Effect of CBD on the Brain

Effect of CBD on the GABAergic System in Patients with Fragile X Syndrome.

This proposal 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). Although most individuals with FXS have moderate to severe intellectual disability (ID), caregivers are mainly concerned about aggressive behavior and anxiety problems, hallmark features of the condition. Concurrent lines of evidence suggest that targeting the endocannabinoid (eCB) system by administration of cannabidiol (CBD) could upregulate GABAergic functions and correct inhibitory deficits presumed responsible for the neuropsychiatric phenotype of FXS. However, the eCB system and its effect on the brain remains unexplored in FXS patients. This clinical trial aims to define the therapeutic relevance of the eCB system for FXS using a multimodal neuroimaging approach to finely characterize the acute effects of oral CBD on the principal inhibitory neurotransmitter system (GABA) in a large cohort of FXS patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Fragile X Syndrome
• Intervention / Treatment: Drug: CBD Oral Solution (eCBD system Target); Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: François Corbin, MD, Ph.D.; Phone Number: 15801 819-346-1110; Email: Francois.Corbin@USherbrooke.ca
• Study Contact Backup: Name: Samantha Cote; Phone Number: 70184 819-346-1110; Email: Samantha.cote@usherbrooke.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Eligibility criteria for FXS participants will include:

• age between 7 and 55 years, molecular diagnosis of FXS,
• intelligence quotient (IQ) <70,
• aberrant behavior questionnaire score (ABC-C) > 20,
• <3 psychoactive drugs, drug stable for > 3 months.

Eligibility criteria for the control group:

• 18 and 55 years old,
• be in good general health, with no history of neurological or psychiatric disorders.

Eligibility Criteria for all Participants:

• A minimum weight of 60 kg;
• no history of liver problems (A complete blood profile to measure liver enzyme levels (bilirubin, aspartate aminotransferase (AST), argininosuccinate lyase (ASL), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT)) will be obtained before randomization for all participants).

Exclusion Criteria:

• The presence of an absolute contraindication to the use of TMS and MRI / MRS (ie presence of metal in the head).
• Individuals with ALT / ASL levels greater than 3 times the upper normal baseline, or if bilirubin exceeds 2 times the upper baseline,

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CBD first; A single dose of CBD dose administered followed by a dose of placebo 3 weeks later.	Drug: CBD Oral Solution (eCBD system Target); Participants receive orally 6 ml of CBD Oral Solution (100 mg / ml; 60 mg / kg; max 600 mg of CBD) followed by 6 ml of a placebo composed of the inactive ingredients of CBD Oral Solution 3 weeks later.; Drug: Placebo; Participants receive orally 6 ml of a placebo composed of the inactive ingredients of CBD Oral Solution followed by 6 ml of Oral CBD Solution (100 mg / ml; 60 mg / kg; max 600 mg of CBD)
Experimental: Placebo first; A single dose of placebo dose administered followed by a dose of CBD 3 weeks later.	Drug: CBD Oral Solution (eCBD system Target); Participants receive orally 6 ml of CBD Oral Solution (100 mg / ml; 60 mg / kg; max 600 mg of CBD) followed by 6 ml of a placebo composed of the inactive ingredients of CBD Oral Solution 3 weeks later.; Drug: Placebo; Participants receive orally 6 ml of a placebo composed of the inactive ingredients of CBD Oral Solution followed by 6 ml of Oral CBD Solution (100 mg / ml; 60 mg / kg; max 600 mg of CBD)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Short Intracortical Inhibition	Transcranial Magnetic Stimulation (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)	Comparison between pre and 2 hours post administration of Oral CBD solution and placebo

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracortical Facilitation	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).	Comparison between pre and 2 hours post administration of Oral CBD solution and placebo
Gaba concentration levels	Estimation of GABA concentrations in the brain from magnetic resonance spectroscopy (MRS)	Comparison between pre and 2 hours post administration of Oral CBD solution and placebo

Collaborators and Investigators

• Sponsor: Université de Sherbrooke
• Collaborators: Canadian Institutes of Health Research (CIHR); Centre de recherche du Centre hospitalier universitaire de Sherbrooke; Jazz Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2025
• Primary Completion (Estimated): December 15, 2027
• Study Completion (Estimated): December 15, 2027

Study Registration Dates

• First Submitted: January 26, 2024
• First Submitted That Met QC Criteria: February 7, 2024
• First Posted (Actual): February 15, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 13, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: MRI; MRS; TMS; Cannabidiol; GABA; FXS
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Pathologic Processes; Genetic Diseases, Inborn; Disease; Neurobehavioral Manifestations; Congenital Abnormalities; Heredodegenerative Disorders, Nervous System; Mental Retardation, X-Linked; Intellectual Disability; Genetic Diseases, X-Linked; Sex Chromosome Disorders; Chromosome Disorders; Syndrome; Fragile X Syndrome
• Other Study ID Numbers: 2020-3424; 236114 (Other Identifier: Health Canada); 202010PJT-451514 (Other Grant/Funding Number: Canadian Institutes of Health Research)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No