Oligodendrocytes produce central nervous system myelin and provide metabolic support to axons. Myelin formation and repair are energetically expensive and oligodendrocyte metabolic defects have been postulated as a cause of neurodegeneration. Endocannabinoids modulate neuronal and astroglial metabolism and attenuate inflammatory demyelination in multiple sclerosis (MS) through the activation of CB1 receptors (CB1Rs). Myelinating oligodendrocytes and precursor cells (OPCs) express CB1Rs that mediate protection from excitotoxicity and promote lineage progression but the metabolic implications of these effects in health and disease remains uncertain. Here we investigated the role of CB1Rs in oligodendrocyte (patho)physiology by analyzing the effects of cannabinoid-modulating drugs on energy metabolism in oligodendrocytes in vitro and the phenotype of mice lacking oligodendrocyte CB1Rs in the experimental autoimmune encephalomyelitis (EAE) model of MS.Seahorse analysis revealed inhibitory effects of the CB1R agonist ACEA on mitochondrial respiration (OCR) and extracellular acidification rate (ECAR) in oligodendrocyte cultures. The selective antagonist AM251 prevented the inhibitory effect of ACEA on maximal OCR thus supporting a role for oligodendrocyte CB1Rs in mitochondrial respiration. On the other hand, conditional mutants lacking CB1Rs in OPCs (NG2-CB1R-KO) or oligodendrocytes (PLP-CB1R-KO) developed EAE with similar severity as their littermate controls. Consistently, histological characterization of lesion load and neuroinflammation did not reveal differences between NG2-CB1R-KO or PLP-CB1R-KO mutants and wild-type controls. These results suggest that CB1Rs modulate mitochondrial respiration in oligodendroglia lineage but do not engage endogenous protection from autoimmune demyelination.Funded by the ISCIII (PI21/00629) and co-funded by the European Union, the Basque Government (PIBA_2023_1_0046) and ARSEP Foundation.