Antisense oligonucleotide (AO) drugs are single-stranded synthetic RNA molecules designed to modulate the expression of target genes and offer unprecedented precision in therapeutics to treat some of the worst diseases afflicting humanity. AO therapeutics in development for treating neurological diseases use the phosphorothioate chemistry that has demonstrated inherent toxicity, including activation of innate immunity, plasma protein binding, and nuclear aggregation of RNA-binding proteins. Here, we investigate the biodistribution and safety of a different chemical class of neutral AOs called phosphorodiamidate morpholino oligomers (PMOs) for treating CNS disorders. High doses (up to 2.5 mg) of a PMO were administered into the CNS of wild-type mice via an intracisternal magna injection. To determine the regional distribution of the PMO in the CNS, we performed miRNAscope™ (ACDBio), with probes that are complementary in sequence to the PMO, on brain and spinal cord sections and showed that the PMO distributed across the CNS. No significant changes in blood biochemistry or liver and kidney histopathology were detected. We showed that high doses of a PMO in the CNS was safe and distributed to mouse CNS tissues, indicating that unconjugated PMOs at high doses may be an option for AO therapeutics treating neurological diseases.