To better understand the current state of evidence regarding the use of cannabinoids among individuals with ASD, we analyzed recently published peer-reviewed literature. Our inclusion guidelines required that an article must be written in English (or a translated text is available), published between the years 2000 and 2019, and focus on cannabinoids in the context of autism spectrum disorders. Academic and publicly-available electronic databases, including the Cochrane Library, MEDLINE, Applied Social Services Index and Abstracts, CINAHL, the Education Resources Information Center (ERIC), EMBASE, and PsycINFO were used as sources of literature that fulfilled the predefined inclusion criteria. Search strategies were customized for each database given its use and depth of controlled vocabulary related to the variables of interest, though “cannabinoids” and “autism spectrum disorder” were the most often used search phrases. As such, systematic reviews, reports, and experimental studies were assessed to understand the nature of the evidence, risks, and benefits of cannabis use for ASD.
Clinical evidence to evaluate the benefits, risks, and effects of medical cannabis use for those with ASD, have only just begun. A prospective observational study is currently underway at the Children’s Hospital of Philadelphia, in collaboration with Zelda Therapeutics (NCT03699527), to create a registry of children with ASD who use medical cannabis, follow their natural history of use, and examine the maximum cannabinoid concentrations in pediatric populations with ASD .
Since 2016, three clinical trials examining the effects of medical cannabis on individuals with ASD have been undertaken. As part of a larger study, the effect of a single oral dose of CBD versus placebo on the brain of individuals with and without ASD was compared using magnetic resonance spectroscopy . Recently published results from this clinical trial, indicate that “CBD modulates glutamate-GABA systems, but prefrontal-GABA systems respond differently in ASD”. As a result, the authors highlight that the effects of a drug tested in a neurotypical population may not generate similar findings in a population with a neurodevelopmental diagnoses .
With a focus on behavioral problems in children and youth with ASD, researchers in Jerusalem are studying the efficacy of a cannibinoid mix, while also examining safety and tolerance. The study is a double-blind randomized placebo-controlled trial and the cannabinoid mix consists of a 20:1 ratio in a 160/8.0 mg per ml of CBD/THC olive oil-based solution . Results from this clinical trial are eagerly anticipated.
A third study is currently ongoing and examining behavioral effects of cannabidivarin (with weight-based dosing of 10 mg/kg/day for 12 weeks) versus placebo on children with ASD. The clinical trial is funded by a $1.3 million grant from the United States Department of Defense [57, 58].
Results from these groundbreaking clinical trials have the potential to help build support for evidence-based recommendations regarding medical cannabis use amongst patients with ASD. Accessing ClinicalTrials.gov is a useful way to follow progress on these studies until the time published results are available. However, additional clinical studies which continue to build on existing evidence remain necessary to fully understand the implications of cannabis use in this population.
Thus far, only five research studies to the best of our knowledge exist which have examined the direct effects of medical cannabis in individuals with ASD. The most recently published study conducted in Israel, examined the safety and efficacy of medical cannabis use amongst 188 patients with ASD. Most patients were treated using cannabis oil (1.5% THC and 30% CBD), and functional activities of daily living, mood, and quality of life were assessed using structured. Only 93 parents of 155 active participants participated in the six-month follow-up, but a third of participants reported a significant improvement on the three endpoints. Side effects were experienced by approximately 25% of patients, with the most common side effects reported as restlessness followed by sleepiness and psychoactive effects. This study is limited by the follow-up attrituion at the one and six-month follow-up, which was not explained in the publication .
In another study also conducted in Israel , 53 children with ASD were administered oral cannabinoids under supervision. A 1:20 ratio of CBD and THC was used for a mean duration of 66 days, at a concentration of 30%, with a recommended daily dose of 16 mg/kg for CBD and 0.8 mg/kg of THC (maximal daily dose of 600 mg and 40 mg respectively). The study examined changes in the child’s comorbid symptoms using prospective bi-weekly interviews with parents. Effects of cannabidiol in respect to hyperactivity, sleep problems, self-injury, and anxiety were reported as an improvement, no change, or worsening. Of interest, changes within the cohort for these symptoms was compared to peer-reviewed data for treatment using conventional methods. As such, hyperactivity was considered improved at 80%, self-injury at 82%, sleep problems at 60% and improvement in anxiety symptoms at 64%. Of the children who displayed hyperactivity symptoms, over 68% reported improvement, over 28% had no change, while almost 3% reported worsening of hyperactivity. Improvements in self-injurious behavior were seen in almost 68% of children, 23.5% had no change while almost 9% reported worsening of self-injury. Over 71% reported improvements in sleep, 23.8% had no change, while 4.7% reported worsening effects. Anxiety was improved in over 47% of children, almost 30% had no change, while 23.5% had worse anxiety symptoms. Consequently, the study reported a 74.5% overall improvement in symptoms of ASD comorbidities, although mild adverse effects of somnolence and decreased appetite were reported in 12 and 6 children respectively. The authors reported no statistically significant difference in hyperactivity, sleep or anxiety of cannabidiol oil compared to conventional treatments of these symptoms. Study limitations, however, include lack of an objective assessment tool and a control group .
A third study from Israel focused on children with ASD and severe behavioral concerns and assessed the tolerability and efficacy of cannabidiol-rich cannabis. Led by Dr. Aran at the Shaare-Zedek Medical Center in Jerusalem, as a retrospective feasibility study for their clinical trial grant mentioned earlier (NCT02956226) , the study systematically assessed 60 children. Participants were prescribed CBD and THC in a 20:1 ratio, as a whole-plant extract dissolved in olive oil ("mean total daily dose was 3.8 ± 2.6 mg/kg/day CBD and 0.29 ± 0.22 mg/kg/day THC for children who received three daily doses (n = 44) and 1.8 ± 1.6 mg/kg/day CBD and 0.22 ± 0.14 mg/kg/day THC for children who received two daily doses (n = 16)") .
The study found 61% of the behavioral problems among participants were “much improved” or “very much improved” according to parent reports. Improvement was also found in anxiety levels in 39% of the children and a 47% improvement in communication. Disruptive behaviors assessed by the Home Situations Questionnaire-Autism Spectrum Disorder  and the Autism Parenting Stress Index  showed improvement by 29 and 33% respectively. An additional benefit following cannabis treatment was the reduced intake of medications; 24% of participants stopped taking medication, over 30% of children received fewer medications or a lower dose, and 8% received more additional or a higher dose of their current regimen .
Despite the fact that promising outcomes were experienced for participants with ASD, adverse events were reported by 57 parents. These side effects most commonly included hypervigilance, which led to worsening sleep concerns (14%), irritability (9%), loss of appetite (9%), and restlessness (9%). Other frequently cited adverse events included gastrointestinal symptoms, mood changes, fatigue and unexplained laugh. One serious adverse event was reported, with one participant experiencing a transient psychotic event. The study suggests that strains of medical cannabis with a high THC concentration (6:1-CBD to THC ratio) might increase the likelihood of lead to a psychotic state requiring antipsychotictreatment. The uncontrolled retrospective nature of this study has been cited by the authors as a limitation of this study, in addition to the potential for placebo effects reported in controlled treatment studies in children with ASD, as reported by King et al. [60, 63].
A Chilean study published by Kuester et al.  examined the effects of cannabis extracts on symptoms of ASD among a small sample of 20 children and one adult with ASD. Participants were monitored after taking sublingual whole plant cannabis extracts for at least 3 months. Almost 72% of the participants used a balanced THC to CBD extract, 19% used a high-CBD option, and almost 10% used high-THC extracts. Details on the administered dosage were not found in the published study or elsewhere; outcomes were assessed using the Clinical Global Impression of Improvement  and Autism Parenting Stress Index .
Based on these assessments, 66.7% of the participants showed significant improvement in at least one core ASD symptom like repetitive behaviors, language and social communication. Some improvement was reported by most participants including accepting food, sensory difficulties, seizures, and/or sleep disorders. Despite these reported benefits, three patients reported adverse symptoms: increased agitation (n = 2) and irritability (n = 1). These conditions were resolved with changes to the cannabis strain .
The earliest study identified was of a 6-year old male child with ASD conducted in Austria utilizing Dronabinol (THC). The child received THC dissolved in sesame oil with an initial dosage in the morning constituting one drop (0.62 mg) which gradually increased over the 6 months to the maximum tolerated dose of two drops in the morning, one drop midday and three drops in the evening (total dose of 3.62 mg). Significant improvements were noted in hyperactivity, irritability, vocal stereotypy and inappropriate speech symptoms, and sterotypic behavior based on assessments using the Aberrant Behavior Checklist  at baseline and after six months of treatment. Hyperactivity dropped by 27 points, lethargy decreased by 25 points, irritability by 12 points, stereotypic behavior by 7 points, and inappropriate speech improved by 6 points .
Evidence from shared conditions
Although the aforementioned studies illustrate the potential of cannabis to treat core symptoms of ASD, these studies are constrained in their scope of evidence given their small sample sizes, lack of control groups, and other reported limitations. As such, results from the two clinical trials pending publication of results and completion, and additional large scale clinical trials specific to this population will help build evidence for the safety and efficacy of medical cannabinoids for ASD patients. Until this time, evidence for cannabis use in this population can be merely inferred from studies conducted for pathological conditions shared by other patient populations . However, as noted by Pretzsch et al. , the inference and transferability of the effects of cannabis treatments from populations without neurodegenerative conditions on the ASD population are speculative.
An estimated 25% of children with treatment-resistant epilepsy (who also display other conditions such as mild to severe intellectual disability, sleep disturbances, mood disorders, and psychosis) are comorbid with ASD . Research on the medicinal use of cannabis for treating individuals with seizures and epilepsy have been extensive and as such, seizure disorders are listed as a qualifying condition in states which permit medical cannabis . Gaston and Friedman  discuss the therapeutic mechanism of CBD in treating epilepsy, reporting that rather than targeting CB1R and CB2R, CBD’s anticonvulsant properties target “TRPV1, voltage gated potassium and sodium channels, and GPR55, among others” .
An Australian survey conducted by Suraev et al.,  reported that “15% of adults with epilepsy and 13% of parents/guardians of children with epilepsy were currently using, or had previously used, cannabis products to treat epilepsy. Of those with a history of cannabis product use, 90% of adults and 71% of parents reported success in reducing seizure frequency after commencing cannabis products.”
In an uncontrolled retrospective case study of 272 patients with epilepsy (such as Dravet Syndrome, Rett syndrome, and Lennox-Gastaut syndrome), participants consumed an effective total cannabinoids dose ranging from 0.05 to 9 mg/kg/day with effective serum levels of CBD ranging from 1.8 to 80 ng/ml. Of the participants, 28% of subjects experienced a 76–99% reduction in seizures, 10% experienced a full clinical response, while 14% of participants found no effect of artisanal cannabis preparations in reducing seizures. In addition, increased alertness was reported as a desired side effect, while mild and infrequent side effects included decreased appetite, fatigue and somnolence .
Substantial interest and willingness to participate in cannabinoid research has offered a long-awaited potential pharmacotherapy solution to treatment-resistant epilepsy and/or limiting the side effects as compared to other treatments . The literature on cannabinoids and epilepsy, specifically for the treatment of intractable seizures in Dravet and Lennox-Gastaut syndromes and co-occurring autism-like behaviors is, as a result, comprehensive  and have led to the recent approval as mentioned earlier, of Epidiolex, an oral cannabidiol .
Problems with sleep is a common comorbidity in children and adolescents with ASD, with prevalance estimated between 40 to 80%. Sleep disorders have a significant impact on these individuals, and affects daily life activities, the ability to interact socially, and have also been associated with increased parental stress . A systematic review by Whiting et al. (2015) assessed the benefits and adverse events of cannabinoids on several diseases and symptoms such as chronic pain, sleep disorders. The review which included 79 trials and over 6400 participants, concluded that there was low-quality of evidence of the effect of cannabinoids on sleep outcomes . In another systematic review conducted by Gates et al. , findings suggested that amongst individuals with a medical condition which may impact sleep, the use of cannabinoids could improve sleep through reduced night-time disturbances. However, amongst studies which utilized objective sleep measures, results of sleep outcomes were inconsistent. In one of the studies examined by Gates et al., a double-blind, placebo-controlled-fourway crossover design assessed the effects of cannabis extracts on memory, early-morning performance, sleep, and sleepiness. The four treatments included: “placebo, 15 mg THC, 5 mg THC combined with 5 mg CBD, and 15 mg THC combined with 15 mg CBD, formulated in 50:50 ethanol to propylene glycol and administered using an oromucosal spray during a 30-min period“ at night. Results from the study indicated that 15 mg of THC appeared to have sedative effects while 15 mg of CBD increased alertness .
An additional core phenotype of ASD is an impaired social functioning ability, including aggression and self-injurious behavior (incidence ranging between 35 and 60%) [68, 77], which can impair academic achievement, education outcomes, rates of employment, and income . Unfortunately, standard treatments do not benefit approximately 40% of children with ASD and disruptive behavior, leaving caregivers distressed and increasing social isolation . In a review undertaken by the National Academies of Sciences, Engineering, and Medicine, evidence assessed from systematic reviews and clinical studies indicate limited evidence for the link between cannabis use and social functioning .
Psychosocial and mental health
Anxiety and mood disorders are also commonly reported to affect those with ASD , and at least 40% are comorbid with anxiety which aggravates other symptoms . In a double-blind randomized study using healthy controls and patients with social anxiety disorder (SAD) with no previous treatment experience, participants received a placebo or a single administration of CBD (600 mg) one and a half hours before a simulated public speaking test. Participants receiving a CBD dose were noted to have decreased “anxiety, cognitive impairment and discomfort in their speech performance as compared to the placebo group“ .
In two studies evaluated by the National Academies of Sciences, Engineering, and Medicine review [2, 79, 80] data was analyzed from waves 1 and 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (n = 34,653). Both studies found no association between cannabis use and anxiety disorders, although both studies reported an association between increased cannabis use with an increased odds of SAD (OR, 1.8; 95% CI = 1.1–2.8 and OR, 1.98; 95% CI = 0.99–6.98). The National Academies of Sciences, Engineering, and Medicine based on their systematic and comprehensive review stated that there is limited evidence for the statistical association between the use of cannabis and the development of any anxiety disorder, with the exception of social anxiety disorders. However, there is moderate evidence to support the association between regular cannabis use and social anxiety disorder.
Although less common, psychosis has also been identified as a comorbidity for ASD . As CBD has been shown to have antipsychotic properties in both human and animal studies, an exploratory double-blind parallel-group study was conducted to examine the safety and efficacy of CBD in patients with schizophrenia. Randomized patients were to receive CBD (1000 mg/day) or placebo. If currently prescribed antipsychotic medications, the placebo or CBD was prescribed in addition to the current regiment. CBD may potentially be offered as a new line of treatment for these psychiatric conditions, as “CBD was well tolerated, and rates of adverse events were similar between the CBD and placebo groups” . However, given the adverse outcome of a serious psychotic event discussed earlier in a preliminary study with a patient with ASD , the effectiveness of CBD to address psychosis in ASD merits further evaluation.
Effects of cannabinoids on the developing brain of children with and without ASD have also demonstrated the potential for adverse effects such as depressive-like symptoms and an increased risk for psychotic symptoms as an adult [20, 68, 83]. In addition, the impact of cannabis on cognition (specifically, learning, memory, and attention) have also been cited as concerns . Evaluations of studies conducted by the National Academies of Sciences, Engineering, and Medicine illustrate moderate evidence of effects of cannabis on learning, memory, and attention impairment [60, 84], which can impact academic, employment, and social outcomes .
Attention-deficit/hyperactivity disorder (ADHD) is also a commonly co-occurring diagnosis in ASD patients with an incidence of 41 to 78% . ADHD also elevates the risk of substance use disorders in children which could complicate the use of CBD for pharmacotherapy in treating ASDs with co-occurring ADHD . An Australian twin study reported “increased liability to ADHD and elevated autistic traits scores were associated with substance use and misuse,” including cannabis use and cannabis use disorders .
In a six-week, double-blind randomized placebo-controlled trial researchers assessed the effect of a cannabinoid medication (Sativex Oromucosal Spray) in 30 adults with ADHD on cognition. The treatment comprised of a 100-μl spray, which contained 2.7 mg THC and 2.5 mg CBD. Improvements were demonstrated in hyperactivity/impulsivity, inhibition measures, and a non-significant trend suggesting inattention improvement. One serious adverse event related to muscular seizures and spasms was reported .
In addition to these comorbidities discussed above, the effect of cannabis should be examined in light of the possibility of medication interactions between cannabis and the various prescription drugs individuals with ASD may be utilizing. Research is lacking regarding dosing regimens [14, 19, 20, 87], which increases the risk of adverse outcomes amongst medical cannabis users.
Toxins such as microbes, heavy metals and pesticides associated with the production of cannabis have also raised concerns. While some studies indicate that CBD has low toxicity in humans and no mutagenic effects  other studies suggest toxic contamination may be harmful to the reproductive and developmental system and can cause carcinogenicity and infection [20, 88]. This may be of substantial consideration given the concerns of toxins and its potential association with ASD etiology .