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Chapter 9282Each disorder has its unique underlying cause, mechanism, and symptomatology. This requires targeted treatment approaches, although treatment effects may also be disorder transcending.2 For instance, a renewed clinical interest in the use of cannabidiol (CBD) has resulted in market approval by the European Medicines Agency (EMA) as add-on treatment for refractory epilepsy in Tuberous Sclerosis Complex (TSC), Dravet syndrome, and Lennox-Gastaut syndrome (GW Pharma Ltd. Epidyolex [Cannabidiol] Oral Solution). Promising findings for effectiveness for severe behavioral manifestations in RGNDs and ID have been reported as well.3–5 As this CBD product will be available due to recent market approval, evidence is needed for the effectiveness and adverse effects when used to treat behavioral manifestations. Therefore, we designed a clinical trial in three different RGNDs, based on availability, urgency and expertise of the centers and patient clinics. The proposed methodology (Chapter 4) may also be used for other RGNDs to provide evidence of the effectiveness of CBD. Although the exact mechanism of action of CBD is unclear, several mechanisms are proposed, including a specific mechanism why it might be effective in individuals with Fragile X syndrome.6,7 If this is indeed the actual working mechanism, it might support accessibility of CBD as a targeted therapy for Fragile X syndrome when positive results are found. However, it is yet unclear whether the medication will be approved and reimbursed for this indication in other individuals with RGNDs or ID of unknown cause not included in this first trial, even though it is not feasible to include all thousands of rare disorders. Without a clearly described mechanism of action, accessibility for those individuals will be hampered. Research on the efficacy of treatment strategies for RGNDs has been limited. This may result in uncertain efficacy and polypharmacy, which is considered a clinical pitfall in individuals with ID and psychiatric disorders, with the risk of causing iatrogenic comorbidity.8 There is increasing evidence for differential treatment response and tolerability for regular medication in RGNDs.9–11 Regular medication might be specifically (in)effective for particular disorders. An example can be found in vigabatrin as a treatment for epilepsy, that is specifically effective in individuals with TSC.12,13 For attention-deficit/hyperactivity disorder (ADHD), more information is needed about treatment efficacy and side effects in RGNDs. Annelieke Muller sHL.indd 282 14-11-2023 09:08