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Chapter 480IntroductionRare genetic neurodevelopmental disorders (RGNDs) affect up to 3% of the population.1 RGNDs are often associated with intellectual disability (ID) and psychiatric comorbidity, including autism spectrum disorder (ASD), and attention-deficit hyperactivity disorder (ADHD), that may result in behavioral manifestations such as irritability, aggression, and self-injurious behavior. Often, these behavioral manifestations pose a great challenge to treating physicians and caregivers as they are refractory to standard psychological, contextual, and pharmacological interventions, and necessitate intensive individual guidance and care. Consequently, these manifestations are associated with the quality of life of not only patients, but also their families, caregivers as well as society. Therefore, there is an urgent unmet need for novel interventional treatment approaches.2Over the last decade, a renewed clinical interest in the use of medicinal cannabis has resulted in promising effects for several indications,3,4 such as treatment of epilepsy.5,6 Recently, CBD (Epidyolex®) has been approved by the European Medicines Agency (EMA) to treat refractory epilepsy associated with TSC, Lennox-Gastaut syndrome and Dravet syndrome in patients aged two years and older.7 There are also indications of efficacy of CBD for severe behavioral manifestations in ID and RGNDs,8–10 with a favorable side-effect profile compared to currently used medication, such as antipsychotics.11,12 Additionally, anecdotal reports of families describe a calming effect of medicinal cannabis in some children. As it will be available due to recent market approval, it is important to examine the effectiveness of CBD on behavioral manifestations in RGNDs considering the increasing interest in CBD and urge to treat behavioral problems.The exact mechanisms of action of CBD are unknown, but previous studies suggest that CBD interacts with many signaling systems, including antagonism of GPR55, desensitization of TRPV1 channels, inhibition of adenosine reuptake, and has neuroprotective and anti-inflammatory effects.5,6 CBD also affects serotonin 5HT1A signal transduction, gammaaminobutyric acid (GABA) receptor signaling, and dopamine receptor signaling, processes that are implicated in behavior. Furthermore, CBD is Annelieke Muller sHL.indd 80 14-11-2023 09:07