed study in Biological Psychiatry investigates whether brain levels of endocannabinoid-related enzymes relate to hazardous alcohol use and subjective and physiological responses to alcohol in young heavy drinkers.
The study, led by Isabelle Boileau, PhD, of the Centre for Addiction and Mental Health and the University of Toronto, examined fatty acid amide hydrolase (FAAH) in young adults who reported recent episodes of heavy drinking. FAAH is the primary enzyme that degrades anandamide, an endogenous cannabinoid neurotransmitter that activates the cannabinoid 1 receptor (CB1). Anandamide and CB1 signaling influence motivation, reward, mood, appetite, and pain perception, and endocannabinoid signaling in brain regions such as the striatum and prefrontal cortex is thought to modulate alcohol’s rewarding properties.
The researchers hypothesized that lower FAAH levels—implying higher anandamide activity—would be associated with heavier, more hazardous drinking and with altered subjective and cardiovascular responses to alcohol.
To test this, the team used positron emission tomography (PET) imaging with [11C]CURB, a selective radiotracer for FAAH, to measure FAAH availability in the striatum, prefrontal cortex, and across the whole brain. The sample included 31 participants aged 19 to 25 who had at least one episode of heavy drinking in the past 30 days. The investigators also determined participants’ FAAH C385A genotype (rs324420) and assessed behavioral and cardiovascular responses during a controlled intravenous alcohol infusion in subgroups of the sample.
Key findings indicated that lower [11C]CURB binding—interpreted as reduced FAAH availability and therefore higher anandamide tone—was not significantly linked to how often participants drank, but it was associated with more severe and hazardous drinking patterns. Importantly, lower FAAH availability correlated with greater self-reported craving for alcohol before infusion, stronger reports of stimulation and “liking” during intoxication, and reduced sensitivity to alcohol’s negative, sedating effects.
During the controlled intravenous alcohol challenge, participants with lower FAAH showed heightened stimulation and urges to drink and reported less sedation. These subjective effects align with the idea that elevated endocannabinoid signaling can amplify alcohol’s rewarding or arousing effects while diminishing awareness of its impairing consequences, a pattern that could promote continued heavy drinking.
Physiologically, lower FAAH availability was also associated with reduced heart-rate variability, a marker of lower parasympathetic (vagal) activity. Reduced heart-rate variability in this context related both to greater alcohol-induced stimulation and to lower [11C]CURB binding, suggesting that endocannabinoid signaling may interact with autonomic responses to influence alcohol-related behavior.
Roughly half the sample reported a family history of AUD, but family history did not predict FAAH binding levels in this cohort.
“In our study, young adults with lower brain levels of FAAH reported greater stimulation and fewer intoxicating and sedating effects from drinking alcohol,” said Dr. Boileau. She and colleagues conclude that lower FAAH may alter the balance of positive and negative alcohol effects, increasing urge and motivation to drink and thereby contributing to the processes that underlie the development and maintenance of AUD.
John Krystal, MD, editor of Biological Psychiatry, noted that the study “provides evidence linking increased endocannabinoid levels to reduced sensitivity to the negative effects of alcohol, an important risk factor for heavy drinking and AUD.”
These results highlight FAAH and endocannabinoid signaling as a potential brain-based target for prevention and treatment strategies aimed at reducing risky drinking among young people. Future research should determine whether altered FAAH activity promotes drinking primarily by enhancing alcohol’s positive, arousing effects or by increasing tolerance to its negative effects, and whether interventions that modulate endocannabinoid signaling can reduce AUD risk.
About this alcohol use and neuroscience research news
Author: Eileen Leahy
Source: Elsevier
Contact: Eileen Leahy – Elsevier
Image: The image is in the public domain
Original Research: Closed access. “Association Between Fatty Acid Amide Hydrolase and Alcohol Response Phenotypes: A PET Imaging Study with [11C]CURB in Heavy-drinking Youth” by Isabelle Boileau et al. Biological Psychiatry
Abstract
Association Between Fatty Acid Amide Hydrolase and Alcohol Response Phenotypes: A PET Imaging Study with [11C]CURB in Heavy-drinking Youth
Background
Reductions in fatty acid amide hydrolase (FAAH), the enzyme that breaks down the endocannabinoid anandamide, may influence drinking behavior and risk for alcohol use disorder (AUD). The study tested whether lower brain FAAH levels in heavy-drinking youth relate to higher alcohol intake, more hazardous drinking, and altered subjective or physiological responses to alcohol.
Methods
FAAH levels in the striatum, prefrontal cortex, and whole brain were measured using PET imaging with [11C]CURB in 31 heavy-drinking youth aged 19–25. The FAAH C385A genotype (rs324420) was determined. Behavioral responses (n=29) and cardiovascular responses (n=22) to alcohol were assessed during a controlled intravenous alcohol infusion.
Results
Lower [11C]CURB binding was not significantly associated with drinking frequency but was positively associated with hazardous drinking and with reduced sensitivity to alcohol’s negative effects. During alcohol infusion, lower [11C]CURB binding corresponded to greater self-reported stimulation and urges to drink, and to lower sedation (p<0.05). Lower heart-rate variability correlated with both greater alcohol-induced stimulation and lower [11C]CURB binding (p<0.05). Family history of AUD did not relate to [11C]CURB binding.
Conclusions
Consistent with preclinical evidence, lower brain FAAH was linked to attenuated negative effects of alcohol, increased alcohol urges, and heightened alcohol-induced arousal. Reduced FAAH may therefore alter the balance of alcohol’s effects—either by amplifying positive, arousing responses or by promoting tolerance to negative effects—thereby contributing to increased motivation to drink and the addiction process. Further work should clarify the mechanisms by which FAAH influences drinking motivation and whether targeting FAAH or endocannabinoid signaling can prevent or treat AUD.