Cannabis and cannabinoid use in autism spectrum disorder : a systematic review
Estácio Amaro da Silva Junior, Wandersonia Moreira Brito Medeiros, Nelson Torro, João Marçal Medeiros de Sousa, Igor Bronzeado Cahino Moura de Almeida, Filipe Barbosa da Costa, Katiúscia Moreira Pontes, Eliane Lima Guerra Nunes, Marine Diniz da Rosa, Katy Lísias Gondim Dias de Albuquerque
Trends in Psychiatry and Psychotherapy, 2021, 1-10.
Doi : 10.47626/2237-6089-2020-0149
Introduction : Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and social interaction, associated with the presence of restricted and repetitive patterns of behavior, interests, or activities. Cannabis has been used to alleviate symptoms associated with ASD.
Method : We carried out a systematic review of studies that investigated the clinical effects of cannabis and cannabinoid use on ASD, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA checklist). The search was carried out in four databases: MEDLINE/PubMed, Scientific Electronic Library Online (SciELO), Scopus, and Web of Science. No limits were established for language during the selection process. Nine studies were selected and analyzed.
Results : Some studies showed that cannabis products reduced the number and/or intensity of different symptoms, including hyperactivity, attacks of self-mutilation and anger, sleep problems, anxiety, restlessness, psychomotor agitation, irritability, aggressiveness perseverance, and depression. Moreover, they found an improvement in cognition, sensory sensitivity, attention, social interaction, and language.
The most common adverse effects were sleep disorders, restlessness, nervousness and change in appetite.
Conclusion : Cannabis and cannabinoids may have promising effects in the treatment of symptoms related to ASD, and can be used as a therapeutic alternative in the relief of those symptoms. However, randomized, blind, placebo-controlled clinical trials are necessary to clarify findings on the effects of cannabis and its cannabinoids in individuals with ASD. Systematic review registration: International Prospective Register of Systematic Reviews (PROSPERO), code 164161.
Keywords : Cannabis, cannabidiol, cannabinoid, autism, systematic review.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and social interaction, in multiple contexts, associated with the presence of restricted and repetitive patterns of behavior, interests, or activities.1 In a multicenter epidemiological study performed in 2012, involving nine countries, the estimated average prevalence of ASD was 62 individuals per 10,000 inhabitants.2 Children with autism commonly exhibit comorbidities such as hyperactivity, self-harm, aggression, restlessness, anxiety and sleep disorders.3 This type of behavior favors social exclusion and limits the child’s abilities, causing more distress to caregivers.4
Conventional medical treatment includes several psychotropic drugs such as atypical antipsychotics, selective serotonin reuptake inhibitors, stimulants and anxiolytics; they do not treat ASD, but aim to eliminate inappropriate behavior, such as psychomotor agitation, aggressiveness, and obsessive-compulsive symptoms.5-8 They may lead to severe side effects such as nephropathy, hepatopathy, and metabolic syndromes, among others.9 Unfortunately, 40% of children with autism and disruptive behaviors do not respond well to standard medical and behavioral treatment.4 This carries a high cost for the individual and society, causing life expectancy to be reduced by 20 years in patients with autism compared to the population average.10
Among the possible pharmacological treatments, researchers began to explore other therapeutic alternatives, such as the use of substances derived from Cannabis sativa.11 Cannabidiol (CBD) represents one of the major components of the plant, having been studied in several disorders. At present, preliminary evidence suggests that CBD can relieve spasticity,12 pain, sleep disorders,13 improve mobility in multiple sclerosis,14 in addition to relieving anxious symptoms and social phobia15; however, further studies are needed to prove its effectiveness.
In autism, cannabis and cannabinoids have also been used to treat symptomatic conditions.16,17 CBD, and some other compounds in the plant, interact with the endocannabinoid system and can modulate different aspects related to cognition, socio-emotional responses, susceptibility to seizures, nociception and neuronal plasticity, which are often altered in autism.18-21 In mammals, the endocannabinoid system is mainly composed of two receptors, CB1 and CB2, endocannabinoids (endogenous substances that activate CB1 and CB2 receptors) and the enzymes responsible for their synthesis and metabolism.22
CB1 receptors are expressed in both the central and peripheral nervous systems, with their most abundant expression in basal ganglia nuclei and pre-synaptic GABAergic and glutamatergic neurons.23 Considering that the endocannabinoid system modulates emotional responses, mood, behavioral reactions to the context and social interaction, investigators have started to formulate the hypothesis that changes in this system would be present in the autistic phenotype.24 Aran et al.25 observed reduced levels of endocannabinoids, such as anandamide (AEA), palmitoylethanolamide (PEA) and oleoethanolamine (OEA), in plasma samples from 93 children with ASD, suggesting the use of such substances as possible biomarkers for diagnosis. Pretzsch et al.26 reported that CBD can change the levels of the metabolites Glx (glutamate + glutamine) and gamma-aminobutyric acid (GABA) – the metabolites that contribute to the regulation of excitatory and inhibitory neurotransmission, both in typical development and in ASD. In an uncontrolled single-case study, delta-9 tetra-hydrocannabinol (Δ9-THC) was administered to a 6-year-old autistic boy who was not taking any medication for 6 months. After the treatment period, there was a decrease in the scores of hyperactivity, lethargy, stereotyped behavior and language change, leading the authors to suggest the use of the substance as a resource to other treatments and early interventions.27
Thus, evidence has indicated that Cannabis sativa derivatives can alleviate symptoms associated with ASD, although there is still no consistent evidence about its efficacy, safety and tolerability, since no randomized, double-blind, placebo-controlled clinical trial with cannabis and cannabinoid for the treatment of the core symptoms of autism and coexisting symptoms have been conducted to date (only prospective studies are currently available). The research so far performed has shown that there are few side effects and, when they do occur, they are generally mild/moderate and transitory. In order to analyze such aspects, we carried out a systematic review of studies that used cannabis derivatives in autism, considering the evolution of symptoms and clinical improvement of these individuals.