Alcohol abuse and depression are severe comorbid psychiatric illnesses often accompanied by peripheral disorders, such as osteoporosis. Crucial members of biological membranes, ceramides, contribute to the pathogenesis of single disorders, while role of the ceramide system in their comorbidities remains unclear. We observed the specific contribution of an enzyme of the ceramide metabolism, neutral sphingomyelinase (NSM), in the comorbidity of alcohol use disorder, anxiety/depression, and osteoporosis. A genetic association analysis performed on 456,693 participants showed an association between SMPD3 gene haplotypes, coding for NSM, with alcohol consumption, depression, and bone density. Reduced NSM activity in transgenic female (Fro) mice resulted in reduced alcohol consumption, depression and anxiety levels, as well as increased hippocampal size. Alcohol diminished the advantageous behavioral phenotype and reduced the hippocampal volume. Resting state functional connectivity analysis revealed higher sensitivity of Fro mice towards chronic alcohol consumption. However, NSM did not control alcohol-induced changes in neurogenesis and neurochemical reward processing. Reduced NSM activity up-regulated blood osteocalcin level, a signalling molecule for bone mineralization. Chronic osteocalcin treatment mimicked the behavioural phenotype of Fro mice. Altogether, NSM is proposed as a joint base for the comorbidity symptom trias of alcohol addiction —depression/anxiety—osteoporosis.