Cannabidiol (CBD) could become a therapeutic tool to address some of the most frequent and disabling consequences of fetal alcohol spectrum disorder (FASD), a condition caused by alcohol exposure during pregnancy. This is one of the main conclusions of a preclinical study conducted in mice by researchers at the Institute for Neurosciences (UMH–CSIC).
Published in Biomedicine & Pharmacotherapy , the study shows that CBD treatment normalizes emotional behavior and vulnerability to addiction in animals exposed to alcohol during the perinatal period, particularly in females. Additionally, the treatment improves gene alterations associated with the gut microbiota.
Fetal alcohol spectrum disorder is the leading preventable cause of intellectual disability worldwide. It occurs when the developing brain is exposed to alcohol at any time during pregnancy. Its consequences include learning difficulties, emotional disturbances, increased risk of anxiety and depression, impaired behavioral regulation, and, in adulthood, a higher vulnerability to addictive behaviors.
"Despite its enormous social and health impact, there is currently no approved pharmacological treatment that targets the root of the disorder. Only symptomatic interventions are available," explains Jorge Manzanares, UMH professor and principal investigator of the study. For this reason, the research team, which also includes scientists from the Institute of Agrochemistry and Food Technology (IATA–CSIC) and the University of Turku (Finland), is exploring therapeutic strategies capable of correcting the alterations produced by alcohol during development.
The relevance of the endocannabinoid system
The study focuses on the endocannabinoid system, a network of molecules and receptors that regulate essential processes, including emotion, motivation, learning, and the stress response. Previous research has shown that this system is profoundly altered after prenatal alcohol exposure, contributing to emotional disturbances and increased vulnerability to addiction.
"Cannabidiol, a non-addictive compound derived from cannabis, modulates this system and has documented neuroprotective, anti-inflammatory, and anxiolytic properties," says Manzanares. "We first characterized the emotional effects of perinatal alcohol exposure in mice, identified brain and microbiota biomarkers of alcohol damage, and then tested the effects of chronic CBD administration starting at weaning."
The researchers report that FASD not only causes direct brain alterations but also triggers systemic effects that impact gut health—and that CBD can modulate this entire cascade of dysfunction. In the experimental model, mice of both sexes exposed to alcohol during the perinatal period developed anxiety- and depressive-like behaviors. Female mice also showed increased motivation to consume alcohol.
"Early and sustained CBD administration normalized emotional alterations in both sexes," Manzanares explains. In females, CBD also eliminated vulnerability to alcohol addiction: their motivation to drink dropped to levels comparable to healthy control mice. The treatment also modulated key brain biomarkers, including dopamine D2/D3 receptors and components of the endocannabinoid system, whose dysregulation is linked to emotional and addictive disorders.
The gut–brain axis
Another significant contribution of the study is its focus on the gut–brain axis. "In both health and disease, there is constant bidirectional communication between the digestive and nervous systems that influences physical and mental health," explains Francisco Navarrete, UMH professor and first author of the study. This communication occurs via neural, hormonal, and immune pathways and is strongly influenced by the gut microbiota. The team found that developmental alcohol exposure induces intestinal dysbiosis, an imbalance in microbial composition, which CBD was able to reverse.
The treatment restored microbial diversity and increased the abundance of bacteria associated with improved gut–brain communication. These effects differed between males and females, consistent with their naturally distinct microbial profiles. "Our data suggest that part of the sex differences in vulnerability to FASD may originate in the gut rather than exclusively in the brain," Navarrete explains. The team also found sex-dependent differences in the expression of genes related to the endocannabinoid system. "These findings show that the gut microbiota plays an active role in FASD and that restoring it may help correct some of its effects on the nervous system."
The researchers emphasize that these results come from a preclinical animal model and must not be interpreted as a recommendation for self-medicating with CBD, nor as a way to counteract the effects of alcohol during pregnancy. FASD can only be prevented by altogether avoiding alcohol during pregnancy.
A well-established line of research
Professor Manzanares has studied the endocannabinoid system for more than 30 years. The Translational Neuropsychopharmacology Laboratory at the Institute for Neurosciences (UMH–CSIC), founded over 20 years ago, has been pioneering research on the role of the endocannabinoid system in addiction and its treatment. In 2023, the team conducted the first study evaluating the effects of CBD on behavioral and brain alterations in an animal model of FASD.
Research team and funding
The study was conducted by Francisco Navarrete, Jorge Manzanares, and Ani Gasparyan (Institute for Neurosciences UMH–CSIC; ISABIAL; RIAPAd–ISCIII), in collaboration with Raúl Cabrera and María del Carmen Collado (IATA–CSIC), and Richard Aarnio, Francisco López, Semi Helin, and Johan Rajander (University of Turku, Finland).
The work was funded by the Spanish Ministry of Health and the Carlos III Health Institute (projects PI21/00488 and RD21/0009/0008), ISABIAL, the Spanish Ministry of Science and Innovation (MAMI Plus project PID2022-139475OB-I00), and the Regional Government of Valencia (GenT Plan CDEIGENT 2020-02). Both IATA–CSIC and the Institute for Neurosciences UMH–CSIC also received Severo Ochoa Centre of Excellence funding (CEX2021-001189-S and CEX2021-001165-S).
