Clinical Takeaway
Transdermal cannabidiol gel (ZYN002) is being studied in an open-label extension trial to assess its long-term safety and tolerability in children and adolescents with Fragile X syndrome, a condition involving dysregulated endocannabinoid signaling. Interim findings from this ongoing study provide early real-world durability data on a synthetic CBD formulation designed for consistent transdermal absorption. This research may help clarify whether cannabidiol can be safely maintained over extended periods as a treatment for behavioral symptoms in this pediatric population.
#19 Long-term safety and tolerability of transdermal cannabidiol gel in children and adolescents with Fragile X syndrome (ZYN2-CL-017): an interim analysis of an ongoing open-label extension study.
Citation: Berry-Kravis Elizabeth et al.. Long-term safety and tolerability of transdermal cannabidiol gel in children and adolescents with Fragile X syndrome (ZYN2-CL-017): an interim analysis of an ongoing open-label extension study.. Journal of neurodevelopmental disorders. 2025. PMID: 41254489.
Design: 5 Journal: 0 N: 2 Recency: 2 Pop: 2 Human: 1 Risk: -2
This interim analysis provides critical long-term safety data for transdermal cannabidiol in a pediatric population with Fragile X syndrome, addressing a significant gap in evidence for extended use of cannabinoid therapeutics in children. Given the dysregulated endocannabinoid signaling implicated in FXS pathophysiology and the lack of effective pharmacological options for behavioral symptoms in this population, establishing the tolerability profile of ZYN002 is essential for determining its clinical utility as a potential disease-modifying treatment. The transdermal gel formulation represents a novel delivery approach that may improve medication adherence and reduce systemic exposure compared to oral cannabinoids, making safety characterization particularly relevant for this vulnerable
Quality Gate Alerts:
- Preclinical only
Methodological Considerations:
- Open-label design — placebo effect not excluded
Abstract: BACKGROUND: Dysregulated endocannabinoid signaling is involved in Fragile X syndrome (FXS), suggesting a potential role for the endocannabinoid signaling modulator, cannabidiol, in treatment. ZYN002 is a synthetic cannabidiol that has been uniquely formulated as a gel for transdermal delivery and is currently under investigation for the treatment of behavioral symptoms associated with FXS. DESIGN: ZYN2-CL-017 is an ongoing, long-term, open-label extension (OLE) safety trial of ZYN002 in patients with FXS. We are enrolling patients from past and current ZYN002 clinical trials to evaluate the safety and tolerability of ZYN002 in patients with FXS. METHODS: Primary safety assessments were conducted in patients who enrolled into the OLE from 2 completed ZYN002 trials. Secondary analyses, conducted in a subgroup enrolled from a completed placebo-controlled trial of ZYN002, included the FXS-specific Aberrant Behavior Checklist-Community Social Avoidance and Irritability subscales (ABC-CFXS SA and ABC-CFXS Irr, examined change from baseline of the randomized study) and the Caregiver Global Impression of Change (CaGI-C, examined change from baseline of the OLE), in which caregivers were asked to rate the change in their child’s overall behavior. RESULTS: At the time of this interim analysis data cut (January 31, 2024), 240 patients had been enrolled from 2 completed ZYN002 trials. Mean age at entry to the OLE was 9.7 years (range 3-17 years), and the majority were male (76.3%) and White (80.4%). Mean exposure to ZYN002 during the initial trials and OLE was 28 months. Treatment-related adverse events (AEs) were reported in 12.9% of patients; the most common (6.7% of patients) was short-term application site pain. The highest degree of skin irritation reported by investigators was moderate erythema in 7 patients (2.9%). In the secondary analysis cohort (n=196 evaluable patients), patients demonstrated clinically meaningful changes in ABC-CFXS SA, ABC-CFXS Irr, and CaGI-C scor
🧬 This interim analysis of an open-label extension trial provides valuable long-term safety data for transdermal cannabidiol in pediatric Fragile X syndrome, a condition with limited therapeutic options and theoretical endocannabinoid system involvement. However, the open-label design without a control group limits our ability to distinguish genuine drug effects from natural disease course, placebo response, or concomitant interventions, and published efficacy data from the parent randomized trial will be essential for interpreting tolerability in context. The transdermal delivery method is notable for potentially improving adherence and avoiding first-pass metabolism, though systemic exposure and pharmacokinetic variability in children warrant careful monitoring. Until we see the full efficacy and safety dataset with appropriate comparators, this work suggests cannabidiol warrants continued investigation in FXS but should not yet shift routine clinical practice; clinicians managing FXS patients may discuss cannabidiol as part of exploratory conversations about emerging options, while emphasizing that evidence remains preliminary and access may