Chelsea Sestak

Background: Fragile X Syndrome (FXS) is a X-linked genetic disorder that is the leading cause (2-6%) of Autism Spectrum Disorders (ASDs).¹ FXS etiology is associated with the silencing of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene and a diminished production of Fragile X Messenger Ribonucleoprotein (FMRP), an important signaling molecule in neurodevelopment.^1,2 Lack of this protein results in altered development of neural stem cells, neurons, astrocytes, and oligodendrocytes.² FXS occurs in 1/5000 boys, 1/8000 girls, and is a life-long illness causing developmental problems and intellectual disabilities.^1,3 There is no curative treatment for FXS; thus, after genetic diagnosis, treatments focus on alleviating symptoms and comorbidities.^2,3,4 One such treatment option, cannabidiol (CBD) has been used to treat social avoidance and anxiety associated with FXS.^2,4 CBD is thought to function through regulation of the endocannabinoid system, a paracrine neuromodulation system responsible for a negative feedback loop that promotes cessation of neuron firing in some brain areas.^2,4

Objective: In this narrative review, we inquired whether the endocannabinoid system (ECS) has a role in FXS phenotypes and whether modulation of this system may alleviate symptoms.

Search Methods: The PubMed Database was used to conduct a search from 2017-2023 using the following terms: “Fragile X Syndrome”, “cannabidiol,” “endocannabinoid system,” and “FXS treatment”.

Results: Studies indicate that the ECS regulates processes deficient in FXS, including synaptic plasticity, cognitive function, and emotional and social behaviors.^5,6 In FMR1 knockout (KO) mice, endogenous cannabinoid receptor 1 (CB1) agonists, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), were decreased in hippocampus, AEA was increased in amygdala, and 2-AG was decreased in auditory cortex association with FXS phenotypes.^6,7 Rescue supplementation or inhibition of CB1 agonist levels at each specific location normalized protein levels and alleviated FXS symptoms and anxiety-like behaviors.^6,7 CBD alters the ECS by increasing AEA and 2-AG bioavailability and preventing CB1 receptor inactivation.⁸ FMR1 KO mice administered CBD by injection showed a decrease in anxiety-like behaviors.⁹ In a phase ½ clinical trial, ZYN002 CBD transdermal gel was administered to 20 pediatric patients over the course of 12 weeks.¹⁰ Behaviors, anxiety, mood, depression, and other symptoms were assessed before and after the completion of the trial, with 18 of the 20 participants finishing the trial.¹⁰ Manic and hyperactive behavior, social avoidance, general anxiety, and compulsive behavior symptoms were markedly improved with adverse events mild in severity and resolved prior to the end of the trial.¹⁰

Conclusion: Studies have found that FXS phenotypes are in part due to alteration of ECS proteins AEA and 2-AG and modulation of this system alleviates FXS associated symptoms such as anxiety, social avoidance, and auditory hypersensitivity. CBD, through its effect on AEA and 2-AG, can similarly reduce negative behaviors in FXS phenotypes in both KO mice and pediatric FXS patients. Therefore, the endocannabinoid system is a promising site of research for future FXS therapies.

Works Cited:

1.   Salcedo-Arellano MJ, Dufour B, McLennan Y, Martinez-Cerdeno V, Hagerman R. Fragile X syndrome and associated disorders: Clinical aspects and pathology. Neurobiol Dis. 2020;136:104740. doi:10.1016/j.nbd.2020.104740
2. Richter JD, Zhao X. The molecular biology of FMRP: new insights into fragile X syndrome. Nat Rev Neurosci. 2021;22(4):209-222. doi:10.1038/s41583-021-00432-0
3. Kraan CM, Godler DE, Amor DJ. Epigenetics of fragile X syndrome and fragile X-related disorders. Dev Med Child Neurol. 2019;61(2):121-127. doi:10.1111/dmcn.13985
4. Protic D, Salcedo-Arellano MJ, Dy JB, Potter LA, Hagerman RJ. New Targeted Treatments for Fragile X Syndrome. Curr Pediatr Rev. 2019;15(4):251-258. doi:10.2174/1573396315666190625110748
5. Palumbo JM, Thomas BF, Budimirovic D, et al. Role of the endocannabinoid system in fragile X syndrome: potential mechanisms for benefit from cannabidiol treatment. J Neurodev Disord. 2023;15(1):1. Published 2023 Jan 9. doi:10.1186/s11689-023-09475-z
6. Schiavi S, Manduca A, Carbone E, et al. Anandamide and 2-arachidonoylglycerol differentially modulate autistic-like traits in a genetic model of autism based on FMR1 deletion in rats [published online ahead of print, 2022 Sep 16]. Neuropsychopharmacology. 2022;10.1038/s41386-022-01454-7. doi:10.1038/s41386-022-01454-7
7. Pirbhoy PS, Jonak CR, Syed R, et al. Increased 2-arachidonoyl-sn-glycerol levels normalize cortical responses to sound and improve behaviors in Fmr1 KO mice. J Neurodev Disord. 2021;13(1):47. Published 2021 Oct 13. doi:10.1186/s11689-021-09394-x
8. Sales AJ, Guimarães FS, Joca SRL. CBD modulates DNA methylation in the prefrontal cortex and hippocampus of mice exposed to forced swim. Behav Brain Res. 2020;388:112627. doi:10.1016/j.bbr.2020.112627
9. Zieba J, Sinclair D, Sebree T, et al. Cannabidiol (CBD) reduces anxiety-related behavior in mice via an FMRP-independent mechanism. Pharmacol Biochem Behav. 2019;181:93-100. doi:10.1016/j.pbb.2019.05.002
10. Heussler H, Cohen J, Silove N, et al. A phase 1/2, open-label assessment of the safety, tolerability, and efficacy of transdermal cannabidiol (ZYN002) for the treatment of pediatric fragile X syndrome. J Neurodev Disord. 2019;11(1):16. Published 2019 Aug 2. doi:10.1186/s11689-019-9277-x