**5. Conclusions**

Sleep disturbances are very common in children with ASD, and they have a substantial impact on the quality of life of the child and the family. Preliminary clinical evidence and preclinical studies, which implicate the endocannabinoid system in the pathophysiology of both ASD and sleep disorders, sugges<sup>t</sup> that cannabinoid treatment might improve sleep in children with ASD. In a controlled study of 150 participants, we found that a wholeplant extract and a pure cannabinoid preparation, which contained CBD and THC in a 20:1 ratio did not improve the sleep parameters, as reflected in the CSHQ scores. Future studies should consider using actigraphy and sleep logs and recruiting participants within narrower ranges of age and functional levels, this might enable the identification of target populations within the autism spectrum that might benefit from this line of treatment.

**Supplementary Materials:** The following supporting information can be downloaded at https:// www.mdpi.com/article/10.3390/biomedicines10071685/s1, Supplementary Methods: interventions, randomization, and blinding; Table S1: inclusion and exclusion criteria for study participation; Table S2: impact of cannabinoid treatment on sleep; comparison of treatment effects in 2nd period; Table S3: comparison of changes in CSHQ scores (Mean ± SE), following the 1st and 2nd treatment that each participant received.

**Author Contributions:** Conceptualization, A.A. and H.C.; methodology, A.A.; software, A.S. and L.P.; validation, A.A., L.P., D.C.-R. and M.H.; formal analysis, A.A. and A.S.; resources, A.A.; data curation, A.A., A.S. and M.H.; writing—original draft preparation, A.S. and A.A.; writing—review and editing, A.A. and D.C.-R.; supervision, A.A. and H.C.; project administration, L.P.; funding acquisition, A.A. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the National Institute for Psychobiology in Israel, gran<sup>t</sup> number 203-17-18, and BOL Pharma, Revadim, Israel. The funding bodies were not involved in any way in the study design, the collection, analysis, and interpretation of data, or in the writing of the manuscript.

**Institutional Review Board Statement:** The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Shaare Zedek Medical center (protocol code 0175-16, date of approval 15 September 2016) and the Israeli Ministry of Health (application number: 20162153, date of approval 27 September 2016).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study. Participants' parents provided written informed consent and written consent was also obtained from participants when appropriate.

**Data Availability Statement:** The authors declare that the data supporting the findings of this study are available within the paper and its Supplemental Information. The remainder of the data are available from the corresponding author upon reasonable request.

**Conflicts of Interest:** Adi Aran reports receiving personal fees and stock options for advisory roles at BOL Pharma between 2018 and 2020. The remaining authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results.
