Psychology Assignment

REVIEW ARTICLE

Nordic JourNal of Psychiatry 2024, Vol. 78, No. 7, 553–560

Cannabinoids as alleviating treatment for core symptoms of autism spectrum disorder in children and adolescents: a systematic review

Emma Wen Dieperink Ibsena,b and Per Hove Thomsena,b

adepartment of clinical Medicine, aarhus university, aarhus, denmark; bdepartment of child and adolescent Psychiatry, research unit, aarhus university hospital, Psychiatry, aarhus, denmark

ABSTRACT Introduction:  Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder affecting about 1% of children. The disorder is characterized by difficulties within three core symptoms: social interactions, communication, and restricted or repetitive behavior. There is currently no approved psychopharmacological treatment; however, it is hypothesized that ASD symptoms might be ameliorated by manipulating the endocannabinoid (eCB) system. This study aims to review the existing research on cannabinoids as a potential effective treatment for the core symptoms of ASD in children and adolescents. Methods:  A literature search was conducted on PubMed, Embase, APA PsychInfo, and Cochrane. The available literature was screened, and studies were included if: the study population consisted of children/adolescents, the treatment involved cannabinoids, and the outcome assessed was the impact on core ASD symptoms. Results:  The search yielded five studies, two RCTs and three cohort studies. All the included studies reported an effect of the cannabinoid treatment; however, most of these effects were non-significant and not related to core symptoms. Only one study found a significant improvement on all three core symptoms. The risk of bias was rated as “high” or “very high” in four studies and as “low” in one study. Discussion: Although the included studies did not find substantial results regarding core ASD symptoms, they all reported that cannabinoid treatment had other positive effects. However, Long term outcome is unknown, and safety aspects are scarcely discussed. Conclusion:  Based on this review, the effect of cannabinoid treatment on ASD core symptoms is not clear; therefore, further studies are required.

Introduction

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder. Currently about 1% of children worldwide have ASD, with an increase in prevalence in recent years. While the cause is still unknown, it is believed to be a multifactorial condition [1]. The diagnosis is defined in the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5). According to DSM-5, the patient must experience difficulties within each of the three core symptoms: social interactions, communication, and restricted or repetitive behavior [2]. Almost 70% of ASD patients experience at least one comor- bid psychiatric disorder and upwards of 40% experience two or more. The psychiatric comorbidities make it harder to adapt, affect daily activities, decrease the quality of life, and accentuate the ASD-related symptoms [3]. Furthermore, there is an increased prevalence of children with ASD combined with a range of somatic diseases, including but not limited to epilepsy, immune diseases, and gastrointestinal diseases [4]. Currently no psychopharmacological treatment is approved for the alleviation of the core symptoms of ASD, and

behavioral interventions are still the primary treatment. Psychopharmacological treatments are, however, currently used to treat the comorbid symptoms of ASD. Multiple new psychopharmacological treatments targeting the underlying neurophysiology of ASD are being tested with the potential to help ameliorate the core symptoms of ASD [5].

It is hypothesized that the endocannabinoid (eCB) system is involved in the pathophysiology of ASD. The eCB system is an important regulator of synaptic plasticity and neuromod- ulation [6]. The eCB system consist of endogenous cannabi- noids (eCBs), receptors, and associated enzymes. The primary eCBs are anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and they act through type 1 and type 2 receptors located throughout the entire nervous system [7]. Previous studies have shown that children with ASD have lower plasma concentrations of certain eCBs than children without ASD [6, 7]. Studies suggest that especially lower concentra- tions of AEA may be associated with ASD symptoms [8]. Studies also show that increasing the levels of AEA reduces the core symptoms of ASD in animal models [9]. In addition, reports have been published displaying anecdotal success

© 2024 the author(s). Published by informa uK limited, trading as taylor & francis Group CONTACT Per hove thomsen per.hove.thomsen@ps.rm.dk department of clinical Medicine, aarhus university, aarhus, denmark.

https://doi.org/10.1080/08039488.2024.2381541

this is an open access article distributed under the terms of the creative commons attribution license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. the terms on which this article has been published allow the posting of the accepted Manuscript in a repository by the author(s) or with their consent.

ARTICLE HISTORY Received 13 November 2023 Revised 25 June 2024 Accepted 13 July 2024

KEYWORDS Autism spectrum disorder; child; cannabinoids; cannabis; treatment

554 E. W. D. IBSEN AND P. H. THOMSEN

with the use of exogenous cannabinoid treatment for ASD [10, 11]. Cannabinoids are the chemicals found in cannabis. They interact with the endocannabinoid receptors [12]. Over 100 different cannabinoids have been identified, yet cannabi- diol (CBD) and δ-9 tetrahydrocannabinol (THC) are the two most well-known and most studied. THC is known to have a potential psychoactive effect, whereas CBD does not. CBD has been reported to have an analgesic, anti-epileptic, anti-emetic, anti-inflammatory, anxiolytic, anti-psychotic, and anti-ischemic effect [13].

Our preliminary literature search did not identify any pre- vious reviews focusing on the effect of cannabinoid treat- ment to alleviate the core symptoms of ASD. The aim of this review was to identify, investigate, and summarize the avail- able original literature on cannabinoids as a potential effec- tive treatment for the core symptoms of ASD.

Methods

In the summer of 2023, a systematic literature review follow- ing the rules of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 version (PRISMA 2020) [14] was conducted. All available literature was screened and assessed by the first author.

The literature search aimed to identify original articles investigating the effect of cannabinoids on the core symp- toms of ASD. The literature search was performed on August 22, 2023, using PubMed, Embase, APA PsychInfo and Cochrane. The following search words were used: “CBD”, “Cannabis”, “Cannabinoid”, “Autism”, “Autism spectrum disor- der”, “ASD”, “Child”, “Youth”, “Adolescent” and “Review”. These search words were combined with the Boolean operators: “OR”, “AND”, and “NOT”. The search results had to include a word from each of blocks 1, 2, and 3, but none from block 4 (Table 1). The search was further restricted to articles pub- lished within the last twenty years (2003–2023). All search results were imported into EndNote where the built-in func- tion “Find Duplicates” was used to remove duplicates, result- ing in the identification of 11 duplicates. The titles and abstracts of the articles were screened by the first author, resulting in the removal of another 7 duplicates, including research protocols for already identified articles. In the same screening, it was determined whether each article met the inclusion and exclusion criteria. If an article could not be included nor excluded based on the preliminary screening or if it lacked an abstract, the full articles were read and further evaluated. All literature had to meet the inclusion and exclu- sion criteria outlined below.

The articles had to be written in either English, Danish, Norwegian, or Swedish so it would be comprehensible for the authors. Since this review had no allocated funds, full-text articles had to either be freely available or accessible through

student access provided by Aarhus University. If an article was not freely accessible, a Google search was conducted for the specific article. Studies which had not yet published any results were excluded. The test subject could not be animal models and had to be children or adolescents. Studies that included both children, adolescents, and adults were included if the results were reported separately for children/adoles- cents and adults. The exposure had to involve exogenous cannabinoid, and the outcome had to examine altered core symptoms of ASD. Articles that reported results assessing both core symptoms and comorbid symptoms were included if the results were separated into these two categories. If the articles studied other mental disorders and ASD was not the main focus, the article was excluded. Studies investigating either maternal or paternal use of cannabinoids prior to the child’s birth (prenatal exposure) were excluded. Additionally, studies primarily focused on potential genetic risk factors were excluded. Case studies were also excluded due to their limited generalizability compared to cohort studies.

The risk of bias in all the included articles was assessed using the revised tool for assessing risk of bias in randomized trials (RoB-2) and the Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS-E).

Results

The search yielded 123 articles after removal of the 18 duplicates, 105 were left and screened according to the described inclusion and exclusion criteria. Ninety-one were excluded based on a screening of the title and abstract. After perusal, another five articles were excluded [7, 15–21] since they were either not original studies, did not assess the core ASD symptoms, or did not involve exposure to exogenous cannabinoids. This left five articles for the final analysis (Figure 1).

Table 2 shows the characteristics of the five included arti- cles [22–26]. The included articles were two randomized con- trolled trials (RCT) [23, 26] and three cohort studies [22, 24, 25].

The RCTs

The study group in the RCT conducted by Aran et  al. con- sisted of 150 patients from a single referral center in Israel. The participants were children aged between 5 and 21 years with DSM-5 validated ASD, which was confirmed by ADOS-2, and moderate or greater behavioral problems. The RCT con- ducted by Silva Junior et  al. included 59 Brazilian children between 5 and 11 years diagnosed with ASD defined by DSM-5. Information about the study and signup advertise- ment was posted on various social media, support institu- tions, and informative lectures. Those who were interested completed a sociodemographic questionnaire and a screen- ing scale for autism, the Childhood Autism Rating Scale (CARS). Both studies included baseline questionnaires. The exposures were either whole plant extract, purified cannabi- noids, or placebo [23], or whole plant extract, or placebo [26]. In the study by Aran et  al. the whole plant extract and the purified extract contained CBD and THC in a 20:1 ratio and was dissolved in olive oil. The placebo was olive oil and

Table 1. Block search words.

Block 1 aNd Block 2 aNd Block 3 Not Block 4 cBd cannabis cannabinoid

autism autism spectrum disorder asd

child youth adolescent

review

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flavorings were added to all three treatments to make them smell and taste identical. In the study by Silva Junior et  al. the whole plant extract had a ratio of 9:1 (CBD:THC) and a concentration of 5 mg/mL. The placebo had the same consis- tency, color, smell, and other organoleptic qualities.

In the study by Aran et  al. the participants were randomly assigned either one of the treatments or placebo for a dura- tion of 12 weeks, following four weeks’ washout and another 12 weeks of another predetermined treatment. The starting dose was 1 mg/kg/day (CBD), and it was increased by 1 mg/ kg/day (CBD) every second day up to 10 mg/kg/day (CBD) or 7.5 mg/kg/day (CBD) for participants weighing >40 kg. The doses were administered orally three times a day. In the study by Silva Junior et  al. the children were treated for twelve weeks. The initial doses were three drops every twelve hours, and if necessary increased by two drops daily twice a week. However, the maximum dosages were 70 drops a day.

Aran et  al. measured the outcomes using the Home Situations Questionnaire-autism spectrum disorder (HSQ-ASD) and Clinical Global Impression-Improvement scale (CGI-I), focusing on behavioral problems, and Autism Parenting Stress Index (APSI) and social responsiveness scale, 2nd edition (SRS-2). Adverse events were measured using Liverpool Adverse

Events Profile (LAEP). Silva Junior et  al. measured outcomes using the Autism Treatment Evaluation Checklist (ATEC) and a semi-structured interview designed by the authors. This inter- view focused on ASD symptoms, including aggressiveness, psy- chomotor agitation, concentration, number of meals/day, hours of sleep/day, social interaction with peers, verbal language, anxiety, and repetitive and stereotyped movements. Both stud- ies used parental assessments. The study conducted by Aran et  al. found that the changes from baseline were overall greater during the first treatment period compared to the sec- ond. As a result, they chose to present results solely for the first period. Overall, neither of the treatments containing CBD and THC demonstrated a significant improvement in symp- toms according to the HSQ-ASD and the APSI. According to the CGI-I, 49% of participants receiving the whole-plant extract showed significant improvement, either as ‘much improved’ or ‘very much improved’. In contrast, only 21% of the participants who received the placebo demonstrated similar levels of improvement. Among the patients receiving the pure extract, 38% showed improvement, either as ‘much improved’ or ‘very much improved’. However, this improvement was not signifi- cantly higher than that observed in the placebo group. On all three measures (HSQ-ASD, CGI-I and APSI), the results did not

Figure 1. flowchart of the process for inclusion and exclusion of the articles. *Barr, s., et al., implementation of a pediatric medical cannabis research program. clinical, Pharmacology in drug development, 2019. 8(suPPl 1): p. 11., castellanos, f., a placebo-controlled double-blind trial of cannabinoids in children and adolescents with autism spectrum disorder. Neuropsychopharmacology, 2019. 44: p. 61-62., heussler, h., et  al., Phase 2 bright (an open-label tolerability and efficacy study of ZyN002 administered as a transdermal gel to children and adolescents with autism spectrum disorder): Baseline characteristics. Neurotherapeutics, 2020. 17: p. 1321-1322., Kuester, G., et  al., oral cannabis extracts as a promising treatment for the core symptoms of autism spectrum disorder: Preliminary experience in chilean patients. Journal of the Neurological sciences, 2017. 381: p. 932-933.

556 E. W. D. IBSEN AND P. H. THOMSEN

differ significantly between participants receiving whole plant extract and those receiving purified extract. However, the whole-plant extract demonstrated a more substantial effect compared to the purified extract. No serious treatment- associated adverse events were identified. The study by Silva Junior et  al. found that the children who received cannabis extract exhibited significant improvements in social interac- tions, psychomotor agitation, anxiety reduction, and an increase in daily meal consumption compared to the children

who received the placebo. The study also found that adverse events were reported by only three of the participants, and these events were characterized as mild and transient.

The cohort studies

The cohort studies included 60 [22], 188 [25], and 110 [24] participants, all aged between 0 and 25 years. All three stud- ies were conducted in Israel and assessed the efficacy and

Table 2. Presentation of the included articles – overview of study design, study population and size, cannabinoid treatment and treatment regimen, and the results of the included articles.

author and year of publication

study design and country study population and size

cannabinoid treatment and treatment regimen results

aran et  al. (2021) randomized control study

israel

Patients aged 5-21 years old recruited at a single israeli referral center with dsM-V verified asd, confirmed by ados-2 and moderate or great behavioral problem (≥4 on cGi)

Participants included: 150 dropouts: 18

1: Whole plant extract (cBd and thc 20:1)

2: purified cBd and thc (20:1)

3: placebo 12 weeks treatment, 4

weeks washout, 12 weeks predetermined crossover treatment

Measured by: Parents assessment by hsQ-asd and cGi-i.

core symptoms: srs-2: overall significant improvement (whole plant) cGi-i: overall significant improvment (whole plant) cGi-i: overall improvement (purified)*

silva Junior, et  al. (2021)

double blinded randomized control study

Brazil

children aged 5-11 years diagnosed with asd according to the dsM-V definition. recruited through posts on social media, support institutions, and informative lectures

Participants included: 64 dropout: 4

Whole plant extract, 9:1 (cBd:thc) or placebo.

12 weeks treatment

Measured by: Parents assessment through atEc and a semi structured interview.

core symptoms: significantly improved social interactions

Bar-lev schleider et  al. (2018)

Prospective cohort study

israel

children aged 0-18 years diagnosed with asd from 2015-2017 and who received a cannabis license from tiku-olam ltd.

Participants included: 188 dropout: 95

cannabis oil, 20:1 (cBd:thc)

6 months treatment

Measured by: Parents assessment using the global assessment approach.

core symptoms: improved communication skills* improved when combining all symptoms

aran et  al. (2019)

retrospective cohort study

israel

children aged 5-18, who met dsM-V criteria for autism, who all attended special educational programs. recruited from the same treatment center.

Participants included: 60 dropouts: 1

Whole plant extract, 20:1 (cdB:thc)

7-13 months of treatment

Measured by: Parent assessment using a modified cGic scale, the hsQ-asd and the aPsi scale.

core symptoms: improved communication skills

hacohen et  al. (2022)

Prospective cohort study

israel

children aged 5-25 years with dsM-V verified asd recruited through hebrew advertisement in the community

Participants included: 110 dropout: 57

Whole plant extract, 20:1 (cBd:thc)

6 months treatment

Measured by ados-2, Vineland-3, and srs-2. core symptoms: social and communicative

skills ados: significant

improvement # srs-2: significant

improvement in social subscale♦

Vineland-3: significant improvement

restricted or repetitive behavior

srs-2: significant improvement

the subjects with the greatest difficulties also had the greatest improvement.

Explanation: *Non-significant result. #collected social affects (both interactions and communication). ♦social subscale: social awareness, social cognition, social communication, social motivation. tiku-olam ltd is the largest national provider of medical cannabis in israel. abbreviations: caregiver Global impression of change scale (cGic scale), home situations Questionnaire–autism spectrum disorder (hsQ-asd scale), autism Parenting stress index (aPsi scale), clinical Global impression-improvement scale (cGi-i), autism treatment Evaluation checklist (atEc), autism diagnostic observation schedule, 2nd edition (ados-2), Vineland adaptive behaviors scale, 3rd edition (Vineland-3), and social responsiveness scale, 2nd edition (srs-2).

NORDIC JOURNAL OF PSYCHIATRY 557

tolerability of cannabinoids as a treatment for alleviating symptoms in children with ASD. Aran et  al. included children who met the DSM-5 criteria for ASD and attended a special education program for children with ASD. Bar-Lev Schleider et  al. invited all children who received a cannabis license from Tikun-Olam Ltd. and was diagnosed with ASD from 2015–2017. Hacohen et  al. recruited participants through advertisements in the community. Subsequently, they were interviewed by a specialized pediatric neurologist to ensure that they met the criteria for ASD according to DSM-5.

All three studies used a whole plant extract dissolved in oil containing THC and CBD in a 1:20 ratio. In the study by Aran et  al. the initial treatment was 1 mg/kg/day of CBD, which was distributed over 2–3 sublingual doses and up-titrated over a period of two to four weeks until the desired effect was achieved. The maximal doses were 10 mg/ kg/day of CBD. Twenty-nine participants exhibited an insuffi- cient response and were treated with a lower CBD:THC ratio (6:1), with good effect. In the study by Bar-Lev Schleider et  al. the starting dose was in general one drop (0.05 mL) containing 15 mg CBD and 0.75 mg THC, three times a day. The dosage was gradually increased depending on effect, tar- geted symptoms, and tolerability for each patient. In the study by Hacohen et  al. the treatment was administered as one drop a day (each containing 0.3 mg THC and 5.7 mg CBD) and increased gradually until effect was achieved; however, the final dose did not exceed 10 mg/kg/day. The treatments span in the study by Aran et al. was seven to thirteen months and in the studies by Bar-Lev Schleider et  al. and Hacohen et  al. it was six months.

The studies used different questionnaires to assess the outcomes. Aran et  al. used: modified LAEP, the Caregiver Global Impression of Change (CGIC) scale, HSQ-ASD, and the APSI. Bar-Lev Schleider et  al. used the global assessment approach. Hacohen et  al. used ADOS-2, Vineland adaptive behaviors scale, 3rd edition (Vineland-3), and SRS-2, in addi- tion, a cognitive assessment was made using an age-a ppropriate Wechsler intelligence scale. Aran et  al. found an overall improvement in disruptive behavior (61% improved), anxiety (39% improved), and communication (47% improved). Additionally, 33% of participants needed less medications than before and 24% stopped taking medication, thus indi- cating that they had benefitted from the cannabis treatment; however, 8% received more medications or higher doses than before the study. Bar-Lev Schleider et  al. found that 30.1% reported a significant improvement, 53.7% reported a moderate improvement, 6.4% reported a slight improvement, and 8.6% had no change. The primary parameters that exhib- ited improvement were behavioral outbreaks (61% improved), communication problems (47% improved), anxiety (39% improved), stress (33% improved), and disruptive behavior (33% improved). Furthermore, according to parent assess- ment, there were also significant improvement in the quality of life, mood, ability to dress and shower independently, con- centration, and sleep quality. Hacohen et  al. found no effect on cognitive functions, but significant effects on social aspects both in the ADOS-2 and the SRS-2. Both scoring sys- tems also found that patients with initially greatest symp- toms also had the greatest improvements after the treatment.

They found no significant association between the improve- ment and age or final dosage. Only the SRS-2 found signifi- cant improvement of restricted and repetitive behavior.

Regarding possible side effects or adverse events, Aran et  al. found that 51% of the participants reported mild adverse events and one participant experienced a psychotic event. Bar-Lev Schleider et  al. found that 25.2% of partici- pants reported one or more of the following side effects: restlessness, sleepiness, psychoactive effect, increased appe- tite, lack of appetite, digestion problems, and dry mouth. Hacohen et  al. reported that 12 participants left the study due to unspecified side effects.

Some of the articles stratified the core symptoms individ- ually, while others considered the core symptoms as a unified construct. All the included studies observed an effect of the cannabinoid treatment; however, the majority of these effects were statistically non-significant. Among the studies, only the study conducted by Hacohen et  al. reported a significant improvement in all three core symptoms, though using two different scoring systems.

Discussion

Methodological issues

Several of the included studies exhibit potential generalizabil- ity bias. Both studies conducted by Aran et  al. exclusively enrolled patients from the same treatment facility who pre- sented severe ASD symptoms. Silva Junior et  al. advertised their study through specific ASD channels. The study con- ducted by Bar-Lev Schleider et  al. only included children whose parents specifically sought the treatment. Furthermore, the majority of the included studies [22–25] were conducted in Israel, which raises the concern that the Israeli population may not be fully representative of the global population. Another potential issue is the presence of an unknown over- lap between the participants in the studies conducted by Aran et  al. (2019) and Bar-Lev Schleider et  al. suggesting that some of the participants have participated in both studies [27]. Hence, the study populations in all the included studies may not be fully representative, thus reducing their external validity. It is important to investigate other possible sources of bias and endeavor to control as many variables as possible [28]. The study population in the study by Silva. Junior et  al. consisted of children who were relatively close in age. This enhances the comparability of the participants as they share greater similarity in terms of brain development. This study also stratified by the severity of ASD symptoms, considered the parent’s socioeconomic status, and conducted blood analysis of the children to ensure tolerability. All these vari- ables were not accounted for by the other studies. The study by Silva Junior et  al. was unfortunately conducted in the early part of 2020, and as a consequence, some of the par- ticipants were undergoing treatment during COVID-19 lock- down, which could potentially have affected the children’s behavioral problems [29–31] and thus the result of the study. In the study conducted by Bar-Lev Schleider et  al. the partic- ipants did not receive the same cannabinoid treatments and the conclusions may therefore be considered less reliable. In

558 E. W. D. IBSEN AND P. H. THOMSEN

all the included studies, some of the participants were treated with other psychiatric medications. However, none of the studies investigated whether the different medications influ- enced the efficacy of the cannabinoid treatment. Furthermore, the dosages of the treatment in all the studies were based on the parents’ perceived effect, so all the dosages varied.

The size of the study population, including the number of participants who completed the entire study is an important factor to consider [32]. The study conducted by Hacohen et  al. included 110 participants; however, only 53 (48%) of the participants completed the entire treatment and assess- ment. Similarly, the study conducted by Bar-Lev Schleider et  al. included 188 participants; however, only 93 (49.5%) completed the treatment and questionnaires. While the rea- sons for participant dropouts are not clarified, if these drop- outs were selective, it could pose a potential bias [33]. Furthermore, only 51% of the remaining participants in the study by Hacohen et  al. reported an improvement in core ASD symptoms as measured by ADOS-2. Therefore, the signif- icant improvement was derived from a small group who experienced a vast improvement. Overall, this reduces the validity of the studies and increases the risk of bias. The stud- ies relied on the parents’ assessments which may not always align with clinical assessments or self-assessments. Previous studies have found that parental reports were in line with direct assessment in terms of attention, speech, and fine motor development [34, 35]. Another study found that clini- cal and parental assessment did not align, but that parents were better at distinguishing between children with and without ASD [36]. The study by Hacohen et  al. compared both parent and clinician assessments and revealed low alignment. Specifically, the parents reported a greater improvement than the clinicians, which raises questions about the validity of the results. When researching the effi- cacy, it is important to be aware of the placebo effect. In cohort studies it can be challenging to determine how much of the potential effect of the treatment that may be attributed to the placebo effect [37]. This is the case with all three of the included cohort studies [22, 24, 25]. Additionally, the RCT conducted by Aran et  al. reported that during period one, there was a more pronounced initial placebo effect com- pared to period two.

Using the RoB-2 and ROBINS-E assessment tools, the included articles [22–25] were rated as having either “high” or “very high” risk of bias, whereas the article by Silva, E.A.D.J., et  al. was evaluated as having a “low” risk of bias.

Clinical aspects

The studies included in this review reported an ameliorating effect of cannabinoid treatment on certain core symptoms of ASD. However, this was not significant across all three core symptoms. Until now, more studies have focused on the overall ASD symptoms rather than the core symptoms. All the included articles also presented results related to comor- bid symptoms, and these findings are all in line with previ- ous studies [15, 38, 39] and each other. However, since the presentation of the disorder is very heterogenous, the treat- ment and follow up/scoring of the patients are very

heterogenous as well, which makes it challenging to com- pare their symptoms and comorbidities [11]. The included studies found that the cannabinoid treatment led to improve- ments in disruptive behavior [22, 23, 25], reduced anxiety [22, 25, 26], and enhanced the patients’ daily quality of life as assessed through various parameters serving as proxies [22, 25, 26]. It could be argued that despite the studies not pro- viding completely conclusive evidence for cannabinoids’ effi- cacy in ameliorating the core symptoms of ASD, they still helped the patients in many other ways, in line with several published case reports [10, 11, 40] which significantly impacted their well-being. This observation supports the the- ory that the treatment is very individual and may not pro- duce significant effects on all ASD patients. By reducing the comorbid symptoms, the patients may experience reduced burden and social isolation, potentially leading to an improve- ment in their quality of life and social and communicative skills [27].

All the included articles also considered safety as a param- eter, and their collective findings indicated that the treatment had no severe adverse effects. However, the longest treat- ment duration was 13 months, making it impossible to con- clude anything about long-term treatment. Previous studies have shown that exposure to cannabinoids during the devel- opmental stages impairs learning and memory development and is also associated with increased anxiety. It is also hypothesized that the timing and duration of exposure may play an important role in the long-term effects [41]. A case report showed that cannabinoid treatment helped ameliorate the patient’s symptoms during childhood and early adoles- cence. Nevertheless, it became inadequate during puberty [40], implying that the timing of treatment might be essen- tial. Previous studies have found that cannabinoid use in chil- dren and adolescents may have serious adverse effects and that it may affect them differently than adults. Previous ani- mal studies have shown that the endocannabinoid levels in children and adolescents differ profoundly from those in adults [41]. Long term THC use in children and adolescents has been associated with decreased intelligence quotient (IQ), increased rates of depression, anxiety, suicidality, psy- chosis, impaired psychomotor functions, and executive func- tions, as well as a distinct impact on attention, concentration, learning, and memory formation. The number and severity of adverse effects seem to correlate with THC dosages, and some evidence implies that the negative impact may be per- manent in young developing brains [13]. Animal studies sug- gest that the use of pure CBD during early development is safe, while the use of THC during this period impairs brain structure and function [27]. Similar results have also been demonstrated in one human study investigating young adults; the neuroimages of individuals using marijuana revealed anatomic differences in grey matter density, volume, and shape compared to a control group [42]. The safety or hazards of using cannabinoids to treat children or adoles- cents have not yet been well-established, and disagreements on their safety persist. Therefore, further research, especially on long-term effects, should be conducted to get a better understanding of the potential risks of the treatment and if they outweigh the potential benefits.

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Additional studies are needed to confirm or reject the hypothesis that cannabinoids have a beneficial effect on the core symptoms of ASD. The literature search for this review identified a previous systematic review [39] which aimed to investigate the clinically effects of cannabinoids on ASD (not limited to children/adolescents). This review also included two of the same articles [22, 25] and the results were mostly regarding comorbid symptoms which were in line with the results from the five articles included in this review. Since then, the two RCTs and another cohort study have been con- ducted. The literature search for this review identified that additional studies investigating cannabinoids as an alleviating treatment for ASD have been approved and are currently underway. While the focus of this review has been on ASD core symptoms, it is important to emphasize that comorbid symptoms and the safety of the treatment are also of immense significance. Hence future studies would benefit from incorporating these factors. Furthermore, it could be argued that the goal should be an overall improved quality of life rather than the alleviation of specific symptoms.

Upon reviewing, an observational study which met the inclusion/exclusion criteria was identified [38]. The study was regrettably not identified through the search, possibly because it did not mention the age group in either the title, abstract or keywords. The study initially exposed 18 children/ adolescents aged 6–17 years to a cannabis sativa extract with a 75:1 (CBD:THC) ratio. 3 participants abandoned the treat- ment within the first month, leaving 15 participants who were treated for 6–9 months. The treatment was given in oral capsules and was up-titrated based on the participants’ symptoms and the average dosages were 4.55 mg/kg/day (CBD) and 0.06 mg/kg/day (THC). The scoring was done monthly and based on the caregivers’ perceptions. Their results were in line with the results of the included articles and showed an average of 30% improvement in “communica- tion and social interaction deficits”. Additionally, they found improvement in non-core/comorbid symptoms most promi- nent for attention deficit/hyperactivity disorder, motor defi- cits, cognitive deficits, sleep disorders, and convulsive seizures. Furthermore, the participants reported only mild and tran- sient adverse effects.

The limitations of this study were the lack of statistical analysis. Sparse research has been conducted with the focus on core symptoms; most previous studies focused on overall ASD symptoms, including comorbid symptoms. Additionally, due to the use of different scoring systems among the included studies, statistical analysis was not carried out. Furthermore, some studies which potentially met the exclu- sion/inclusion criteria, were not freely available as full text [43–46] and where therefor not included. Lastly, the literature was only screened and assessed by the first author. The authors have no competing interests to declare.

Conclusion

The evidence identified is sparse and considered to be of low quality. Nevertheless, the treatment appears to benefit some individuals significantly, though not necessarily in relation to core ASD symptoms. Consequently, further studies are required

to either confirm or reject the hypothesis that cannabinoids can help alleviate core ASD symptoms.

Disclosure statement

All authors have no conflicts of interest to declare

Notes on contributors

Emma Wen Dieperink Ibsen is MSc in Medicine from Aarhus University.

Per Hove Thomsen is professor in Child and Adolescent Psychiatry, MD, DMSc at Aarhus University Hospital and co-editor of Nordic Journal of Psychiatry.

Data availability

All the included studies were identified by a search on PubMed. The ret- rospective study by Aran et  al. [20] is published in Springer Link and can be purchased through link.springer.com or accessed through a Google search where the article is uploaded by tikun-olam.org.li. The RCT by Aran et  al. [21], the studies by Hacohen et  al. [22] and Bar-Lev Schleider et  al. are all available for free on PubMed Central. The study by Silva Junior et  al. is available for free through Trends in Psychiatry and Psychotherapy.

Funding

This review received no funds.

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