Lower circulating endocannabinoid levels in children with autism spectrum disorder.

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“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

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Oral Cannabidiol Use in Children With Autism Spectrum Disorder to Treat Related Symptoms and Co-morbidities.

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“Children with autism spectrum disorder (ASD) commonly exhibit comorbid symptoms such as aggression, hyperactivity and anxiety. Several studies are being conducted worldwide on cannabidiol use in ASD; however, these studies are still ongoing, and data on the effects of its use is very limited.

In this study we aimed to report the experience of parents who administer, under supervision, oral cannabinoids to their children with ASD.

Results: 53 children at a median age of 11 (4-22) year received cannabidiol for a median duration of 66 days (30-588). Self-injury and rage attacks (n = 34) improved in 67.6% and worsened in 8.8%. Hyperactivity symptoms (n = 38) improved in 68.4%, did not change in 28.9% and worsened in 2.6%. Sleep problems (n = 21) improved in 71.4% and worsened in 4.7%. Anxiety (n = 17) improved in 47.1% and worsened in 23.5%. Adverse effects, mostly somnolence and change in appetite were mild.

Conclusion: Parents’ reports suggest that cannabidiol may improve ASD comorbidity symptoms; however, the long-term effects should be evaluated in large scale studies.”

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Real life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy.

Scientific Reports

“There has been a dramatic increase in the number of children diagnosed with autism spectrum disorders (ASD) worldwide. Recently anecdotal evidence of possible therapeutic effects of cannabis products has emerged.

The aim of this study is to characterize the epidemiology of ASD patients receiving medical cannabis treatment and to describe its safety and efficacy.

We analysed the data prospectively collected as part of the treatment program of 188 ASD patients treated with medical cannabis between 2015 and 2017. The treatment in majority of the patients was based on cannabis oil containing 30% CBD and 1.5% THC. Symptoms inventory, patient global assessment and side effects at 6 months were primary outcomes of interest and were assessed by structured questionnaires.

After six months of treatment 82.4% of patients (155) were in active treatment and 60.0% (93) have been assessed; 28 patients (30.1%) reported a significant improvement, 50 (53.7%) moderate, 6 (6.4%) slight and 8 (8.6%) had no change in their condition. Twenty-three patients (25.2%) experienced at least one side effect; the most common was restlessness (6.6%).

Cannabis in ASD patients appears to be well tolerated, safe and effective option to relieve symptoms associated with ASD.”

https://www.ncbi.nlm.nih.gov/pubmed/30655581

https://www.nature.com/articles/s41598-018-37570-y

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Autism Spectrum Disorders: Potential Neuro-Psychopharmacotherapeutic Plant-Based Drugs.

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“Over the years, scientific researches have validated the healing benefits of many psychopharmacotherapeutic plant-based drugs to ameliorate psychiatric disorders. In contrast, the use of chemical procedures to isolate and purify specific compounds from plants that have been used to treat autism spectrum disorders (ASDs) and its clinical features may contribute to improve the quality of life of many patients. Also, herbal pharmacological treatments could improve the core symptoms of autism with fewer side effects. This review will focus on the uses and actions of phytopharmaceuticals in the behavioral conditions of ASDs. A large number of natural compound-based plant drugs have been tested in murine models of autism and in clinical trials with remarkable success in reversing the core and associated behaviors with autism such as flavonoids, cannabinoids, curcuminoids, piperine, resveratrol, and bacosides. This plant-based drug alternative is safer given that many psychiatric disorders and neurodegenerative pathologies do not often respond well to currently prescribed medications or have significant side effects. However, it is noteworthy to consider the need for large clinical trials to determine safety and efficacy. Many results are based on case reports or small size samples, and often the studies are open label. Standardization of procedures (i.e., purity and concentrations) and quality controls are strictly required to ensure the absence of side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/30427697

https://www.liebertpub.com/doi/10.1089/adt.2018.848

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Brief Report: Cannabidiol-Rich Cannabis in Children with Autism Spectrum Disorder and Severe Behavioral Problems-A Retrospective Feasibility Study.

“Anecdotal evidence of successful cannabis treatment in autism spectrum disorder (ASD) are accumulating but clinical studies are lacking. This retrospective study assessed tolerability and efficacy of cannabidiol-rich cannabis, in 60 children with ASD and severe behavioral problems (age = 11.8 ± 3.5, range 5.0-17.5; 77% low functioning; 83% boys). Efficacy was assessed using the Caregiver Global Impression of Change scale. Adverse events included sleep disturbances (14%) irritability (9%) and loss of appetite (9%). One girl who used higher tetrahydrocannabinol had a transient serious psychotic event which required treatment with an antipsychotic. Following the cannabis treatment, behavioral outbreaks were much improved or very much improved in 61% of patients. This preliminary study supports feasibility of CBD-based cannabis trials in children with ASD.”

https://www.ncbi.nlm.nih.gov/pubmed/30382443

https://link.springer.com/article/10.1007%2Fs10803-018-3808-2

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Cannabidiol as a suggested candidate for treatment of autism spectrum disorder.

 Progress in Neuro-Psychopharmacology and Biological Psychiatry “Autism Spectrum Disorder (ASD) is characterized by persistent deficits in social communication, restricted and repetitive patterns of behavior, interests, or activities and often intellectual disabilities.

No effective treatment for the core symptoms of ASD is currently available.

There is increasing interest in cannabinoids, especially cannabidiol (CBD), as monotherapy or add-on treatment for the core symptoms and co-morbidities of ASD.

In this review we summarize the available pre-clinical and clinical data regarding the safety and effectiveness of medical cannabis, including CBD, in young ASD patients.

Cannabidiol seems to be a candidate for the treatment of ASD.”

https://www.ncbi.nlm.nih.gov/pubmed/30171992

https://www.sciencedirect.com/science/article/pii/S0278584618304445?via%3Dihub

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Palmitoylethanolamide as adjunctive therapy for autism: Efficacy and safety results from a randomized controlled trial.

 Journal of Psychiatric Research Home

“Inflammation as well as glutamate excitotoxicity have been proposed to participate in the propagation of autism. Palmitoylethanolamide (PEA) is an endocannabinoid proven to prevent glutamatergic toxicity and inhibit inflammatory responses simultaneously.

The present randomized, parallel group, double-blind placebo-controlled trial is the first study depicted to probe the efficacy of co-treatment with risperidone and PEA over 10 weeks in children with autism.

Seventy children (aged 4-12 years) with autism and moderate to severe symptoms of irritability were randomly assigned to two treatment regimens. The study outcomes were measured using the Aberrant Behavior Checklist-Community Edition (ABC-C). At trial endpoint (week 10), combination of PEA and risperidone had superior efficacy in ameliorating the ABC-irritability and hyperactivity/noncompliance symptoms (Cohen’s d, 95% confidence interval (CI) = 0.94, 0.41 to 1.46, p = 0.001) compared with a risperidone plus placebo regimen. Interestingly, effect of combination treatment on hyperactivity symptoms was also observed at trial midpoint (week 5) but with a smaller effect size (d = 0.53, p = 0.04) than that at the endpoint (d = 0.94, p = 0.001). Meanwhile, there was a trend toward significance for superior effect of risperidone plus PEA over risperidone plus placebo on inappropriate speech at trial endpoint (d = 0.51, p = 0.051). No significant differences existed between the two treatment groups for the other two ABC-C subscales (lethargy/social withdrawal and stereotypic behavior).

The findings suggest that PEA may augment therapeutic effects of risperidone on autism-related irritability and hyperactivity. Future studies are warranted to investigate whether PEA can serve as a stand-alone treatment for autism.”

https://www.ncbi.nlm.nih.gov/pubmed/29807317

https://www.journalofpsychiatricresearch.com/article/S0022-3956(17)31405-X/fulltext

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Cannabidiol Based Medical Cannabis in Children with Autism- a Retrospective Feasibility Study

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“Objective: This retrospective study assessed safety, tolerability and efficacy of cannabidiol (CBD) based medical cannabis, as an adjuvant therapy, for refractory behavioral problems in children with ASD.

Background: Anecdotal evidence of successful cannabis treatment in children with autism spectrum disorder (ASD) are accumulating but formal studies are lacking.

Design/Methods: Sixty children with ASD (age = 11.8± 3.5, range 5.0–17.5; 77% low functioning; 83% boys) were treated with oral CBD and tetrahydrocannabinol (THC) at a ratio of 20:1. The dose was up-titrated to effect (maximal CBD dose − 10mg/kg/d). Tolerability and efficacy were assessed using a modified Liverpool Adverse Events Profile, the Caregiver Global Impression of Change (CGIC) scale, the Home Situations Questionnaire–Autism Spectrum Disorder (HSQ-ASD) and the Autism Parenting Stress Index (APSI).

Results: Following the cannabis treatment, behavioral outbreaks were much improved or very much improved (on the CGIC scale) in 61% of patients. The anxiety and communication problems were much or very much improved in 39% and 47% respectively. Disruptive behaviors, were improved by 29% from 4.74±1.82 as recorded at baseline on the HSQ-ASD to 3.36±1.56 following the treatment. Parents reported less stress as reflected in the APSI scores, changing by 33% from 2.04±0.77 to 1.37±0.59. The effect on all outcome measures was more apparent in boys with non-syndromic ASD. Adverse events included sleep disturbances (14%) irritability (9%) and loss of appetite (9%).

Conclusions: This preliminary study support the feasibility of CBD based medical cannabis as a promising treatment option for refractory behavioral problems in children with ASD. Based on these promising results, we have launched a large, double blind, placebo controlled cross-over trial with 120 participants (NCT02956226).”

http://n.neurology.org/content/90/15_Supplement/P3.318

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Plasma anandamide concentrations are lower in children with autism spectrum disorder.

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“Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted, stereotyped behaviors and impairments in social communication.

Although the underlying biological mechanisms of ASD remain poorly understood, recent preclinical research has implicated the endogenous cannabinoid (or endocannabinoid), anandamide, as a significant neuromodulator in rodent models of ASD. Despite this promising preclinical evidence, no clinical studies to date have tested whether endocannabinoids are dysregulated in individuals with ASD.

Here, we addressed this critical gap in knowledge by optimizing liquid chromatography-tandem mass spectrometry methodology to quantitatively analyze anandamide concentrations in banked blood samples collected from a cohort of children with and without ASD (N = 112).

FINDINGS:

Anandamide concentrations significantly differentiated ASD cases (N = 59) from controls (N = 53), such that children with lower anandamide concentrations were more likely to have ASD (p = 0.041). In keeping with this notion, anandamide concentrations were also significantly lower in ASD compared to control children (p = 0.034).

CONCLUSIONS:

These findings are the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD. Although preliminary, these data suggest that impaired anandamide signaling may be involved in the pathophysiology of ASD.”

https://www.ncbi.nlm.nih.gov/pubmed/29564080

https://molecularautism.biomedcentral.com/articles/10.1186/s13229-018-0203-y

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Oral cannabis extracts as a promising treatment for the core symptoms of autism spectrum disorder: Preliminary experience in Chilean patients

Cover image volume 384, Issue

“Preclinical studies and several anecdotal case reports suggest a dysfunctional endocannabinoid system implicated in Autism Spectrum Disorder (ASD).

Objective: To report our preliminary findings in patients with ASD treated with oral cannabis extracts.

Most cases improved at least one of the core symptoms of ASD, including social communication, language, or repetitive behaviors. Additionally, sensory difficulties, food acceptance, feeding and sleep disorders, and/or seizures were improved in most cases.

71,5% of patients received balanced CBD:THC extracts; 19,0% high-CBD; and 9,5% high-THC extracts.

Oral cannabis extracts were well tolerated.

Two patients had more agitation and one had more irritability, effects that were solved by changing the strain.

Conclusion: In this small series of ASD patients, oral cannabis extracts were dramatically more effective than conventional medicines. Large randomized controlled trials are needed to establish efficacy and safety of medicinal cannabis in ASD.”

http://www.jns-journal.com/article/S0022-510X(17)33120-9/fulltext

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