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. 2025 Sep;182(18):4236-4261.
doi: 10.1111/bph.70070. Epub 2025 May 27.

Cannabidiol dose dependently reduces alcohol intake in mice via a non-5-HT1A receptor mechanism: Exploration of other potential receptor targets

Connie J Badolato  1   2 , Erin A Lynch  1   2 , Jonathon C Arnold  1   3   4 , Iain S McGregor  1   3 , Michael T Bowen  1   2
Affiliations

Cannabidiol dose dependently reduces alcohol intake in mice via a non-5-HT1A receptor mechanism: Exploration of other potential receptor targets

Connie J Badolato et al. Br J Pharmacol. 2025 Sep.

Abstract

Background and purpose: Binge drinking is a risky pattern of alcohol intake and a major predictor of alcohol use disorder (AUD). Current AUD medications have limited efficacy and poor patient compliance, calling for more effective therapeutics. Cannabidiol (CBD), a non-intoxicating component of cannabis, has emerged as a potential novel therapeutic. However, receptor mechanisms in CBD's alcohol-related effects have not been investigated comprehensively.

Experimental approach: Using the murine drinking-in-the-dark model of binge drinking, our research aimed to confirm a reduction of alcohol consumption with CBD (7.5, 15, 30, 60, 120 mg kg-1) in male and female mice. Behavioural pharmacological approaches were used to explore CBD interactions with identified target mechanisms: serotonin-1A receptor (5-HT1AR) and peroxisome proliferator-activated receptor-gamma (PPARɣ), and the novel targets, chemokine receptor type-4 (CXCR4) and neuropeptide S receptor (NPSR).

Key results: Acute CBD dose dependently suppressed binge-like drinking and blood ethanol concentration. The effect was not driven by locomotor impairments and was maintained across sub-chronic treatment. Blockade of 5-HT1AR and PPARɣ had no impact on CBD's reduction of alcohol consumption. Co-administration of subthreshold CBD doses and a NPSR antagonist implicated NPSR blockade as a potential mechanism contributing to CBD's effect, whereas co-administration of CBD and a CXCR4 antagonist suggested CXCR4 was not involved. However, the potent and selective CXCR4 antagonist AMD3100 reduced ethanol consumption.

Conclusions and implications: CBD represents a promising candidate to reduce voluntary alcohol consumption. Mechanisms driving CBD's alcohol-related effects remain unclear and may involve polypharmacology, including actions at the NPSR identified in the present study.

Keywords: alcohol use disorder; cannabidiol; chemokine receptor type 4; drinking‐in‐the‐dark; neuropeptide S receptor; peroxisome proliferator‐activated receptor‐gamma; serotonin‐1A receptor.

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