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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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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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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The Endocannabinoid System and Autism Spectrum Disorders: Insights from Animal Models.

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“Autism spectrum disorder (ASD) defines a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction with restricted or repetitive motor movements, frequently associated with general cognitive deficits. Although it is among the most severe chronic childhood disorders in terms of prevalence, morbidity, and impact to the society, no effective treatment for ASD is yet available, possibly because its neurobiological basis is not clearly understood hence specific drugs have not yet been developed. The endocannabinoid (EC) system represents a major neuromodulatory system involved in the regulation of emotional responses, behavioral reactivity to context, and social interaction. Furthermore, the EC system is also affected in conditions often present in subsets of patients diagnosed with ASD, such as seizures, anxiety, intellectual disabilities, and sleep pattern disturbances. Despite the indirect evidence suggestive of an involvement of the EC system in ASD, only a few studies have specifically addressed the role of the EC system in the context of ASD. This review describes the available data on the investigation of the presence of alterations of the EC system as well as the effects of its pharmacological manipulations in animal models of ASD-like behaviors.”

https://www.ncbi.nlm.nih.gov/pubmed/28880200

http://www.mdpi.com/1422-0067/18/9/1916

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Cannabis ‘mimics love hormone in the brain’, study finds – marking new research possibilities for autism

Cannabis behaves like the human 'love hormone'

“Cannabis has a reputation for inducing feelings of peace and love – and now scientists claim they have found the reason why.

A new study reveals the illegal drug acts much in the same way as chemicals produced by the natural ‘love hormone’ oxytocin, which is known to boost emotional feelings and bonding towards romantic partners, between mothers and babies and friends.

The research, conducted on mice, found that higher levels of oxytocin led to the release of anandamide – which behaves very similarly in the brain to the psychoactive ingredient in cannabis, THC.

Both chemicals attach to the same brain cell receptors, producing a similar ‘high’.

As part of the study, the researchers found that blocking anandamide reduced the pro-social effects of oxytocin – while a drug which preserved anandamide in the mice’s brains seemed to make them happier around other mice than other, untreated, animals.

Scientists say the results could highlight new paths for research in the treatment of autism, for which symptoms often include difficulty socialising.

It is very difficult to directly deliver oxytocin to the brain, however.

Dr Daniele Piomelli, of the Italian Institute of Technology in Genoa, Italy, said another strategy could be to intervene further down the oxytocin-anandamide pathway.

Our findings open the exciting possibility that drugs that block the degradation of anandamide, which are currently being tested for various anxiety disorders, could give a boost to the brain’s own oxytocin and help people with autism socialise more.

– DR DANIELE PIOMELLI, RESEARCHER

The findings were published in the journal Proceedings of the National Academy of Sciences.”

http://www.itv.com/news/2015-10-27/cannabis-mimics-love-hormone-in-the-brain-study-finds/

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Enhancement of Anandamide-Mediated Endocannabinoid Signaling Corrects Autism-Related Social Impairment

Mary Ann Liebert, Inc. publishers

We recently uncovered a signaling mechanism by which the endocannabinoid anandamide mediates the action of oxytocin, a neuropeptide that is crucial for social behavior, to control social reward. Oxytocin signaling has been implicated in autism spectrum disorder (ASD), and social reward is a key aspect of social functioning that is thought to be disrupted in ASD. Therefore, as a proof of principle for the core component of ASD—social impairment—we tested an endocannabinoid-enhancing compound on two widely studied mouse models of ASD, the BTBR and fmr1−/− (model of Fragile X Syndrome).

Remarkably, we found that FAAH blockade completely reversed the social impairment in both mouse models. CB1 receptor blockade prevented the prosocial action of FAAH inhibition in BTBR mice.

The results suggest that increasing anandamide activity at CB1 receptors improves ASD-related social impairment and identify FAAH as a novel therapeutic target for ASD.

In conclusion, the present study provides new insights into the role of endocannabinoid signaling in social behavior and validates FAAH as a novel therapeutic target for the social impairment of ASD.”
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Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome

“Fragile X syndrome, the most commonly known genetic cause of autism, is due to loss of the fragile X mental retardation protein, which regulates signal transduction at metabotropic glutamate receptor-5 in the brain.

The results identify the endocannabinoid signalosome as a molecular substrate for fragile X syndrome, which might be targeted by therapy.”  http://www.nature.com/articles/ncomms2045

“Cannabis-like chemical combats chief genetic cause of autism” http://www.belfasttelegraph.co.uk/news/health/cannabislike-chemical-combats-chief-genetic-cause-of-autism-28867862.html#ixzz2DRLsbjJO

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Targeting anandamide metabolism rescues core and associated autistic-like symptoms in rats prenatally exposed to valproic acid.

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“Autism spectrum disorders (ASD) are characterized by altered sociability, compromised communication and stereotyped/repetitive behaviors, for which no specific treatments are currently available. Prenatal exposure to valproic acid (VPA) is a known, although still underestimated, environmental risk factor for ASD.

Altered endocannabinoid activity has been observed in autistic patients, and endocannabinoids are known to modulate behavioral traits that are typically affected in ASD. On this basis, we tested the hypothesis that changes in the endocannabinoid tone contribute to the altered phenotype induced by prenatal VPA exposure in rats, with focus on behavioral features that resemble the core and associated symptoms of ASD.

In the course of development, VPA-exposed rats showed early deficits in social communication and discrimination, compromised sociability and social play behavior, stereotypies and increased anxiety, thus providing preclinical proof of the long-lasting deleterious effects induced by prenatal VPA exposure. At the neurochemical level, VPA-exposed rats displayed altered phosphorylation of CB1 cannabinoidreceptors in different brain areas, associated with changes in anandamide metabolism from infancy to adulthood.

Interestingly, enhancing anandamide signaling through inhibition of its degradation rescued the behavioral deficits displayed by VPA-exposed rats at infancy, adolescence and adulthood.

This study therefore shows that abnormalities in anandamide activity may underlie the deleterious impact of environmental risk factors on ASD-relevant behaviors and that the endocannabinoid system may represent a therapeutic target for the core and associated symptoms displayed by autistic patients.”

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Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model.

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“Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability.

The cognitive deficits in the mouse model for this disorder, the Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mouse, have been restored by different pharmacological approaches, among those the blockade of cannabinoid type 1 (CB1) receptor.

In this regard, our previous study showed that the CB1 receptor antagonist/inverse agonist rimonabant normalized a number of core features in the Fmr1 knockout mouse. Rimonabant was commercialized at high doses for its anti-obesity properties, and withdrawn from the market on the bases of mood-related adverse effects.

In this study we show, by using electrophysiological approaches, that low dosages of rimonabant (0.1 mg/kg) manage to normalize metabotropic glutamate receptor dependent long-term depression (mGluR-LTD). In addition, low doses of rimonabant (from 0.01 mg/kg) equally normalized the cognitive deficit in the mouse model of FXS.

These doses of rimonabant were from 30 to 300 times lower than those required to reduce body weight in rodents and to presumably produce adverse effects in humans. Furthermore, NESS0327, a CB1 receptor neutral antagonist, was also effective in preventing the novel object-recognition memory deficit in Fmr1 KO mice.

These data further support targeting CB1 receptors as a relevant therapy for FXS.”

http://www.ncbi.nlm.nih.gov/pubmed/27589806

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Dissecting the signaling pathways involved in the crosstalk between mGlu5 and CB1 receptors.

“The metabotropic glutamate (mGlu) receptor 5 and the cannabinoid type 1 (CB1) receptor are G-protein-coupled receptors (GPCR) that are widely expressed in the central nervous system (CNS). mGlu5 receptors, present at the postsynaptic site, are coupled to Gαq/11 proteins and display an excitatory response upon activation, while the CB1 receptor, mainly present at presynaptic terminals, is coupled to the Gi/o protein and triggers an inhibitory response. Recent studies suggest that the glutamatergic and endocannabinoid systems exhibit a functional interaction to modulate several neural processes. In this review we discuss possible mechanisms involved in this crosstalk and its relationship with physiological and pathological conditions, including nociception, addiction and fragil X syndrome.”

http://www.ncbi.nlm.nih.gov/pubmed/27338080

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