Role of the endocannabinoid system in fragile X syndrome: potential mechanisms for benefit from cannabidiol treatment

Abstract

Multiple lines of evidence suggest a central role for the endocannabinoid system (ECS) in the neuronal development and cognitive function and in the pathogenesis of fragile X syndrome (FXS). This review describes the ECS, its role in the central nervous system, how it is dysregulated in FXS, and the potential role of cannabidiol as a treatment for FXS. FXS is caused by deficiency or absence of the fragile X messenger ribonucleoprotein 1 (FMR1) protein, FMRP, typically due to the presence of >200 cytosine, guanine, guanine sequence repeats leading to methylation of the FMR1 gene promoter. The absence of FMRP, following FMR1 gene-silencing, disrupts ECS signaling, which has been implicated in FXS pathogenesis. The ECS facilitates synaptic homeostasis and plasticity through the cannabinoid receptor 1, CB1, on presynaptic terminals, resulting in feedback inhibition of neuronal signaling. ECS-mediated feedback inhibition and synaptic plasticity are thought to be disrupted in FXS, leading to overstimulation, desensitization, and internalization of presynaptic CB1 receptors. Cannabidiol may help restore synaptic homeostasis by acting as a negative allosteric modulator of CB1, thereby attenuating the receptor overstimulation, desensitization, and internalization. Moreover, cannabidiol affects DNA methylation, serotonin 5HT1A signal transduction, gamma-aminobutyric acid receptor signaling, and dopamine D2 and D3 receptor signaling, which may contribute to beneficial effects in patients with FXS. Consistent with these proposed mechanisms of action of cannabidiol in FXS, in the CONNECT-FX trial the transdermal cannabidiol gel, ZYN002, was associated with improvements in measures of social avoidance, irritability, and social interaction, particularly in patients who are most affected, showing ≥90% methylation of the FMR1 gene.

State‐of‐the‐art therapies for fragile X syndrome

“…53,54 CBD has several effects on the endocannabinoid system, influencing natural ligands like anandamide and 2-arachidonoylglycerol for cannabinoid receptors (CB1 and CB2). 55 In FXS, where FMRP is lacking, the endocannabinoid system is dysregulated, disrupting the balance of inhibitory and excitatory neurotransmitters. CBD helps by increasing 2-arachidonoylglycerol availability, preventing CB1 receptor internalization, [56][57][58] boosting anandamide levels, 59 binding to serotonin 1A receptors, 60 acting as a dopamine partial agonist, 61 and positively modulating γaminobutyric acid subtype A receptors.…”

Fragile X Syndrome as an interneuronopathy: a lesson for future studies and treatments

“…We hypothesize that metformin could have an effect also on IN development and maturation due to its effect on MMP-9 expression. In addition, cannabidiol has a positive allosteric modulation on GABA A receptors (Bakas et al, 2017), enhancing GABAergic transmission, and improves the balance in inhibitory and excitatory transmission, restoring neuronal function and synaptic plasticity in patients with FXS (Palumbo et al, 2023).…”

Phenotypic variability to medication management: an update on fragile X syndrome

“… Adapted from [ 53 , 69 , 116 – 119 ] SSRIs selective serotonin reuptake inhibitors, HMG-CoA 3-hydroxy-3-methyl glutaryl coenzyme, GABA Gamma-aminobutyric acid …”

“…The transdermal gel of CBD was applied to children with FXS and showed efficacy in reducing anxiety and improving other behavioral measures [ 138 ]. Palumbo et al [ 119 ] have recently reviewed the potential mechanisms for benefit from CBD treatment. Thus, the drug affects DNA methylation, serotonin 5HT-1A signal transduction, gamma-aminobutyric acid receptor signaling, and dopamine D2/D3 receptor signaling, which may help restore synaptic homeostasis in patients with FXS [ 119 ].…”