Supplemental Methods MiceAll animal procedures were approved by the Institutional Animal Care and Use Committee of the University of North Carolina at Chapel Hill and were performed in accordance with the guidelines of the U.S. National Institutes of Health. Mice were group-housed on a 12:12 light/dark cycle with ad libitum access to food and water. Male and female mice were used for experiments in equal genotypic ratios. Mice were randomly assigned to experimental groups. Our AS mouse colony has been maintained on two different congenic background strains: 129S2/SvPasCrl (129) and C57BL/6J (B6). Dr. Ype Elgersma (Erasmus Medical Center) provided the 129 mice. B6 mice were purchased from Jackson Labs (JAX #: 016590). AS model mice (Ube3a m-/p+ ) and their wild-type (WT) littermates were generated by breeding Ube3a m+/pfemales with WT males. Drug treatmentSynthetic CBD (99.2±0.18% purity) was provided by RTI International (Log #3857-52-1). CBD was freshly prepared by dissolving in the solvent of ethanol, cremophor, and 0.9% saline at the ratio of 2:1:17. CBD or Vehicle (equal amount of solvent) was intraperitoneally (i.p.) injected at the indicated doses.

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, lack of speech, ataxia, EEG abnormalities, and epilepsy. Seizures in AS individuals are often refractory to existing antiepileptic medications. Therefore, there is an unmet need for better seizure control, which could potentially improve other symptomatic domains such as cognitive function.Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, has anti-seizure activity and behavioral benefits in preclinical and clinical studies for some disorders associated with epilepsy, suggesting that the same could be true for AS. Here we show that acute CBD (100 mg/kg) attenuated hyperthermia-and acoustically-induced seizures in a mouse model of AS. However, neither acute CBD nor a two-weeklong course of CBD administered immediately after a kindling protocol could halt the pro-epileptogenic plasticity observed in AS model mice. CBD had a mild sedative effect, but did not have a major impact on motor performance. CBD abrogated the enhanced delta rhythms observed in AS model mice, indicating that CBD administration could also help normalize the EEG deficits observed in individuals with AS. Our results provide critical preclinical evidence supporting CBD treatment of seizures and alleviation of EEG abnormalities in AS, and will thus help guide the rational development of CBD as an AS adjunctive treatment.

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