Effect of CANnabidiol on Anxiety and GABAergic Function in Individuals with Fragile-X Syndrome
- Conditions
- Fragile X Syndrome
- Interventions
- Drug: Placebo
- Registration Number
- NCT06261502
- Lead Sponsor
- Université de Sherbrooke
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 40
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Placebo First CBD Oral Solution 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. Placebo First Placebo 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. CBD First Placebo 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. CBD First CBD Oral Solution 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.
- Primary Outcome Measures
Name Time Method Impact of Oral CBD Solution anxiety. At baseline, 12 weeks, 20 weeks, and 32 weeks Caregivers will complete The Anxiety, Depression, and Mood Scale (ADAMS). The ADAMS consists of 29 items on a 4-point scale from 0 (behavior have not occurred or is not a problem) to 3 (behavior occurs a lot, or is a severe problem). It evaluates emotional disturbances along five dimensions: mania/hyperactivity, depressed mood, social avoidance, general anxiety, and obsessive behavior.
Impact of Oral CBD Solution on disruptive behavior At baseline, 12 weeks, 20 weeks, and 32 weeks Caregivers will complete the Aberrant Behavior Checklist-Community Fragile-X (ABC-C FX). The ABC-C FX has 55 items and is subdivided into explores 6 subdomains: irritability, hyperactivity, lethargy/withdrawal, stereotypy, inappropriate speech, and social avoidance. Higher scores reflect higher aberrant behavior.
ABC-C FX is considered the gold standard for assessing behavioral changes in clinical trials in FXS.Impact of Oral CBD Solution on Behavioral Inhibition At baseline, 12 weeks, 20 weeks, and 32 weeks Participants will complete the NIH Toolbox Cognitive Battery Flanker Task, a behavioral inhibition task validated in FXS. Global scores range from 0 to 10 and are algorithmically defined using accuracy and reaction time. Higher scores reflect better performance.
- Secondary Outcome Measures
Name Time Method Impact of Oral CBD Solution on intracortical inhibition At baseline, 12 weeks, 20 weeks, and 32 weeks TMS-derived measure of Intracortical inhibition: The degree of decrease of peak-to-peak motor evoked potential (MEP) amplitude induced by the administration of a conditioning stimulus (set at 70% of resting motor threshold) 2-4 ms before the test stimulus (stimulation intensity required to produce an MEP of 1 millivolt (mV), approximately 120% of resting motor threshold)
Impact of Oral CBD Solution on intracortical facilitation At baseline, 12 weeks, 20 weeks, and 32 weeks Transcranial magnetic stimulation (TMS) -derived measure of Intracortical facilitation: The degree of increase of peak-to-peak motor evoked potential (MEP) amplitude induced by the administration of a conditioning stimulus (set at 80% of resting motor threshold) 12-24 ms before the test stimulus (stimulation intensity required to produce an MEP of 1 mV, approximately 120% of resting motor threshold).
Impact of Oral CBD Solution on At baseline, 12 weeks, 20 weeks, and 32 weeks Estimation of GABA concentrations in the brain from magnetic resonance spectroscopy