A phase 1/2, open-label assessment of the safety, tolerability, and efficacy of transdermal cannabidiol (ZYN002) for the treatment of pediatric fragile X syndrome
Open accessAbstract
Fragile X syndrome (FXS) is characterized by a range of developmental, neuropsychiatric, and behavioral symptoms that cause significant impairment in those with the disorder. Cannabidiol (CBD) holds promise as a potential treatment for FXS symptoms due to its safety profile and positive effects on a number of emotional and behavioral symptoms associated with FXS. The aim of the current study was to evaluate the safety, tolerability, and initial efficacy of ZYN002, a transdermal CBD gel, in a pediatric population with FXS. Twenty children and adolescents (aged 6–17 years) with a diagnosis of FXS (confirmed through molecular documentation of FMR1 full mutation) were enrolled in an open-label, multi-site, trial of ZYN002. Transdermal CBD gel was administered twice daily for 12 weeks, titrated from 50 mg to a maximum daily dose of 250 mg. The primary efficacy endpoint was change from screening to week 12 on the Anxiety, Depression, and Mood Scale (ADAMS). Secondary endpoint measures included the Aberrant Behavior Checklist—Community for FXS (ABC-CFXS), Pediatric Anxiety Rating Scale (PARS-R), Pediatric Quality of Life Inventory (PedsQL™), three Visual Analogue Scales (VAS), and the Clinical Global Impression Scale—Severity (CGI-S) and Improvement (CGI-I). The majority of treatment-emergent AEs (reported by 85% of participants) were mild in severity (70%), and no serious adverse events were reported. There was a statistically significant reduction in ADAMS total score from screening to week 12 and significant reductions on nearly all other secondary endpoints, including all ADAMS subscales (except depressed mood), all ABC-CFXS subscale scores (e.g., social avoidance, irritability), PARS-R total severity score, and PedsQL total score. ZYN002 was well tolerated and produced clinically meaningful reductions in anxiety and behavioral symptoms in children and adolescents with FXS. These findings support further study of ZYN002 in a randomized, well-controlled trial for the treatment of behavioral symptoms of FXS. ANZCTR, ACTRN12617000150347 Registered 27 January 2017
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In an open label trial of Zyn002 in children with FXS, both the primary outcome (ADAMS) and secondary measures including the ABC demonstrated efficacy.
“Both the primary outcome, the Anxiety Mood and Depression (ADAMS) scale and the secondary measures including the ABC, demonstrated efficacy.”
From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [126]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
(1976) · Medical Entomology and Zoology · Cited by 8,899 · see citing works
The PedsQL™: Measurement Model for the Pediatric Quality of Life Inventory
Varni, J. W., Seid, M., & Rode, C. A. (1999) · Medical Care · doi:10.1097/00005650-199902000-00003 · Cited by 3,291 · see citing works
The Endocannabinoid System as an Emerging Target of Pharmacotherapy
Pacher, P., Bátkai, S., & Kunos, G. (2006) · Pharmacological Reviews · doi:10.1124/pr.58.3.2 · Cited by 2,077 · see citing works
The clinical global impressions scale: applying a research tool in clinical practice.
Busner, J., & Targum, S. D. (2007) · PubMed Central · Cited by 1,952 · see citing works
The mGluR theory of fragile X mental retardation
Bear, M. F., Huber, K. M., & Warren, S. T. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2004.04.009 · Cited by 1,580 · see citing works
Kojima, K., Takata, A., Vadnais, C., Otsuka, M., Yoshikawa, T., Akanuma, M., Kondo, Y., Kang, Y. J., Kishikawa, T., Kato, N., et al. (2012) · Nature Communications · doi:10.1038/ncomms2081 · Cited by 1,284 · see citing works
Endocannabinoid Signaling and Synaptic Function
Castillo, P. E., Younts, T. J., Chávez, A. E., & Hashimotodani, Y. (2012) · Neuron · doi:10.1016/j.neuron.2012.09.020 · Cited by 1,126 · see citing works
Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia
Leweke, F. M., Piomelli, D., Pahlisch, F., Muhl, D., Gerth, C. W., Hoyer, C., Klosterkötter, J., Hellmich, M., & Koethe, D. (2012) · Translational Psychiatry · doi:10.1038/tp.2012.15 · Cited by 1,059 · see citing works
Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial
Devinsky, O., Marsh, E., Friedman, D., Thiele, E., Laux, L., Sullivan, J., Miller, I., Flamini, R., Wilfong, A., Filloux, F., et al. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(15)00379-8 · Cited by 900 · see citing works
Bergamaschi, M. M., Queiroz, R. H. C., Chagas, M. H. N., de Oliveira, D. C. G., De Martinis, B. S., Kapczinski, F., Quevedo, J., Roesler, R., Schröder, N., Nardi, A. E., et al. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.6 · Cited by 771 · see citing works
FMR1 and the fragile X syndrome: Human genome epidemiology review
Crawford, D. C., Acuña, J. M., & Sherman, S. L. (2001) · Genetics in Medicine · doi:10.1097/00125817-200109000-00006 · Cited by 711 · see citing works
Varni, J. W., Seid, M., Smith Knight, T., Burwinkle, T., Brown, J., & Szer, I. S. (2002) · Arthritis & Rheumatism · doi:10.1002/art.10095 · Cited by 535 · see citing works
The Pediatric Anxiety Rating Scale (PARS): development and psychometric properties
P, T. R. U. O. P. (2002) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-200209000-00006 · Cited by 532 · see citing works
The Pediatric Anxiety Rating Scale (PARS): Development and Psychometric Properties
Riddle, M., Ginsburg, G. S., Walkup, J., Labellarte, M. J., Pine, D. S., Davies, M., Greenhill, L., Sweeney, M., KLEIN, R. G., Abikoff, H., et al. (2002) · Institutional Research Information System University of Turin (University of Turin) · doi:10.1097/01.chi.0000020259.43550.f4 · Cited by 331 · see citing works
Cordeiro, L., Ballinger, E., Hagerman, R., & Hessl, D. (2011) · Journal of Neurodevelopmental Disorders · doi:10.1007/s11689-010-9067-y · Cited by 316 · see citing works
Elmes, M. W., Kaczocha, M., Berger, W. T., Leung, K., Ralph, B. P., Wang, L., Sweeney, J., Miyauchi, J. T., Tsirka, S. E., Ojima, I., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.618447 · Cited by 315 · see citing works
Esbensen, A. J., Rojahn, J., Aman, M. G., & Ruedrich, S. (2003) · Journal of Autism and Developmental Disorders · doi:10.1023/b:jadd.0000005999.27178.55 · Cited by 308 · see citing works
Psychometric evaluation of a visual analog scale for the assessment of anxiety
Williams, V. S., Morlock, R. J., & Feltner, D. (2010) · Health and Quality of Life Outcomes · doi:10.1186/1477-7525-8-57 · Cited by 287 · see citing works
Evaluation of the Clinical Global Impression Scale among individuals with social anxiety disorder
ZAIDER, T. I., HEIMBERG, R. G., FRESCO, D. M., SCHNEIER, F. R., & LIEBOWITZ, M. R. (2003) · Psychological Medicine · doi:10.1017/s0033291703007414 · Cited by 286 · see citing works
Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome
Jung, K., Sepers, M. D., Henstridge, C. M., Lassalle, O., Neuhofer, D. N., Martin, H. G. S., Ginger, M. R., Frick, A., DiPatrizio, N. V., Mackie, K., et al. (2012) · Nature Communications · doi:10.1038/ncomms2045 · Cited by 282 · see citing works
Wong, W. S., Chan, T. M. S., Fung, V. B., & Fielding, R. (2010) · Health and Quality of Life Outcomes · doi:10.1186/1477-7525-8-1 · Cited by 256 · see citing works
The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABA A receptors
Bakas, T., van Nieuwenhuijzen, P. S., Devenish, S. O., McGregor, I. S., Arnold, J. C., & Chebib, M. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.02.022 · Cited by 246 · see citing works
Endocannabinoid-mediated retrograde modulation of synaptic transmission
Ohno‐Shosaku, T., & Kano, M. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.03.017 · Cited by 244 · see citing works
Arbaclofen in fragile X syndrome: results of phase 3 trials
Berry-Kravis, E., Hagerman, R., Visootsak, J., Budimirovic, D., Kaufmann, W. E., Cherubini, M., Zarevics, P., Walton-Bowen, K., Wang, P., Bear, M. F., et al. (2017) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-016-9181-6 · Cited by 183 · see citing works
Sansone, S. M., Widaman, K. F., Hall, S. S., Reiss, A. L., Lightbody, A. A., Kaufmann, W. E., Berry‐Kravis, E., Lachiewicz, A. M., Brown, E. C., & Hessl, D. R. (2011) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-011-1370-2 · Cited by 177 · see citing works
Marshburn, E. C., & Aman, M. G. (1992) · Journal of Autism and Developmental Disorders · doi:10.1007/bf01048240 · Cited by 171 · see citing works
Wati, R. K., Graaf, E. D., Bogarín, D., Heijungs, R., van Vugt, R., SMETS, E. F., & Gravendeel, B. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.586345 · Cited by 156 · see citing works
Leucht, S., & Engel, R. R. (2006) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300873 · Cited by 154 · see citing works
Cannabidiol bioavailability after nasal and transdermal application: effect of permeation enhancers
Paudel, K. S., Hammell, D. C., Agu, R. U., Valiveti, S., & Stinchcomb, A. L. (2010) · Drug Development and Industrial Pharmacy · doi:10.3109/03639041003657295 · Cited by 134 · see citing works
The challenges of clinical trials in fragile X syndrome
Jacquemont, S., Berry‐Kravis, E., Hagerman, R. J., von Raison, F., Gasparini, F., Apostol, G., Ufer, M., Portes, V. D., & Gomez‐Mancilla, B. (2013) · Psychopharmacology · doi:10.1007/s00213-013-3289-0 · Cited by 125 · see citing works
Wei, D., Dinh, D., Lee, D., Li, D., Anguren, A., Moreno-Sanz, G., Gall, C. M., & Piomelli, D. (2016) · Cannabis and Cannabinoid Research · doi:10.1089/can.2015.0008 · Cited by 122 · see citing works
FAAH and anandamide: is 2-AG really the odd one out?
Marzo, V. D., & Maccarrone, M. (2008) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2008.03.001 · Cited by 107 · see citing works
EEG power at 3 months in infants at high familial risk for autism
Levin, A. R., Varcin, K. J., O’Leary, H. M., Tager-Flusberg, H., & Nelson, C. A. (2017) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-017-9214-9 · Cited by 107 · see citing works
Enhanced Endocannabinoid Signaling Elevates Neuronal Excitability in Fragile X Syndrome
Zhang, L., & Alger, B. E. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0795-10.2010 · Cited by 104 · see citing works
Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence
Rohleder, C., Müller, J. K., Lange, B., & Leweke, F. M. (2016) · Frontiers in Pharmacology · doi:10.3389/fphar.2016.00422 · Cited by 94 · see citing works
Endocannabinoid system: An overview of its potential in current medical practice.
Mouslech, Z., & Valla, V. (2009) · PubMed · Cited by 83 · see citing works
Ligsay, A., Dijck, A. V., Nguyen, D. V., Lozano, R., Chen, Y., Bickel, E., Hessl, D. R., Schneider, A., Angkustsiri, K., Tassone, F., et al. (2017) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-017-9207-8 · Cited by 80 · see citing works
Steinberg, J., & Webber, C. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.09.013 · Cited by 71 · see citing works
Qin, M., Zeidler, Z., Moulton, K., Krych, L., Xia, Z., & Smith, C. B. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.05.003 · Cited by 69 · see citing works
A Comparative Meta-Analysis of Clinical Global Impressions Change in Antidepressant Trials
Spielmans, G. I., & McFall, J. P. (2006) · The Journal of Nervous and Mental Disease · doi:10.1097/01.nmd.0000244554.91259.27 · Cited by 63 · see citing works
Vig, P. J. S., Lu, D., Paul, A. M., et al. (2018) · Brain Sciences · doi:10.3390/brainsci9010001 · Cited by 63 · see citing works
Tartaglia, N. R., Bonn‐Miller, M. O., & Hagerman, R. J. (2019) · Cannabis and Cannabinoid Research · doi:10.1089/can.2018.0053 · Cited by 57 · see citing works
Self-citationWeber, J. D., Smith, E. G., Berry‐Kravis, E., Cadavid, D., Hessl, D. R., & Erickson, C. A. (2019) · Brain Sciences · doi:10.3390/brainsci9020018 · Cited by 53 · see citing works
Lozano, R., Martínez‐Cerdeño, V., & Hagerman, R. J. (2015) · Current Pharmaceutical Design · doi:10.2174/1381612821666150914121038 · Cited by 19 · see citing works
Russo‐Ponsaran, N. M., Yesensky, J. A., Hessl, D. R., & Berry‐Kravis, E. (2014) · American Journal on Intellectual and Developmental Disabilities · doi:10.1352/1944-7558-119.1.1 · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
An Update on Psychopharmacological Treatment of Autism Spectrum Disorder
Aishworiya, R., Valica, T., Hagerman, R., & Restrepo, B. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01183-1 · Cited by 233 · see citing works
- Authors
- Heussler, H., Cohen, J., Silove, N., Tich, N., Bonn-Miller, M. O., Du, W., O’Neill, C., & Sebree, T.
- Affiliations
- The University of Queensland (AU)
- Children's Hospital at Westmead (AU)
- Zynerba Pharmaceuticals (United States) (US)
- Corresponding author
- Tich, Nancy
- Venue
- Journal of Neurodevelopmental Disorders
- Published
- 2019-08-02
- Volume
- 11
- Issue
- 1
- Pages
- 16-16
- ISSN
- 1866-1947 (ISSN-L)
- 1866-1955
- PMC
- PMC6676516
- OpenAlex
- W2965554962
- Cited by
- 106
- References
- 45
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 18 · 2023: 28 · 2022: 17 · 2021: 14 · 2020: 8 · 2019: 5
- FWCI
- 6.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neurodevelopmental Disorders (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Zynbera Pharrmaceuticals
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- fragile X syndrome, cannabidiol, pediatric patients, anxiety, depression, behavioral symptoms, irritability, social avoidance, quality of life, safety and tolerability, FMR1 full mutation
- MeSH terms
- Administration, Cutaneous, Adolescent, Anxiety, Behavioral Symptoms, Cannabidiol, Child, Female, Fragile X Syndrome, Gels, Humans, Male, Treatment Outcome, Cannabinoid Receptor Modulators
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
