A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX)

“Background: Fragile X syndrome (FXS) is associated with dysregulated endocannabinoid signaling and may therefore respond to cannabidiol therapy.

Design: CONNECT-FX was a double-blind, randomized phase 3 trial assessing efficacy and safety of ZYN002, transdermal cannabidiol gel, for the treatment of behavioral symptoms in children and adolescents with FXS.

Methods: Patients were randomized to 12 weeks of ZYN002 (250 mg or 500 mg daily [weight-based]) or placebo, as add-on to standard of care. The primary endpoint assessed change in social avoidance (SA) measured by the Aberrant Behavior Checklist-Community Edition FXS (ABC-CFXS) SA subscale in a full cohort of patients with a FXS full mutation, regardless of the FMR1 methylation status. Ad hoc analyses assessed efficacy in patients with ≥ 90% and 100% methylation of the promoter region of the FMR1 gene, in whom FMR1 gene silencing is most likely.

Results: A total of 212 patients, mean age 9.7 years, 75% males, were enrolled. A total of 169 (79.7%) patients presented with ≥ 90% methylation of the FMR1 promoter and full mutation of FMR1. Although statistical significance for the primary endpoint was not achieved in the full cohort, significant improvement was demonstrated in patients with ≥ 90% methylation of FMR1 (nominal P = 0.020). This group also achieved statistically significant improvements in Caregiver Global Impression-Change in SA and isolation, irritable and disruptive behaviors, and social interactions (nominal P-values: P = 0.038, P = 0.028, and P = 0.002). Similar results were seen in patients with 100% methylation of FMR1. ZYN002 was safe and well tolerated. All treatment-emergent adverse events (TEAEs) were mild or moderate. The most common treatment-related TEAE was application site pain (ZYN002: 6.4%; placebo: 1.0%).

Conclusions: In CONNECT-FX, ZYN002 was well tolerated in patients with FXS and demonstrated evidence of efficacy with a favorable benefit risk relationship in patients with ≥ 90% methylation of the FMR1 gene, in whom gene silencing is most likely, and the impact of FXS is typically most severe.”

https://pubmed.ncbi.nlm.nih.gov/36434514/

https://jneurodevdisorders.biomedcentral.com/articles/10.1186/s11689-022-09466-6

Parent and Caregiver Perspectives towards Cannabidiol as a Treatment for Fragile X Syndrome

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“Cannabidiol (CBD) is a non-intoxicating chemical in cannabis plants that is being investigated as a candidate for treatment in Fragile X Syndrome (FXS), a leading known cause of inherited intellectual developmental disability. Studies have shown that CBD can reduce symptoms such as anxiety, social avoidance, hyperactivity, aggression, and sleep problems. This is a qualitative study that utilized a voluntary-anonymous survey that consisted of questions regarding demographics, medical information, the form, type, brand, dose, and frequency of CBD use, the rationale for use, the perception of effects, side effects, and costs. The full survey contained a total of 34 questions, including multiple-choice, Likert-scale, and optional free-response questions. This research revealed that there are a wide range of types, brands, and doses of CBD being administered to individuals with FXS by their parents and caregivers. There were many reasons why CBD was chosen, the most common ones being that respondents had heard positive things about CBD from members of the community, the perception that CBD had fewer side effects than other medications, and because respondents felt that CBD was a more natural substance. Most of the parents and caregivers who responded agreed that CBD improved some of the symptoms of FXS and made a positive difference overall. CBD has the therapeutic potential to help relieve some FXS symptoms. Future research is necessary to understand the benefits of CBD in FXS.”

https://pubmed.ncbi.nlm.nih.gov/36140762/

https://www.mdpi.com/2073-4425/13/9/1594

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

ijms-logo“The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems.

In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development.

The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development.

The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases.

This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.”

https://pubmed.ncbi.nlm.nih.gov/34502379/

https://www.mdpi.com/1422-0067/22/17/9472

 

“Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830475/

Possible therapeutic applications of cannabis in the neuropsychopharmacology field.

European Neuropsychopharmacology“Cannabis use induces a plethora of actions on the CNS via its active chemical ingredients, the so-called phytocannabinoids.

These compounds have been frequently associated with the intoxicating properties of cannabis preparations. However, not all phytocannabinoids are psychotropic, and, irrespective of whether they are psychotropic or not, they have also shown numerous therapeutic properties.

These properties are mostly associated with their ability to modulate the activity of an intercellular communication system, the so-called endocannabinoid system, which is highly active in the CNS and has been found altered in many neurological disorders.

Specifically, this includes the neuropsychopharmacology field, with diseases such as schizophrenia and related psychoses, anxiety-related disorders, mood disorders, addiction, sleep disorders, post-traumatic stress disorder, anorexia nervosa and other feeding-related disorders, dementia, epileptic syndromes, as well as autism, fragile X syndrome and other neurodevelopment-related disorders.

Here, we gather, from a pharmacological and biochemical standpoint, the recent advances in the study of the therapeutic relevance of the endocannabinoid system in the CNS, with especial emphasis on the neuropsychopharmacology field. We also illustrate the efforts that are currently being made to investigate at the clinical level the potential therapeutic benefits derived from elevating or inhibiting endocannabinoid signaling in animal models of neuropsychiatric disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/32057592

https://www.sciencedirect.com/science/article/abs/pii/S0924977X20300365?via%3Dihub

Effects of CBD-Enriched Cannabis sativa Extract on Autism Spectrum Disorder Symptoms: An Observational Study of 18 Participants Undergoing Compassionate Use.

Image result for frontiers in neurology“Autism Spectrum Disorders comprise conditions that may affect cognitive development, motor skills, social interaction, communication, and behavior. This set of functional deficits often results in lack of independence for the diagnosed individuals, and severe distress for patients, families, and caregivers.

There is a mounting body of evidence indicating the effectiveness of pure cannabidiol (CBD) and CBD-enriched Cannabis sativa extract (CE) for the treatment of autistic symptoms in refractory epilepsy patients. There is also increasing data support for the hypothesis that non-epileptic autism shares underlying etiological mechanisms with epilepsy.

Here we report an observational study with a cohort of 18 autistic patients undergoing treatment with compassionate use of standardized CBD-enriched CE (with a CBD to THC ratio of 75/1).

Among the 15 patients who adhered to the treatment (10 non-epileptic and five epileptic) only one patient showed lack of improvement in autistic symptoms. Due to adverse effects, three patients discontinued CE use before 1 month.

After 6-9 months of treatment, most patients, including epileptic and non-epileptic, showed some level of improvement in more than one of the eight symptom categories evaluated: Attention Deficit/Hyperactivity Disorder; Behavioral Disorders; Motor Deficits; Autonomy Deficits; Communication and Social Interaction Deficits; Cognitive Deficits; Sleep Disorders and Seizures, with very infrequent and mild adverse effects.

The strongest improvements were reported for Seizures, Attention Deficit/Hyperactivity Disorder, Sleep Disorders, and Communication and Social Interaction Deficits. This was especially true for the 10 non-epileptic patients, nine of which presented improvement equal to or above 30% in at least one of the eight categories, six presented improvement of 30% or more in at least two categories and four presented improvement equal to or above 30% in at least four symptom categories.

Ten out of the 15 patients were using other medicines, and nine of these were able to keep the improvements even after reducing or withdrawing other medications.

The results reported here are very promising and indicate that CBD-enriched CE may ameliorate multiple ASD symptoms even in non-epileptic patients, with substantial increase in life quality for both ASD patients and caretakers.”

https://www.ncbi.nlm.nih.gov/pubmed/31736860

“The findings presented here, taken together, support the notion that many autism symptoms are associated to neuronal hyperexcitability, and indicate that CBD-enriched CE yields positive effects in multiple autistic symptoms, without causing the typical side effects found in medicated ASD patients. Most patients in this study had improved symptoms even after supervised weaning of other neuropsychiatric drugs.”

https://www.frontiersin.org/articles/10.3389/fneur.2019.01145/full

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.

 

Image result for journal of neurodevelopmental disorders“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.

RESULTS:

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.

CONCLUSIONS:

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.”

https://www.ncbi.nlm.nih.gov/pubmed/31370779

https://jneurodevdisorders.biomedcentral.com/articles/10.1186/s11689-019-9277-x

Cannabidiol (CBD) reduces anxiety-related behavior in mice via an FMRP1-independent mechanism.

Pharmacology Biochemistry and Behavior

“Fragile X Syndrome is a neurodevelopmental disorder which affects intellectual, social and physical development due to mutation of the Fragile X mental retardation 1 (FMR1) gene. The resultant loss of Fragile X mental retardation protein can be modelled by Fmr1 gene knockout (KO) in mice.

The current study investigated the behavioural effects of cannabidiol (CBD; a non-psychoactive phytocannabinoid) in male Fmr1 KO mice as a preclinical model for therapeutic discovery.

Overall, acute CBD at the doses chosen did not selectively normalize behavioural abnormalities in Fmr1 KO mice, but reduced anxiety-like behaviour in both Fmr1 KO and WT mice.” https://www.ncbi.nlm.nih.gov/pubmed/31063743

“Acute cannabidiol (CBD) decreased anxiety-related behaviours in both Fmr1 knockout mice and wildtype controls in the elevated plus maze. Fmr1 KO mice were hyperlocomotive, showed fewer anxiety-related behaviours and habituated more slowly to a novel environment than controls. Acute CBD had no impact on locomotion, spatial working memory or fear-associated memory in Fmr1 knockout mice or controls.”   https://www.sciencedirect.com/science/article/pii/S0091305718306464?via%3Dihub

Treatment of Fragile X Syndrome with Cannabidiol: A Case Series Study and Brief Review of the Literature.

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“Fragile X syndrome (FXS) is an X-linked dominant disorder caused by a mutation in the fragile X mental retardation 1 gene.

Cannabidiol (CBD) is an exogenous phytocannabinoid with therapeutic potential for individuals with anxiety, poor sleep, and cognitive deficits, as well as populations with endocannabinoid deficiencies, such as those who suffer from FXS.

The objective of this study was to provide a brief narrative review of recent literature on endocannabinoids and FXS and to present a case series describing three patients with FXS who were treated with oral CBD-enriched (CBD+) solutions.

We review recent animal and human studies of endocannabinoids in FXS and present the cases of one child and two adults with FXS who were treated with various oral botanical CBD+ solutions delivering doses of 32.0 to 63.9 mg daily. Multiple experimental and clinical models of FXS combine to highlight the therapeutic potential of CBD for management of FXS.

All three patients described in the case series exhibited functional benefit following the use of oral CBD+ solutions, including noticeable reductions in social avoidance and anxiety, as well as improvements in sleep, feeding, motor coordination, language skills, anxiety, and sensory processing. Two of the described patients exhibited a reemergence of a number of FXS symptoms following cessation of CBD+ treatment (e.g., anxiety), which then improved again after reintroduction of CBD+ treatment. Findings highlight the importance of exploring the therapeutic potential of CBD within the context of rigorous clinical trials.”

“The present findings, coupled with the available preclinical data, highlight the potential for CBD as an intervention for individuals with FXS. The existing literature combines to demonstrate that CBD may positively impact individuals with FXS through many mechanisms, including the endocannabinoid system, GABA, and serotonin. While a number of drugs have been developed to target specific systems (e.g., GABA agonists), CBD has the potential to yield a multifaceted benefit to individuals with FXS due to its multiple mechanisms of action.”

Perspectives on the Role of Endocannabinoids in Autism Spectrum Disorders.

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“Autism spectrum disorders (ASDs) are diagnosed on the basis of three behavioral features, namely, (1) deficits in social communication, (2) absence or delay in language and (3) stereotypy. The consensus regarding the neurological pathogenesis of ASDs is aberrant synaptogenesis and synapse function. Further, it is now widely accepted that ASD is neurodevelopmental in nature, placing emphasis on derangements occurring at the level of intra- and intercellular signaling during corticogenesis. At present, there is an ever-growing list of mutations in putative susceptibility genes in affected individuals, preventing effective transformation of knowledge gathered from basic science research to the clinic. In response, the focus of ASD biology has shifted toward the identification of cellular signaling pathways that are common to various ASD-related mutations in hopes that these shared pathways may serve as more promising treatment targets than targeting individual genes or proteins. To this end, the endogenous cannabinoid (endocannabinoid, eCB) system has recently emerged as a promising therapeutic target in the field of ASD research. The eCB system is altered in several neurological disorders, but the role of these bioactive lipids in ASD etiology remains poorly understood. In this perspective, we review current evidence linking eCB signaling to ASDs and put forth the notion that continued focus on eCBs in autism research may provide valuable insight into pathophysiology and treatment strategies. In addition to its role in modulating transmitter release at mature synapses, the eCB signaling system plays important roles in many aspects of cortical development, and disruption of these effects of eCBs may also be related to ASD pathophysiology.”

https://www.ncbi.nlm.nih.gov/pubmed/30854511

“Advances in our understanding of eCB actions will undoubtedly facilitate pharmacological interventions and further, provide patients the best quality of life possible.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407886/

Lower circulating endocannabinoid levels in children with autism spectrum disorder.

 Image result for bmc molecular autism

“The endocannabinoid system (ECS) is a major regulator of synaptic plasticity and neuromodulation. Alterations of the ECS have been demonstrated in several animal models of autism spectrum disorder (ASD). In some of these models, activating the ECS rescued the social deficits. Evidence for dysregulations of the ECS in human ASD are emerging, but comprehensive assessments and correlations with disease characteristics have not been reported yet.

METHODS:

Serum levels of the main endocannabinoids, N-arachidonoylethanolamine (AEA or anandamide) and 2-arachidonoylglycerol (2-AG), and their related endogenous compounds, arachidonic acid (AA), N-palmitoylethanolamine (PEA), and N-oleoylethanolamine (OEA), were analyzed by liquid chromatography/tandem mass spectrometry in 93 children with ASD (age = 13.1 ± 4.1, range 6-21; 79% boys) and 93 age- and gender-matched neurotypical children (age = 11.8 ± 4.3, range 5.5-21; 79% boys). Results were associated with gender and use of medications, and were correlated with age, BMI, and adaptive functioning of ASD participants as reflected by scores of Autism Diagnostic Observation Schedule (ADOS-2), Vineland Adaptive Behavior Scale-II (VABS-II), and Social Responsiveness Scale-II (SRS-2).

RESULTS:

Children with ASD had lower levels (pmol/mL, mean ± SEM) of AEA (0.722 ± 0.045 vs. 1.252 ± 0.072, P < 0.0001, effect size 0.91), OEA (17.3 ± 0.80 vs. 27.8 ± 1.44, P < 0.0001, effect size 0.94), and PEA (4.93 ± 0.32 vs. 7.15 ± 0.37, P < 0.0001, effect size 0.65), but not AA and 2-AG. Serum levels of AEA, OEA, and PEA were not significantly associated or correlated with age, gender, BMI, medications, and adaptive functioning of ASD participants. In children with ASD, but not in the control group, younger age and lower BMI tended to correlate with lower AEA levels. However, these correlations were not statistically significant after a correction for multiple comparisons.

CONCLUSIONS:

We found lower serum levels of AEA, PEA, and OEA in children with ASD. Further studies are needed to determine whether circulating endocannabinoid levels can be used as stratification biomarkers that identify clinically significant subgroups within the autism spectrum and if they reflect lower endocannabinoid “tone” in the brain, as found in animal models of ASD.”

https://www.ncbi.nlm.nih.gov/pubmed/30728928

https://molecularautism.biomedcentral.com/articles/10.1186/s13229-019-0256-6