Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in communication and social interaction and by a pattern of restricted interests and repetitive behaviors that might vary in severity [1
]. It was estimated that around 1.5% of the general population might belong to the autism spectrum [2
]. Along with core symptoms, ASD might present with several associated problems, such as irritability, challenging behaviors [3
], and self-injury [4
], especially in the presence of associated intellectual disability (ID), a condition that seemed to regard at least one-third of the autistic population [5
]. Conversely, individuals with higher cognitive abilities are more frequently burdened by psychiatric comorbidities, such as depression, anxiety, attention deficit-hyperactivity disorder (ADHD), or sleep problems [6
]. Medical comorbidities are also highly prevalent among the ASD population [9
]. In particular, epilepsy represents the most frequent co-occurring neurological condition, affecting 5 to 30% of individuals with ASD [12
]. Even in absence of frank seizures, people with ASD seem to present subclinical electrical discharges with abnormalities in EEG patterns [16
The etiopathogenesis of ASD still needs to be clarified. Several genetic [18
], perinatal [19
], and environmental factors [21
] seem to be involved. Research has also evidenced an imbalance in some endogenous neurotransmission systems [23
], such as the serotoninergic [24
], γ-aminobutyric acid (GABA)-ergic [17
], and endocannabinoid (eCB) system [26
Imbalances in the eCB neurotransmission system were found in animal models of ASD [29
]. Additionally, lower serum levels of eCB were detected in children with ASD compared to typically developing peers [30
]. Notably, the eCB system is relevant, as it seems to regulate some of the functions typically impaired in ASD, such as the form of emotional responses and social interaction [32
Given the alterations in the eCB systems, researchers started to hypothesize that phytocannabinoids, which are naturally present in the plant of Cannabis sativa
, might exert beneficial effects on the core and associated symptoms of ASD. First, multiple experimental studies conducted on mouse models showed that cannabidiol (CBD), the non-intoxicating component of cannabis, affects social interaction [33
], which is severely impaired in ASD. Although CBD does not exert psych mimetic properties or the ability to induce addiction, it indirectly affects the transmission of the cannabinoid-related signal, the degradation of the endocannabinoid anandamide, and thus act on autistic-like symptoms in rats [35
Interestingly, in June 2019, the US Food and Drug Administration (FDA) approved the Epidyolex, a CBD-based oral solution, for the treatment of seizures in Dravet and Lennox-Gastaut syndrome, two rare forms of epilepsy, in children older than two years of age [36
]. As mentioned above, epilepsy is one of the most frequent co-occurring conditions of ASD, and the presence of seizures or non-epileptic abnormalities in EEG patterns might be partially responsible for the challenging behaviors or aggression in people with ASD. Thus, the correction of these abnormalities could improve, at least in part, the behavioral problems [37
]. Moreover, the common co-existence of ASD and epilepsy suggests the presence of shared neuropathological mechanisms. Of note, both conditions are associated with abnormalities in the inhibitory GABA neurotransmission, including reduced GABAA
subunit expression. These abnormalities can elevate the excitatory/inhibitory balance, resulting in a hyper-excitability of the cortex, with an increased risk of seizures [38
]. The literature showed that CBD seems to act similarly to antiepileptic drugs, as it increases the GABA transmission, thus reducing neuronal excitability [39
Additionally, CBD exerts an agonist activity on the 5-HT1a receptors (i.e., serotoninergic system), which could mediate its pharmacological antidepressant, anxiolytic, and pro-cognitive properties [41
]. In fact, the therapeutic effects of CBD were tested in patients suffering from anxiety disorder [43
], a psychiatric comorbidity affecting at least 20% of people with ASD [8
]. Possible benefits of CBD, due to its potential effects on the dopaminergic system, were also studied on subjects suffering from psychosis, [44
], which could also represent a mental health issue for autistic individuals [8
The effects of other cannabinoids were scarcely explored in clinical research. Cannabidivarin (CBDV) improved neurological and social deficits in early symptomatic Mecp2 mutant mice, a model of the Rett syndrome [45
]. Moreover, it was proven to be an effective anticonvulsant in several models of epilepsy [46
]. Delta-9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, might increase sleep duration [47
], thus being a potential candidate for a sedative effect. Additionally, it seems to reduce locomotor activity, which is indicative of a decrease in anxiety-like behavior [48
]. According to a recent pilot randomized trial [49
], a cannabinoid compound containing a 1:1 ratio of THC:CBD, significantly improved symptoms of hyperactivity, impulsivity, and inhibition measures in adults with ADHD, a condition that seemed to affect around 28% of autistic subjects [8
As mentioned above, ASD presents serious deficits in social interaction and communication, as well as repetitive behaviors. However, till date, no effective pharmacological treatment exists for ASD core symptoms; only two atypical antipsychotics (i.e., risperidone and aripiprazole) were approved by the FDA for the treatment of irritability in children and adolescents with ASD [50
]. Nevertheless, psychotropic medications are frequently prescribed in everyday clinical practice, with the frequent onset of side effects [51
]. Given their properties, cannabinoids were proposed as candidate therapeutic options in people with ASD. Two recent narrative reviews were conducted on the topic [52
]. However, to the best of our knowledge, no systematic reviews have comprehensively summarized the effects of cannabinoids for the treatment of individuals with ASD. The present paper aimed to describe the current state-of-the-art regarding the use of cannabinoids in individuals with ASD, focusing on both published and ongoing trials.
2. Materials and Methods
2.1. Search Strategy
We followed the PRISMA Statement guidelines to perform a systematic search [54
]. First, we searched the following databases from inception up to 26 May 2020: Web of KnowledgeTM
(including Web of Science, MEDLINE®
, KCI—Korean Journal Database, Russian Science Citation Index, and SciELO Citation Index), PsycINFO, Embase, and ClinicalTrials.gov, without any time or language restriction. We used the following search strategy: (cannab *) AND (autis * OR asperger OR kanner OR “neurodevelop * disorder *”).
Second, we reviewed all references of relevant reviews and meta-analyses to find any additional eligible study.
2.2. Eligibility Criteria
Two review authors (LF and VC) screened all retrieved papers, independently and in duplicate. Any doubt was solved by consensus. The authors included all original studies written in English, published as full papers or abstracts in peer-reviewed journals, and met the following criteria:
(1) Participants: Individuals with a diagnosis of autism spectrum disorder (ASD), according to international valid criteria or measured by a validated scale, regardless of age.
(2) Intervention: Cannabis sativa or cannabinoids, such as, cannabidiol (CBD), cannabidivarin (CBDV), delta-9-tetrahydrocannabinol (THC) and others, administered at any dosage and any form.
(3) Comparison: Studies with or without a comparison group (placebo or other forms of treatment).
(4) Outcomes: Any outcome.
(5) Study design: Case report, case series, retrospective, observational longitudinal, randomized or controlled clinical trials, both parallel and crossover.
2.3. Data Extraction
Data were extracted by two authors (S.T. and I.C.) who worked independently and in duplicate. Any doubt was solved by consensus. A standardized form was used to extract data from the included studies. We extracted information about study characteristics (authors, year, study design, country), characteristics of the ASD sample (sample size, age, presence of ID, presence of epilepsy, concomitant medications), type and duration of the intervention and the comparison, outcomes and outcome measures, findings, and side effects. We also reported data regarding ongoing studies, as retrieved in ClinicalTrials.gov. Results of the study were reported in a narrative summary that was organized around the study characteristics.
Our systematic review was the first to critically summarize the published and ongoing studies investigating the use of cannabinoids in the ASD population. Despite cannabinoids having shown promising effects on some ASD-associated problems (e.g., aberrant behaviors, sleep disorders, hyperactivity, seizures), their efficacy on core symptoms (i.e., socio-communication impairments, restricted interests, and stereotypies) remains largely unknown. The main limitation of the present paper is the absence of a statistical analysis of results that was hampered by the heterogeneity of study design, populations, type of cannabinoid, and particularly, outcomes, and measures. Future studies investigating the acute effects of cannabinoids in people with ASD on neurotransmitters levels could clarify the mechanisms of action of cannabinoids. Moreover, the comparison with healthy samples might clarify at least some aspects of the etiopathology of ASD and lay the ground for potential treatments for core and associated symptoms. Even if some clinical trials are ongoing, there is the need for further long-term studies, with homogeneous samples in terms of age, medication use, level of functioning, and presence/absence of seizures. Of great importance would be the choice of specific primary and secondary outcomes, focused on the cluster of symptoms that could benefit from the use of cannabinoids.