Cannabidiol as a suggested candidate for treatment of autism spectrum disorder

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Abstract

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. ASD has a number of prevalent co-morbidities, such as sleep disorders, attention deficit/hyperactivity disorder and epilepsy. 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. At present, however, there are no convincing pre-clinical or clinical data showing efficacy and safety of cannabinoid treatment in ASD patients.

Introduction

Autism spectrum disorder (ASD) defines a group of neurodevelopmental disorders that are frequently associated with general cognitive deficits (Zamberletti et al., 2017). DSM-5 criteria of ASD include:

  • A.

    Persistent deficits in social communication and social interaction across multiple contexts as expressed by deficits in social-emotional reciprocity, in nonverbal communicative behaviors used for social interaction or in developing, maintaining, and understanding relationships.

  • B.

    Restricted, repetitive patterns of behavior, interests, or activities including stereotyped or repetitive motor movements, insistence on sameness, inflexible adherence to routines or ritualized patterns of behavior, as well as hyper- or hyporeactivity to sensory input, or unusual interests in sensory aspects of the environment.

  • C.

    Symptoms must be present in the early developmental period.

  • D.

    Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning.

  • E.

    These disturbances are not better explained by intellectual disability or global developmental delay (American Psychiatric Association, 2013).

Worldwide prevalence of ASD is estimated to be approximately 1% (Lai et al., 2014). A recent study, however, demonstrated that by the age of 8 years one of 59 children in the USA meets the DSM-5-ASD criteria (American Psychiatric Association, 2013; Baio et al., 2018). ASD is more prevalent in males and is frequently accompanied by co-morbidities (Lai et al., 2014), the most common of which are sleep disorders (Garstang and Wallis, 2006) and attention deficit/hyperactivity disorder (ADHD) (Ghaziddin and Zafar, 2008). Other co-morbidities include psychosis, anxiety, mood and cognitive disorders.

Over the last decade, understanding of the genetic changes and the involvement of de-novo mutations in ASD is expanding (Ramaswami and Geschwind, 2018). Several dozen ASD susceptibility genes have been identified, collectively accounting for 10–20% of ASD cases (Geschwind, 2011). Involvement of epigenetic mechanisms and specific gene-environment interplay is also suspected, but more research is needed (Lai et al., 2014). Despite it being one of the most severe chronic childhood disorders with relatively high prevalence, morbidity and impact on the society, no effective treatment for the core symptoms of ASD is available yet. This may stem from the paucity of scientific data regarding the neurobiological basis of the disorder (Zamberletti et al., 2017). Most current interventions are behavioral and educational; pharmacotherapy (e.g. anti-psychotics, selective serotonin reuptake inhibitors (SSRIs) and stimulants) plays only a minor role (Lai et al., 2014), mainly in the treatment of irritability and aggressive behavior. Those are treated at present with the two FDA approved antipsychotics risperidone and aripiprazole (Stepanova et al., 2017). Unfortunately, these agents are not effective for the core symptoms of ASD.

Cannabidiol (CBD) is a non-psychotropic constituent of the cannabis plant (Chagas et al., 2014). More details on CBD and Δ9-Tetrahydrocannabinol (THC), are presented in Section 3 “Cannabinoids” below. The current review reports the available pre-clinical and clinical data regarding the potential effectiveness and safety of CBD in the behavioral symptoms and co-morbidities of ASD.

Section snippets

The endocannabinoid system in ASD

The endocannabinoid system (EC) consists of the endocannabinoids (Arachidonic Acid-derived compounds), endocannabinoid receptors and associated metabolic enzymes. The EC system acts as a neuromodulating network involved in the regulation of emotional responses, behavioral reactivity to context, and social interaction. The two main endocannabinoids are anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), both produced in the post-synaptic cell membrane as required. Binding of endocannabinoids to

Cannabinoids

Cannabis is one of the most widely used recreational drugs today. It derives from the genus of a flowering plant that includes three species: Sativa, Indica, and Ruderalis (Behere et al., 2017). A cannabis plant contains hundreds of different chemicals with about 60–80 ingredients known as cannabinoids (Brenneisen, 2007).

Cannabinoids are often divided into three sub-groups: phytocannabinoids, endocannabinoids and synthetic cannabinoids. Phytocannabinoids are the plant's naturally occurring

CBD use in medicine

The controversy regarding the benefits of medical cannabis and especially the use of the plant extracts in children is ongoing. In most countries worldwide cannabis, whether medicinal or not, is currently illegal. Still, the use of medical cannabis is growing, especially in countries such as Belgium, Canada, Australia, Netherlands and some US states (Behere et al., 2017).

Today, many commercial companies offer products consisting of medical cannabis extracts. These products differ in their

CBD and psychosis

In some cases, psychosis can be a comorbidity of ASD, with simultaneous onset of schizophrenia at adolescence or early adulthood (Sagar et al., 2013). The relatively high comorbidity rate of schizophrenia in ASD could be related to shared neurobiology, but also to arbitrary restrictions imposed by current diagnostic systems (Raja and Azzoni, 2010).

In children with ASD, fears, exaggerated anxiety reactions and thought process disorders may increase the risk of psychosis (Kyriakopoulos et al.,

CBD, neurodevelopment, mental disorders and ASD

The administration of cannabinoids for children and adolescents suffering from ASD is a controversial legal and ethical issue (Khalil, 2012). Those who oppose the use of medical cannabis in pediatrics claim that this treatment might harm young children and adolescents' brain development. Indeed, several pre-clinical and clinical studies that investigated the effects of cannabinoid consumption on brain development reported such harmful effects (Dow-Edwards, 2018; Rubino et al., 2016).

Brain

Conclusions

The use of cannabinoids in general and CBD in particular in the treatment of numerous medical and mental conditions, including ASD, is growing rapidly. In this review article we attempted to summarize the findings of pre-clinical and clinical studies regarding the involvement of the endocannabinoid system in physical and mental disorders and in neurodevelopment, as well as the safety and efficacy of CBD treatment in autistic behaviors and common co-morbidities of ASD. Unfortunately, no

Funding

This research did not receive any grant from any funding agency in the public, commercial, or not-for-profit sectors.

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