Cannabinoid treatment for the symptoms of autism spectrum disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting approximately 3% of school-age children. The core symptoms are deficits in social communication and restricted and repetitive patterns of behavior. Associated problems in cognition, language, behavior, sleep and mood are prevalent. Currently, no established pharmacological treatment exists for core ASD symptoms. Risperidone and aripiprazole are used to manage associated irritability, but their effectiveness is limited and adverse events are common. AREAS COVERED: This mini-review summarizes existing scientific literature and ongoing clinical trials concerning cannabinoid treatment for ASD. Uncontrolled case series have documented improvements in both core ASD symptoms and related behavioral challenges in children treated with cannabis extracts rich in cannabidiol (CBD). Placebo-controlled studies involving CBD-rich cannabis extracts and/or pure CBD in children with ASD have demonstrated mixed efficacy results. A similar outcome was observed in a placebo-controlled study of pure CBD addressing social avoidance in Fragile X syndrome. Importantly, these studies have shown relatively high safety and tolerability. EXPERT OPINION: While current clinical data suggest the potential of CBD and CBD-rich cannabis extract in managing core and behavioral deficits in ASD, it is prudent to await the results of ongoing placebo-controlled trials before considering CBD treatment for ASD.

Mediators of Placebo Response to Cannabinoid Treatment in Children with Autism Spectrum Disorder.

The placebo response has a substantial impact on treatment outcome. However, data regarding mediators of the placebo response in children with autism spectrum disorder (ASD) are sparse. This retrospective study investigated possible mediators of the placebo response among participants of a placebo-controlled trial of cannabinoid treatment for behavioral problems in children with ASD (CBA trial, age 5-21 years). We used a specifically designed questionnaire to explore possible mediators of the placebo response in 88 participants of the CBA trial who received a placebo and had valid outcome scores. The parents of 67 participants completed the questionnaire. The placebo response was positively associated with the child's comprehension of the treatment purpose (p = 0.037). There was also a trend for participants who had a relative aggravation of symptoms before treatment onset to improve following placebo treatment (p = 0.053). No other domains, including parental expectations, previous positive experience with similar treatments (behavioral conditioning), parental locus of control, quality of the patient-physician relationships, and adherence to study medications were associated with placebo-response. This finding suggests that efforts to explain the treatment purpose to children with disabilities may enhance treatment efficacy in clinical practice and decrease differences in the placebo response between study arms. Contrary to our hypothesis, parental expectations regarding cannabinoid treatment were not associated with the placebo response.

A Placebo-Controlled Trial of Cannabinoid Treatment for Disruptive Behavior in Children and Adolescents with Autism Spectrum Disorder: Effects on Sleep Parameters as Measured by the CSHQ.

Autism spectrum disorder (ASD) is often associated with debilitating sleep disturbances. While anecdotal evidence suggests the positive effect of cannabinoids, randomized studies are lacking. Here, we report the effects of cannabinoid treatment on the sleep of 150 children and adolescents with ASD, as part of a double-blind, placebo-controlled study that assessed the impact of cannabinoid treatment on behavior (NCT02956226). Participants were randomly assigned to one of the following three treatments: (1) whole-plant cannabis extract, containing cannabidiol (CBD) and Δ9-Tetrahydrocannabinol (THC) in a 20:1 ratio, (2) purified CBD and THC extract in the same ratio, and (3) an oral placebo. After 12 weeks of treatment (Period 1) and a 4-week washout period, participants crossed over to a predetermined, second 12-week treatment (Period 2). Sleep disturbances were assessed using the Children's Sleep-Habit Questionnaire (CSHQ). We found that the CBD-rich cannabinoid treatment was not superior to the placebo treatment in all aspects of sleep measured by the CSHQ, including bedtime resistance, sleep-onset delay, and sleep duration. Notably, regardless of the treatment (cannabinoids or placebo), improvements in the CSHQ total score were associated with improvements in the autistic core symptoms, as indicated by the Social Responsiveness Scale total scores (Period 1: r = 0.266, p = 0.008; Period 2: r = 0.309, p = 0.004). While this study failed to demonstrate that sleep improvements were higher with cannabinoids than they were with the placebo treatment, further studies are required.

Interaction between Preterm White Matter Injury and Childhood Thalamic Growth.

OBJECTIVE: The purpose of this study was to determine how preterm white matter injury (WMI) and long-term thalamic growth interact to predict 8-year neurodevelopmental outcomes. METHODS: A prospective cohort of 114 children born at 24 to 32 weeks' gestational age (GA) underwent structural and diffusion tensor magnetic resonance imaging early in life (median 32 weeks), at term-equivalent age and at 8 years. Manual segmentation of neonatal WMI was performed on T1-weighted images and thalamic volumes were obtained using the MAGeT brain segmentation pipeline. Cognitive, motor, and visual-motor outcomes were evaluated at 8 years of age. Multivariable regression was used to examine the relationship among neonatal WMI volume, school-age thalamic volume, and neurodevelopmental outcomes. RESULTS: School-age thalamic volumes were predicted by neonatal thalamic growth rate, GA, sex, and neonatal WMI volume (p < 0.0001). After accounting for total cerebral volume, WMI volume remained associated with school-age thalamic volume (ß = -0.31, p = 0.005). In thalamocortical tracts, fractional anisotropy (FA) at term-equivalent age interacted with early WMI volume to predict school-age thalamic volumes (all p < 0.02). School-age thalamic volumes and neonatal WMI interacted to predict full-scale IQ (p = 0.002) and adverse motor scores among those with significant WMI (p = 0.01). Visual-motor scores were predicted by thalamic volumes (p = 0.04). INTERPRETATION: In very preterm-born children, neonatal thalamic growth and WMI volume predict school-age thalamic volumes. The emergence at term of an interaction between FA and WMI to impact school-age thalamic volume indicates dysmaturation as a mechanism of thalamic growth failure. Cognition is predicted by the interaction of WMI and thalamic growth, highlighting the need to consider multiple dimensions of brain injury in these children. ANN NEUROL 2021;90:584-594.

Medical Cannabis in Children.

The use of medical cannabis in children is rapidly growing. While robust evidence currently exists only for pure cannabidiol (CBD) to treat specific types of refractory epilepsy, in most cases, artisanal strains of CBD-rich medical cannabis are being used to treat children with various types of refractory epilepsy or irritability associated with autism spectrum disorder (ASD). Other common pediatric disorders that are being considered for cannabis treatment are Tourette syndrome and spasticity. As recreational cannabis use during youth is associated with serious adverse events and medical cannabis use is believed to have a relatively high placebo effect, decisions to use medical cannabis during childhood and adolescence should be made with caution and based on evidence. This review summarizes the current evidence for safety, tolerability, and efficacy of medical cannabis in children with epilepsy and in children with ASD. The main risks associated with use of Δ9-tetrahydrocannabinol (THC) and CBD in the pediatric population are described, as well as the debate regarding the use of whole-plant extract to retain a possible "entourage effect" as opposed to pure cannabinoids that are more standardized and reproducible.

Predicting developmental outcomes in preterm infants: A simple white matter injury imaging rule.

OBJECTIVE: To develop a simple imaging rule to predict neurodevelopmental outcomes at 4.5 years in a cohort of preterm neonates with white matter injury (WMI) based on lesion location and examine whether clinical variables enhance prediction. METHODS: Sixty-eight preterm neonates born 24-32 weeks' gestation (median 27.7 weeks) were diagnosed with WMI on early brain MRI scans (median 32.3 weeks). 3D T1-weighted images of 60 neonates with 4.5-year outcomes were reformatted and aligned to the posterior commissure-eye plane and WMI was classified by location: anterior or posterior-only to the midventricle line on the reformatted axial plane. Adverse outcomes at 4.5 years were defined as Wechsler Preschool and Primary Scale of Intelligence full-scale IQ <85, cerebral palsy, or Movement Assessment Battery for Children, second edition percentile <5. The prediction of adverse outcome by WMI location, intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), and retinopathy of prematurity (ROP) was assessed using multivariable logistic regression. RESULTS: Six children had adverse cognitive outcomes and 17 had adverse motor outcomes. WMI location predicted cognitive outcomes in 90% (area under receiver operating characteristic curve [AUC] 0.80) and motor outcomes in 85% (AUC 0.75). Adding IVH, BPD, and ROP to the model enhances the predictive strength for cognitive and motor outcomes (AUC 0.83 and 0.88, respectively). Rule performance was confirmed in an independent cohort of children with WMI. CONCLUSIONS: WMI on early MRI can be classified by location to predict preschool age outcomes in children born preterm. The predictive value of this WMI classification is enhanced by considering clinical factors apparent by term-equivalent age.

Association of Socioeconomic Status and Brain Injury With Neurodevelopmental Outcomes of Very Preterm Children.

Importance: Studies of socioeconomic status and neurodevelopmental outcome in very preterm neonates have not sensitively accounted for brain injury. Objective: To determine the association of brain injury and maternal education with motor and cognitive outcomes at age 4.5 years in very preterm neonates. Design, Setting, and Participants: Prospective cohort study of preterm neonates (24-32 weeks' gestation) recruited August 16, 2006, to September 9, 2013, at British Columbia Women's Hospital in Vancouver, Canada. Analysis of 4.5-year outcome was performed in 2018. Main Outcomes and Measures: At age 4.5 years, full-scale IQ assessed using the Wechsler Primary and Preschool Scale of Intelligence, Fourth Edition, and motor outcome by the percentile score on the Movement Assessment Battery for Children, Second Edition. Results: Of 226 survivors, neurodevelopmental outcome was assessed in 170 (80 [47.1%] female). Based on the best model to assess full-scale IQ accounting for gestational age, standardized ß coefficients demonstrated the effect size of maternal education (standardized ß = 0.21) was similar to that of white matter injury volume (standardized ß = 0.23) and intraventricular hemorrhage (standardized ß = 0.23). The observed and predicted cognitive scores in preterm children born to mothers with postgraduate education did not differ in those with and without brain injury. The best-performing model to assess for motor outcome accounting for gestational age included being small for gestational age, severe intraventricular hemorrhage, white matter injury volume, and chronic lung disease. Conclusions and Relevance: At preschool age, cognitive outcome was comparably associated with maternal education and neonatal brain injury. The association of brain injury with poorer cognition was attenuated in children born to mothers of higher education level, suggesting opportunities to promote optimal outcomes.