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Cannabidiol for severe behavioral manifestations in TSC, MPS III, and FXS814believed to interact with the endocannabinoid system in several ways,13which is involved in regulating a variety of physiological and cognitive processes.14Due to the rarity and heterogeneity of RGNDs, interventional research is challenging. In this study, three RGNDs that are characterized by severe refractory behavioral manifestations and for which CBD has been used at patients’ own initiative are Tuberous Sclerosis Complex (TSC), Sanfilippo disease or mucopolysaccharidosis type III (MPS III) and Fragile X syndrome (FXS). These are included as a result of the specific outpatient clinics at the Amsterdam UMC, and due to availability, urgency, and heterogeneity. These patient groups reflect varying neurobiological backgrounds and phenotypes. TSC, MPS III, and FXS are all associated with ID and a severe behavioral phenotype, allowing cross-disorders comparisons. This provides more insight into treatment effects and predictors for treatment response.TSC is a multisystem, autosomal dominant disorder affecting about 1:6000 children and adults.15 It is caused by a pathogenic variant in one of two genes, TSC1 (encoding hamartin) or TSC2 (encoding tuberin).16,17 TSC-associated neuropsychiatric disorders (TAND) include epilepsy (85%), ID (50%), ASD (50%), ADHD (30-50%) and behavioral problems (50%).18,19 Recently, promising results on seizures were found in a randomized, double-blind, controlled trial for CBD in TSC-related seizures in patients with drug-resistant epilepsy, with good efficacy and safety.20 The use of pharmaceutical-grade CBD in TSC, including relevant mechanism of action, efficacy and safety data, and drug-drug interactions with other anticonvulsant medication was previously described,21 and a zebrafish model of TSC has been used to examine the influence of CBD on TSC pathology.22 However, its effect on TSC-related behavioral and cognitive manifestations has not yet been explored sufficiently.21MPS III is an autosomal recessive lysosomal storage disorder caused by a deficiency of 1 of 4 enzymes involved in the degradation of the glycosaminoglycan heparan sulphate. Four types, caused by deficiencies of the different enzymes, are recognized: MPS III type A, B, C and D, with MPS IIIA the most frequent subtype.23 As a group, MPS III comprises 47% Annelieke Muller sHL.indd 81 14-11-2023 09:07