Effect of CANnabidiol on Anxiety and GABAergic Function in Individuals with Fragile-X Syndrome (CANAX)

Université de Sherbrooke

Status and phase: Begins enrollment this month; Phase 2

Conditions: Fragile X Syndrome

Treatments: Drug: CBD Oral Solution; Drug: Placebo

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT06261502

202010PJT-451514 (Other Grant/Funding Number)

275882 (Other Identifier)

2023-4527

Details and patient eligibility

About

This study focuses on the therapeutic relevance of the endocannabinoid (eCB) system for the treatment of Fragile-X syndrome (FXS), the primary hereditary cause of autism spectrum disorder (ASD). Most individuals with FXS have moderate to severe intellectual disability (ID), and caregivers are mainly concerned about aggressive behavior and anxiety problems. Since FXS individuals have a normal lifespan, the overall lifetime cost for the Canadian society of a single case is estimated at $1.2 to $4.7 millions reaching $18 billions for all FXS cases. There is no cure for FXS, as all clinical trials so far have been unsuccessful.FXS is caused by transcriptional silencing of the Fragile X mental retardation protein (FMR1) gene, making FXS a simple model to study ASD and ID pathophysiological mechanisms. Of those, neuronal hyperexcitability is largely recognized as a core deficit in FXS, and a critical therapeutic target for the disorder. Using transcranial magnetic stimulation (TMS) in FXS patients, our team provided the first direct evidence of Gamma-aminobutyric acid (GABA) receptor a (GABAa) dysfunctions in humans with this disorder and showed that this inhibitory deficit is linked with cortical hyperexcitability (PMID: 31748507). Concurrent lines of evidence suggest that stimulation of the endocannabinoid (eCB) system with the administration of Cannabidiol (CBD) could upregulate GABAergic function and correct inhibitory deficits presumed responsible for the neuropsychiatric phenotype of FXS. CBD has been shown to increase GABA concentration levels in the brains of healthy individuals, an effect that could help correct the hyperexcitability typically found in FXS. Thus, this trial aims to define the therapeutic potential of the eCB system for FXS, by measuring the impacts of oral CBD administration on the principal inhibitory neurotransmitter system of FXS patients, and the severity of the clinical phenotype.

Enrollment: 40 estimated patients

Sex: All

Ages: 7 to 40 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Molecular diagnosis of FXS
• Age 7 to 40 inclusively
• Overall ABC-C score > 20
• Taking up to 3 psychoactive drugs
• No therapeutic change for the last 3 months

Exclusion criteria

• Taking valproic acid
• Taking clobazam
• History of liver problems
• aspartate aminotransferase (AST) or alanine transaminase (ALT), > 3 times the reference values
• Bilirubin > 2 times the reference values
• Absolute contraindication to the use of TMS and MRI (e.g. presence of metal in the body), will also be considered as an exclusion criterion.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

---

40 participants in 2 patient groups

CBD First

Experimental group

Description:

Participants will start with CBD to stimulate the eCB for 12 weeks, undergo an 8-week washout period, and then receive a 12-week placebo.

Treatment:

Drug: Placebo

Drug: CBD Oral Solution

Placebo First

Experimental group

Description:

Participants will start with a placebo for 12 weeks, undergo an 8-week washout period, and then receive a 12-week CBD to stimulate the eCB system.

Treatment:

Drug: Placebo

Drug: CBD Oral Solution