A Phase 2, Placebo-Controlled, Randomized, Double-Blind Study to Assess the Safety, Tolerability and Efficacy of Terpenes-enriched Cannabis Oil T1/C28, Administered to Pediatric Subjects With Autism Spectrum Disorder (ASD)
Phase: PHASE2
Conditions: Autism, Autism Spectrum Disorder
Sponsor: Bazelet Nehushtan LtD.

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CLINICAL PROTOCOL 
 
 
A Phase II, Placebo-Controlled, Randomized, Double-Blind 
Study to Assess the Safety, Tolerability and Efficacy of 
terpenes-enriched CBD-predominant cannabis oil, 
Administered to Pediatric Subjects with Autism Spectrum 
Disorder (ASD) 
 
 
 
 
 
Protocol Number: 0336-24-SZMC 
Investigational Product: Terpenes-enriched cannabis oil T1/C28 
Protocol Version: September 1, 2025, Version 3.0  
ClinicalTrials.gov Identifier: NCT07199218 
 
 
 
 
 
 
 
Prepared by: 
Title 
Date 
Signature 
Adi Aran, MD 
Principal Investigator 
01/09/2025 
 

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Revision History – After recruitment of first patient 
 
Version 
Author 
Date 
Description 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Short Synopsis 
Title 
A Phase 2, Placebo-Controlled, Randomized, Double-Blind Study to Assess the 
Safety, Tolerability and Efficacy of terpenes-enriched cannabis oil T1/C28, 
Administered to Pediatric Subjects with Autism Spectrum Disorder (ASD) 
Short Title 
A placebo-controlled trial of terpenes-enriched CBD-predominant cannabis oil in 
children with ASD 
Running Head 
Terpenes-enriched CBD oil in ASD 
Protocol Number 
0336-24-SZMC 
Study Center 
Shaare Zedek Medical Center, Jerusalem, Israel 
CinicalTrials.gov Identifier 
NCT07199218 
- 
Registration Date  
September 29, 2025 
Ethic Approval Date 
May 25, 2025 
Trial Commencement 
TBD 
Planned Number of Participants 78 
Study duration per participant 
Placebo-controlled phase: 8 weeks; After completing the first 8-week period, 
participants who received placebo will receive terpenes-enriched CBD, and 
participants who received the study drug will continue with the same treatment 
for another 8 weeks.  
Study Intervention 
Cannabidiol (CBD; 7.2mg/kg/d); Tetrahydrocannabinol (THC; 0.257mg/kg/d); 
and Terpenes (0.5mg/kg/d). Study intervention will be administered separately 
as an add-on to any existing treatment.  
Primary outcome  
ASD-associated behavioral problems, using the Aberrant Behavior Checklist-
Irritability Subscale (ABC-I) score - change from baseline to week 8. 
 
 
 

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Contents 
1. 
Title page .................................................................................................................... 1 
2. 
Revision history  Short synopsis ................................................................................... 2 
3. 
Contents...................................................................................................................... 4 
4. 
Abstract ...................................................................................................................... 5 
5. 
Introduction ................................................................................................................ 7     
6.     Hypotheses and Significance ...................................................................................... 10 
7.     Study Design ............................................................................................................. 10 
8.     Subjects .................................................................................................................... 12 
9.     Procedures................................................................................................................. 12  
10.   Outcomes and Measures ............................................................................................. 14 
11.    Assessment schedule ................................................................................................. 18 
12.    Study Flow Chart ...................................................................................................... 19 
13.    Statistical Considerations........................................................................................... 20 
14.    Data Management ..................................................................................................... 24 
15.    Informed Consent Process, Vulnerable Population and DSMB ..................................... 24 
16.     Randomization and blinding ..................................................................................... 25 
17.     Study Interventions, Dose Justification and Administration ......................................... 26 
18.    Amendments to the protocol & Deviations from the protocol ....................................... 27 
19.    Statement Of Compliance, Eearly Termination, and Publication Policy ........................ 28 
20.    Adverse Events ......................................................................................................... 29 
21.    Appendix 1 – Non-Generic Questionaires ................................................................... 30 
22.    Appendix 2 – Detailed summary of previous related randomised studies  ...................... 39 
    23.    Bibliography………………………………………………………………………...….. 40 
 
 

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A Placebo-Controlled Trial of Terpenes-Enriched, Cannabidiol-Predominant 
Cannabis Oil in Children with ASD 
 
Background: Autism spectrum disorder (ASD) encompasses a wide range of 
neurodevelopmental disorders with diverse etiologies and symptoms. Efforts to develop a single 
pharmacological treatment for the core symptoms of ASD have been unsuccessful. Approved 
antipsychotic medications for managing associated irritability often result in substantial metabolic 
side effects. Cannabidiol (CBD), a non-psychoactive cannabinoid, targets multiple neuronal and 
glial pathways to reduce excitation and inflammation. In contrast, tetrahydrocannabinol (THC), a 
psychoactive cannabinoid, directly activates the endocannabinoid system, which is impaired in 
ASD, and decreases social anxiety and hostility. Preliminary trials in children with ASD have 
demonstrated the efficacy of a CBD-predominant formulation combined with low-dose THC. 
Preclinical data suggest that efficacy may be further enhanced by enriching cannabinoid 
compounds with selected terpenes, which activate CB1 and CB2 receptors both directly and by 
modulating THC interactions at these receptors. 
Objective: To assess the impact of terpenes-enriched, CBD-predominant, cannabis oil on 
children with ASD in a randomized, double-blind, placebo-controlled trial.  
Specific aims:  
The primary aim is to assess the effect of the study drug compared to placebo on behavioral 
problems, using the Aberrant Behavior Checklist-Irritability Subscale (ABC-I) score - change 
from baseline to week 8. 
The main secondary aim is to assess the effect of the study drug compared to placebo on core 
ASD symptoms using the Vineland ™ Adaptive Behavior Scales (3rd edition, VABS3)- 
Socialization Domain Score, and the Social Responsiveness Scale 2nd edition (SRS-II) total score 
- change from baseline to week 8. 
Other secondary aims include: (1) To assess the tolerability and safety of the study drug 
compared to placebo, using detailed questionnaires, physical examination, blood count, and liver 
enzyme tests. (2) To assess global change in ASD-associated symptoms since baseline using the 
Clinical Global Impression- Improvement (CGI-I) and the Caregiver Global Impression of 
Change (CGIC) assessments – at week 8. (3) To assess changes in the quality of life, sleep 
parameters, and gastrointestinal problems using the Quality of Life in Autism Questionnaire 
(QOLA) – Parent version, the Children’s Sleep Habits Questionnaire (CSHQ) and a modified 
gastrointestinal sign and symptoms inventory (GISSI) - change from baseline to week 8. (4) To 
compare the effect of CBD-predominant, cannabis oil (study drug) with terpenes-enriched CBD, 
using the above assessments - change from baseline to week 8 and week 17.  
Study design: In this phase 2, randomized, double-blind, placebo-controlled, parallel-group 
study,78 children with ASD and behavioral problems, will be randomized (in a 1:1 ratio) to 
receive either placebo or a terpenes-enriched CBD-predominant cannabis oil (CBD 7.2mg/kg/d; 
THC 0.257mg/kg/d; Total terpenes 0.5mg/kg/d). The treatment will be given as an add-on to any 
existing treatment, for 8 weeks. The treatment dose will be up-titrated over 8 days. After 
completing the first 8-week period, participants who received placebo will receive terpenes-
enriched pure CBD, and participants who received the study drug will continue with the same 
treatment for another 8 weeks.  
Inclusion criteria: A diagnosis of ASD according to the DSM-5 criteria; Age 4-12 years; 
Bodyweight between 12.5kg and 57.5kg; CGI-Severity score ≥ 4; ABC-I score ≥ 18; and SRS-II 
total T score ≥ 66.  
Exclusion criteria: Seizures or changes in anticonvulsive therapy within the last 16 weeks; 
Treatment with cannabinoids or any change in the pharmacological or behavioral treatment in the 

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4 weeks prior to randomization; Participants or caregivers are unlikely (in the investigator's 
opinion) to comply with all trial requirements including blood tests. 
Significance: Previous studies suggest that CBD-rich cannabis oil (CBD:THC ratio = 20:1) 
reduces disruptive behavior and improves core symptoms in children with ASD. However, THC 
use remains controversial. While whole-plant extracts may enhance benefits via the "entourage 
effect" (synergy of cannabinoids and terpenes), cannabinoid isolates offer precise and consistent 
dosing. Enriching cannabinoid isolates with selected terpenes preserves the entourage effect and 
enables reducing THC dosage while ensuring both efficacy and consistency. 
 
 
 
 
 

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Introduction 
There is no established pharmacological treatment for the core symptoms of autism spectrum 
disorder (ASD), persistent deficits in social communication, and repetitive, restrictive patterns of 
behavior.1 Risperidone and aripiprazole have been approved by the U.S. Food and Drug 
Administration (FDA) to treat comorbid irritability2 but these medications often cause obesity and 
metabolic syndrome.2,3  Additionally, Up to 80% of children with ASD also have sleep 
disorders.4,5 Cannabinoid therapy with various THC to CBD ratios is being increasingly used to 
alleviate sleep disorders regardless of cause. However, currently there is insufficient evidence to 
support this line of treatment.6-9 
Cannabinoids, have been assessed before to treat core and comorbid symptoms in children with 
ASD with mixed results.10 
The partial effects demonstrated in these studies can be attributed to the heterogeneous and 
multifactorial etiology of ASD which should probably better be addressed with polytherapy. 
The current study aims to assess the combined impact of cannabidiol (CBD), terpenes and low-
dose THC which target multiple key biochemical hubs in antioxidative, anti-inflammatory, and 
cytoprotective pathways.10 
We hypothesize that combined treatment with these 3 compounds will lead to significantly higher 
improvement in disruptive behavior and core autistic symptoms compared with placebo in 
children with ASD. 
The endocannabinoid system is a cell-signaling system composed of the cannabinoid receptors, 
their endogenous ligands [endocannabinoids, mainly anandamide (AEA) and 2-AG], transporters, 
and enzymes that produce and degrade the endocannabinoids.11   
Studies in animal models suggest a reduced endocannabinoid tone in ASD.12-16 Stimulation of the 
endocannabinoid system12-17 have improved social deficits in some models. Additionally, children 
with ASD have lower peripheral endocannabinoid levels.16,18,19 
The main components of the cannabis plant (phytocannabinoids) are Δ9-tetrahydrocannabinol 
(THC) and cannabidiol (CBD). THC activates the type-1 cannabinoid receptor (CB1R) – the main 
cannabinoid receptor in neurons (Figure 1). THC is psychoactive (causes a ‘high’ feeling) and 
can lead to anxiety, addiction, cognitive decline, motivational loss, and psychosis.20 CBD, on the 
other hand, is a negative allosteric modulator of the CB1R which decreases the effects of CB1R 
agonists such as THC.  Nevertheless, CBD can activate the endocannabinoid system by 
decreasing the reuptake of the endocannabinoids (AEA and 2-AG) and the degradation of AEA 
(Figure 1). CBD is not psychoactive and has a relatively high toxicity threshold.20 It also appears 
to have anxiolytic, antipsychotic, antiepileptic, and neuroprotective properties that may be 
mediated through receptors such as serotonin 5-HT1A, TRPV1, GPR55, GABAA, D2, and PPARγ, 
and by inhibiting adenosine reuptake (Figure 1).21-25  
Besides its direct effects on multiple receptor targets in neurons, CBD has prominent direct and 
indirect antioxidant and immunomodulatory effects26-33 that were extensively studied in 
microglia34-37 (Figure 2). Immune system dysregulation has a direct impact on numerous 
neurodevelopmental processes.38  In ASD, immune dysregulation includes differential monocyte, 
macrophage, and microglia responses,39-44 and abnormal cytokine, and T cell levels.38,45,46  
Additionally, in most of the ASD cases, there are indications of mitochondrial function 
impairments including lactic acidemia, abnormal lactate: pyruvate ratios, and accumulation of 
alanine in the plasma and urine indicating defects in oxidative phosphorylation.47-49 
Hence, the immunomodulatory and antioxidative effects of CBD and its effects on the 
endocannabinoid system and various other receptors could be beneficial in ASD. 
Previously, we demonstrated in a placebo-controlled trial that a CBD-rich cannabis extract (with 
a CBD-to-THC ratio of 20:1) can reduce disruptive behaviors associated with ASD and improve 
core autistic symptoms with acceptable tolerability.50 However, due to the potential risks of THC, 

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particularly in children with neuropsychiatric disorders, ongoing and emerging placebo-controlled 
studies are focusing on the effects of CBD isolates devoid of THC.51 
Nevertheless, animal studies,17 preliminary evidence from randomised studies,10 and our clinical 
experience suggest that CBD alone has significantly lower efficacy. Recent preliminary clinical 
and preclinical studies indicate that efficacy might be enhanced by enriching CBD-dominant 
compounds with specific terpenes. These terpenes can activate CB1 and CB2 receptors directly or 
modulate THC interactions with these receptors.52-57 
In the current study, we aimed to evaluate the efficacy, safety, and tolerability of terpene-
enriched, CBD-predominant cannabis oil with a CBD-to-THC ratio of 28:1 
 
 
Figure 1: The main cannabinoid receptor in neurons is the Cannabinoid receptor type-1 (CB1R). 
Activated CB1R increases outflow of potassium and decreases inflow of calcium reducing 
synaptic transmission.  THC directly activates the CB1R. Specific terpenes directly activate the 
CB1R and increase CB1R activation by THC. CBD is a negative allosteric modulator of the CB1R. 
However, CBD can activate the endocannabinoid system by inhibiting the endocannabinoid 
membrane transporter (EMT) and the degradation of anandamide (AEA) through Fatty acid 
amide hydrolase (FAAH). This, in turn, increases the levels of the endocannabinoids AEA (a 
main agonist of CB1R) and 2-Arachidonoylglycerol (2-AG). Other neuronal effects of CBD are 
mediated through full agonism at 5‐HT1A serotonin receptors and TRPV1 channel reducing 
anxiety and pain; Partial agonism at D2 dopamine receptors increasing emotional regulation; A 
negative allosteric modulation of MOR reducing opioid drug abuse and relapse; and Agonism of 
the nuclear PPARγ receptors increasing expression of cytoprotective enzymes. CBD also has 
direct antioxidative effects. 
D2: dopamine receptor 2; ENT: equilibrative nucleotide transporter; 5‐HT1A: 5‐
hydroxytryptamine1A receptor; GPR55: G protein-coupled receptor 55; MOR: µ opioid 
receptor; PPARγ: peroxisome proliferator‐activated receptor gamma; ROS, reactive oxygen 
species; TRPV1:  transient receptor potential vanilloid 1. 
 
 

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Figure 2: Molecular targets of CBD in microglia. CBD has anti-inflammatory and antioxidative 
effects in the microglia which are mostly not related to the cannabinoid receptors.  
CBD is a full agonist of adenosine A2A, and the TRPV1 cell membrane receptors and the nuclear 
PPARγ receptor – all convey anti-inflammatory effects. PPARγ is a ubiquitin E3 ligase that leads 
to proteasomal degradation of the p65 subunit of the proinflammatory transcription factor 
nuclear factor kappa B (NF-κB). In the nucleus, PPARγ reduces the expression of 
proinflammatory cytokines and increases the expression of anti-inflammatory and anti-oxidative 
mediators. CBD also has direct antioxidative effects. The main cannabinoid receptor in microglia 
is Cannabinoid receptor type-2 (CB2R). Expression of CB2R is upregulated in reactive microglia. 
The main effect of the CB2R is anti-inflammatory. While initially activating the proinflammatory 
mediators of the mitogen-activated protein kinase (MAPK) family, CB2R prevents further 
activation of MAPK by powerful triggers such as lipopolysaccharide (LPS).   CBD has a weak 
affinity to the CB2R (mostly as an inverse agonist). However, CBD can activate the 
endocannabinoid system through the CB2R by inhibiting the endocannabinoid membrane 
transporter (EMT) which leads to reuptake inhibition of 2-Arachidonoylglycerol (2-AG) the main 
agonist of CB2R. 
ENT: equilibrative nucleotide transporter; GDNF: a glial cell line-derived neurotrophic factor; 
GPR55: G protein-coupled receptor 55; PPARγ: peroxisome proliferator‐activated receptor 
gamma; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-alpha; TRPV1: transient 
receptor potential vanilloid 1 
 

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Working hypothesis and expected significance:  
In the proposed study, we will assess the effects of CBD and low-dose THC isolates, enriched 
with selected terpenes, on alleviating disruptive behavior and core symptoms in children with 
ASD. Combination therapy is anticipated to achieve higher efficacy compared to monotherapy 
and is a standard of care in many medical disorders, including cancer and cardiovascular disease. 
CBD and terpenes are plant-derived compounds with high safety and tolerability, possessing 
proven anti-inflammatory, antioxidative, and mitochondrial-supportive properties. These 
compounds have shown promising preliminary efficacy in ASD trials. 
THC directly activates the endocannabinoid system, which has been shown to be impaired in 
ASD. Due to concerns regarding THC safety in children, we will use a lower THC dose in this 
study (0.27 mg/kg/day) compared to our previous study, where a dose of 0.5 mg/kg/day was used. 
We hypothesize that this combination of compounds will lead to significantly greater 
improvements in disruptive behavior and core autistic symptoms compared to placebo. The use of 
cannabinoid isolates enriched with terpenes, rather than whole-plant extracts (which can vary by 
batch), will ensure consistency of treatment and allow for a substantial increase in the dose of 
terpenes, the safest component of the formulation. 
Despite the efficacy of atypical antipsychotics (mainly risperidone) in treating behavioral 
problems in individuals with ASD,58-60 approximately 40% of patients experience drug-refractory 
aggression, self-injurious behavior, and severe tantrums.61 Furthermore, risperidone and other 
atypical antipsychotics are associated with substantial adverse effects, such as sleepiness and 
weight gain. Consequently, many patients continue to suffer from disruptive behaviors that 
significantly impact their daily functioning and place a heavy burden on their caregivers. 
Even a minor improvement in the severity of ASD core and associated symptoms can have a 
profound impact on the lives of countless families and reduce public health costs. 
 
Methods 
Study design 
This is a phase 2, randomized, double-blind, placebo-controlled, parallel-group study, involving 
78 children with ASD and behavioral problems, age 4-12 years. Participants who will pass 
screening will be randomized (in a 1:1 ratio) to receive either placebo or terpenes-enriched CBD 
rich cannabis oil (CBD: 3.6 mg/kg twice daily, terpenes: 0.25mg/kg twice daily, and THC: 0.128 
mg/kg twice daily). The treatment will be given orally as an add-on to any existing treatment, for 
8 weeks. The treatment dose will be up-titrated over 8 days.  
After completing the first 8-week period, participants who received placebo will receive pure 
CBD (3.6 mg mg/kg twice daily enriched with terpenes (0.25mg/kg twice daily), and participants 
who received the study drug will continue with the same treatment for another 8 weeks of the 
second phase. (Figure 3).  
 
First phase 
Every 4 days during the titration phase and every 2 weeks thereafter, parents or primary 
caregivers will rate adverse events and document: any use of medical services, any change in the 
doses of the study intervention and concomitant medications, any change in the regular diet and 
intake of food supplements, and any change in the home or school routine or in the behavioral or 
emotional treatments.  
Additionally, at each study visit, physicians will assess physical examination and BMI, and 
parents or primary caregivers will rate behavioral symptoms on the Aberrant Behavior Checklist- 
Community (ABC-C) – Irritability subscale (ABC-I) and ASD core symptoms on the Social 
Responsiveness Scale – second edition (SRS-2).  

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Other assessments at the onset and end of the first phase:    
1. Parents will rate their child’s: (a) Communication, Socialization and maladaptive 
behavior using the Vineland Adaptive Behavior Scales (VABS-III; a structured 
interview); (b) behavior using the emotion dysregulation inventory (EDI) and the 
multidimensional assessment of disruptive behavior (MAP-DB); (c) severity of core 
symptoms using the autism impact measure (AIM); (d)  sleep habits using the Children’s 
Sleep Habits Questionnaire (CSHQ); (d) health-related quality of life of themselves using 
the Quality of Life in Autism Questionnaire (QOLA) – Parent version; and (e)  
gastrointestinal symptoms the gastrointestinal symptoms a modified gastrointestinal sign 
and symptoms inventory (GISSI) and executive functions using the Behavior Rating 
Inventory of Executive Function (BRIEF).  
2. Complete blood count (CBC), liver transaminases (LTs), and total bilirubin. 
3. Plasma levels of 7-carboxy-CBD (the major circulating metabolite of CBD. 
4. Possible biomarkers of treatment response (exploratory outcomes) including serum 
endocannabinoid (eCB) levels, relative mRNA expression levels of components of the 
eCB system in whole blood, RNA-sequencing of whole blood samples (transcriptome), 
plasma proteome, and gut microbiota  
Additionally, at the end of the first phase physicians and caregivers will rate the global change in 
ASD-associated symptoms using the Overall Function Clinical Global Impression- Improvement 
(CGI-I) and the Caregiver Global Impression of Change (CGIC) assessments. Parents or primary 
caregivers will complete an Assessment of Blinding Questionnaire.  
 
Second phase: Assessments at the end of the second phase will include: CGI-I and CGIC (global 
change in ASD-associated symptoms); adverse events; ABC-I, EDI, and MAP-DB (behavioral 
symptoms); SRS-2 and AIM (ASD core symptoms); CSHQ (sleep habits); BRIEF (executive 
functions), QOLA (quality of life); modified GISSI (gastrointestinal symptoms) and Assessment 
of Blinding Questionnaire. 
 
 
 Figure 3: Study design 

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Participants 
The study will be conducted at Shaare Zedek Medical Center, Jerusalem, Israel. Written informed 
consent will be obtained from a parent or legal guardian of participants after approval by the local 
institutional review board.  
 
Inclusion criteria are: 
- 
Children aged 4 to 12 years. 
- 
A diagnosis of ASD based on the Diagnostic and Statistical Manual of Mental 
Disorders [Fifth Edition; DSM-V], confirmed by CARS-2 assessment. 
- 
Moderate or greater ASD-associated symptoms as measured by a rating of moderate or 
higher (≥4) on the Overall Function Clinical Global Impression–Severity (CGI-S).  
- 
Aberrant Behavior Checklist-Irritability Subscale (ABC-I) score of 18 or higher. 
- 
Social Responsiveness Scale 2nd edition (SRS-II) total score of 66T or higher. 
 
Exclusion criteria are:  
- 
Bodyweight below 12.5kg or above or equal 57.5 kg. 
- 
Current or past diagnosis of heart failure, drug addiction, schizophrenia, psychosis, 
bipolar disorder PTSD or MDD or diagnosis of schizophrenia in a first degree relative. 
- 
A seizure or change in the antiepileptic medications in the 4 months prior to 
randomization. 
- 
A physical exam and laboratory results are out of the normal range for individuals with 
ASD, including a significant impairment in heart, liver, or renal function. 
- 
Any change in the pharmacological or behavioral treatment or change in the home or 
school settings (other than school holidays) in the 4 weeks prior to randomization or 
planned changes during the study. 
- 
Cannabinoid treatment in the 4 weeks prior to randomization. 
- 
Predicted low compliance to the study procedures (such as blood tests). 
- 
Concurrent use of opiates or alcohol. 
 
Criteria for termination of participation:  
- 
The Principal Investigator believes that continued participation endangers the participant. 
- 
Upon a decision of the regulatory bodies: IRB or MOH.  
- 
Upon request of one of the legal guardians  
 
Terms for termination of participation: After termination of participation – participants will 
continue to receive the same treatments they received before termination, excluding the study 
treatment. These treatments will not be affected in any way by their decision to terminate their 
participation in the study 
 
Procedures 
Screening: ASD diagnosis will be established using a structured assessment of DSM-5 criteria 
together with a Childhood Autism Rating Scale, Second Edition (CARS-2) total score ≥30. 
Caregivers will complete a medical history questionnaire covering demographic information, 
potential etiological factors (perinatal, genetic, imaging), comorbidities (epilepsy, allergies, 
immune-mediated disorders, sleep disturbances), autistic regression, diet, nutritional supplements, 
and behavioral treatments. Other assessments will include the CGI-S, ABC-I, SRS, and NVIQ (as 
detailed below). ADOS-2 - module, date and calibrated severity score will be documented. 
Blood samples- (15 ml) will be collected at 0 and 8 weeks. 

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- 
Complete blood count (CBC), liver transaminases (LTs) and total bilirubin will be 
measured as part of the safety analyses. 
- 
Plasma levels of 7-carboxy-CBD62 will be assessed to determine individual 
bioavailability of CBD. At 2-month, blood will be collected 3-4 hours post treatment 
administration. 
- 
Serum endocannabinoids (ECs)16,19 and relative mRNA expression levels (real-time PCR) 
of components of the eCB system in whole blood,16  RNA-sequencing of whole blood 
samples (transcriptome),63 and plasma proteome,64 will be assessed to explore possible 
markers of treatment response.  
 
Stool samples will be collected at 0 and 8 weeks. 
- 
Gut microbiota was demonstrated to be associated with ASD as well as symptom severity 
in multiple studies.65-67  
 
Study treatment:  
Participants will receive terpenes-enriched CBD-predominant cannabis oil for oral administration 
(8.96 mg CBD and 0.32 mg THC per drop, T1/C28, Bazelet, Israel) or matched placebos: an oil 
with similar appearance, taste and smell for 8 weeks (first phase).  
The target dose is: CBD- 7.2mg/kg/d, THC- 0.257mg/kg/d, and terpenes - 0.5mg/kg/d. 
 
The initiation dose will be 0.1 drops/kg twice daily: morning and afternoon (6-9 hours apart) for 4 
days (1.8mg CBD/kg/d); followed by 0.2 drops/kg twice daily (3.6mg CBD/kg/d) for 4 days and 
0.4 drops/kg twice daily (7.2mg/kg/d) thereafter.  
 
Second phase: At the end of the first 8-week phase participants will gradually stop the treatment 
they received in the first phase over 1 week: 0.2 drops/kg twice daily for 3 days; followed by 0.1 
drops/kg twice daily for 4 days.  
Participants who received placebo in the first phase will receive terpenes-enriched CBD isolate, 
and participants who received the study drug will continue with the same treatment for another 8 
weeks. 
The titration in the second phase will be like the first 8-week phase: at week 9: 0.1 drops/kg twice 
daily for 4 days (1.8mg CBD/kg/d); followed by 0.2 drops/kg twice daily (3.6mg CBD/kg/d) for 
4 days and 0.4 drops/kg twice daily (7.2mg/kg/d) until week 17. At week 17, participants will 
gradually stop the treatment over 1 week: 0.2 drops/kg twice daily for 3 days; followed by 0.1 
drops/kg twice daily for 4 days.   
 
Based on previous studies the safety of the study treatment (in the target dose) is very high. If the 
LTs (at 0 or 8 weeks) will be between 2 to 3 times higher than the upper limits of the norm 
(ULN) we will not change the target doses and repeat the tests after 2 weeks. If the LTs are more 
than 3 times higher than the ULN we will decrease the target dose of the CBD by 50% and repeat 
the tests after 2 weeks. If the repeated LTs are less than 2 times higher than the ULN we will 
increase the daily CBD dose to 5mg/kg. 
 
Study visits 
On-site visits: 4 visits: Screening (visit #1), Baseline (visit #2), 4 weeks (visit #3), 8 weeks (visit 
#4 - end of the first phase) and 17 weeks (visit #5 - end of the second phase). Phone visits to 
document compliance and adverse events: Three visits at study onset- (days 4, 8, and 12) and 
another 3 visits on weeks 6, 11, and 13. The PI may decide to hold the third meeting on Zoom 
 

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Outcomes and measures: 
Baseline evaluations (at screening): 
Childhood Autism Rating Scale – Second Edition (CARS2):68 CARS-2 is a validated tool for 
screening and classifying ASD, based on direct behavioral observation across 15 items (14 
specific domains such as communication, body use, and response to stimuli, plus one global 
severity rating). Each item is scored from 1 (normal) to 4 (severely abnormal). Total scores of 
30–36.5 indicate mild to moderate ASD, and scores >36.5 indicate severe ASD. The High-
Functioning Form (CARS2-HF) is used for children ≥6 years with IQ >80, while the Standard 
Form (CARS2-ST) is used for all others. 
 
Nonverbal Intelligence Quotient (NVIQ): NVIQ will be assessed using Raven’s Colored 
Progressive Matrices (RPM), an untimed measure of problem-solving and abstract reasoning. The 
RPM consists of colored pattern sets (A, Ab, B) of increasing difficulty to assess observational 
and fluid intelligence. Test–retest reliability is typically >0.80. The RPM is generally considered 
to provide a more accurate estimate of NVIQ in children with ASD compared to the WISC or 
WPPSI.69-71 
 
Outcome Measures 
ABC-I:  The ABC72,73  is a caregiver-completed questionnaire with 58 items, organized into five 
subscales. The ABC-I (irritability) subscale consists of 15 items that measure the emotional and 
behavioral symptoms of ASD, including aggression toward others, deliberate self-injuriousness, 
temper tantrums, depressed mood and rapidly changing moods. The ABC-I has been accepted as 
the gold standard for measuring irritability in medication trials for ASD74 and therefore, we will 
use it as the primary endpoint in this study. Individual items are rated from 0 (never a problem) to 
3 (severe problem). 
 
VABS-III 75: The VABS is a semi-structured caregiver interview designed to assess functional 
skills in three domains: Communication, Socialization, and Daily Living Skills. It also contains a 
short Maladaptive Behavior Domain. The Adaptive Composite Score estimates overall adaptive 
behavior. Vineland items are scored based on an open-ended question as 0 (behavior not 
performed), 1 (performed sometimes), or 2 (performed on a regular basis). The instrument 
provides Standard scores (mean = 100, SD = 15) and Age Equivalent scores 
 
SRS (Hebrew version) 76,77: The SRS is a 65-item caregiver or teacher questionnaire with five 
subscales: Social Awareness, Social Cognition, Social Communication, Social Motivation, and 
Autistic Mannerisms. Items are rated on a 4-point Likert scale (0–3, total 0–195), with higher 
scores indicating greater impairment. Subscales yield T-scores; a Total T-score of 60–75 
indicates mild to moderate impairment, and >75 indicates severe impairment. Caregivers will 
complete the SRS based on behavior during the previous 6 weeks. The SRS is widely used in 
ASD research. 78-83 
 
CGI 84: this is a 7-point scale designed to measure the severity of illness (CGI-S) and, an overall 
improvement from baseline (CGI-I). This measure has been used in many clinical trials in 
ASD.58,85,86  Scores in the severity scale range from 1 (normal) through to 7 (amongst the most 
severely ill patients); in the improvement scale, scores range from 1 (very much improved) 
through 4 (unchanged) to 7 (very much worse).  
 
CGIC: this is a 7-point scale designed to measure the overall improvement from baseline. This 
measure is completed by the primary caregivers and is similar to the CGI-I 

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Autism Impact Measure (AIM)87,88: This is a 41-item caregiver-reported questionnaire designed to 
characterize core symptoms of ASD in individuals aged 3–18 years  
 
Multidimensional Assessment of Preschool Disruptive Behavior (MAP-DB)89: This 40-item 
caregiver-reported questionnaire assesses behavior across four domains: Temper Loss, 
Noncompliance, Aggression, and Low Concern for Others. It is available in three age-specific 
versions: 3-5 years, 6-8 years, and 9-10+ years. 
 
Emotion dysregulation inventory (EDI)90: This 30-item caregiver-reported questionnaire assesses 
observable signs of poor emotion regulation in children with autism.  
 
Behavior Rating Inventory of Executive Function (BRIEF)91: this is an 88 items Hebrew validated 
questionnaire, consists of 8 subscales, grouped into two index scores—Behavioral Regulation 
Index and Metacognition Index. Raw scores are converted into age- and sex-normed T scores.  
 
Children’s Sleep Habits Questionnaire (CSHQ)92: this is a 33 items Hebrew validated 
questionnaire. A higher score reflects more significant sleep disturbances (range: 33–99, a score 
of ≥41 classifies a “poor sleeper). The CSHQ has eight subscales: bedtime resistance; sleep onset 
delay; sleep duration; sleep anxiety; night waking; parasomnias; sleep-disordered breathing; and 
daytime sleepiness. This questionnaire has been used extensively in previous research in ASD  
 
 
Quality of Life in Autism Questionnaire (QOLA) – Parent version:93The QOLA is a 48-item tool 
with two subscales to measure quality of life in parents of children with ASD. Part A (QoL 
subscale) includes 28 items assessing parents’ overall quality of life, with scores ranging from 28 
to 140 (higher scores indicate greater QoL). Part B (impact of ASD symptoms subscale) includes 
20 items evaluating how problematic a child’s ASD-related difficulties are for the parent, with 
scores ranging from 20 to 100 (higher scores indicate fewer problems). 
 
Modified gastrointestinal signs and symptoms inventory (GISSI): This 15-item questionnaire was 
adapted to this study based on the GISSI-17,94 a brief parent-report screen for common 
gastrointestinal problems in children with ASD.   
 
Adverse events (AE) will be monitored using a 31-item modification of the Dosage Record 
Treatment Emergent Symptom Scale. Recent health concerns, use of medical services, and 
change in study treatment dose and concomitant medications will be recorded as well. BMI, pulse 
rate, and blood pressure will be assessed at each clinic visit. Reports of new adverse events or 
worsening of previously reported events will be rated mild (present, but not persistent or 
requiring intervention), moderate (requiring intervention), or severe (posing a severe problem and 
requiring immediate intervention). Hospitalization will be documented as a serious adverse event. 
The PI will systematically evaluate all AEs for timing, biological plausibility, alternative causes, 
dose–response relationship, and prior knowledge to determine relatedness to the study drug, 
categorized as: not related, unlikely, possibly, probably, or definitely related. 
 
 
 

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Table 1: Primary, secondary, and exploratory outcomes 
  
Primary outcome measure:  Change in the Aberrant Behavior Checklist-Irritability Subscale 
(ABC-I) score from Baseline to week 8.  
 
Main secondary outcome measures:  
1) Change from baseline to week 8 in the Vineland ™ Adaptive Behavior Scales (VABS3)- 
Socialization Domain Score  
2) Change from baseline to week 8 in the Social Responsiveness Scale (SRS-II) total raw score. 
 
Other secondary outcome measures: 
1) Number of participants with severe, moderate, and mild treatment-emergent adverse events 
during the 8-week first phase.  
2) Number of participants with clinically significant abnormal values in the CBC, liver 
transaminases, or total bilirubin or clinically significant abnormal values in the vital signs or 
physical examination at week 8 
3) Change from baseline to week 8 in the BMI  
4) Clinical Global Impressions-Improvement since baseline at week 8. 
5) Caregiver Global Impression of Change (CGIC) since baseline at week 8. 
6) Change from baseline to week 8 in the Vineland ™ Adaptive Behavior Scales (VABS3)- 
Communication and maladaptive behavior Domains Scores 
7) Change from baseline to week 8 in the emotion dysregulation inventory (EDI)  
8) Change from baseline to week 8 in the multidimensional assessment of disruptive behavior 
(MAP-DB)  
9) Change from baseline to week 8 in the autism impact measure (AIM). 
10) Change from baseline to week 8 in the Quality of Life in Autism Questionnaire (QOLA) – 
Parent version – part A: parents’ overall perception of their QOL- subscale score; and (c) part B: 
impact of ASD symptoms on parents’ QOL- subscale score 
11) Change from baseline to week 8 in the Children’s Sleep Habits Questionnaire (CSHQ)  
12) Change from baseline to week 8 in the gastrointestinal signs and symptoms inventory. 
13) Change from baseline to week 8 in the Behavior Rating Inventory of Executive Function 
14) Global Impressions-Improvement since baseline at week 17 
15) Caregiver Global Impression of Change (CGIC) since baseline at week 17. 
16) Change from baseline to week 17 in the Vineland ™ Adaptive Behavior Scales (VABS3)- 
Communication and maladaptive behavior Domains Scores 
17) Change from baseline to week 17 in the emotion dysregulation inventory (EDI)  
18) Change from baseline to week 17 in the multidimensional assessment of disruptive behavior 
(MAP-DB)  
19) Change from baseline to week 17 in the autism impact measure (AIM). 
20) Change from baseline to week 17 in the Quality of Life in Autism Questionnaire (QOLA) – 
Parent version – part A: parents’ overall perception of their QOL- subscale score; and (c) part B: 
impact of ASD symptoms on parents’ QOL- subscale score 
21) Change from baseline to week 17 in the CSHQ -total score 
22) Change from baseline to week 17 in the gastrointestinal signs and symptoms inventory. 
23) Change from baseline to week 17 in the BRIEF -Global Executive Composite (GEC) -T score 
 
 
 
 

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Exploratory outcomes 
1) Correlations between ‘markers of CBD’ at  8weeks (Plasma levels of 7-carboxy-CBD) and 
treatment outcomes, in the active treatment group.  
2) Correlations between ‘biomarkers’ at baseline [markers of the endocannabinoid system, 
transcriptome, proteome, and gut microbiota] and treatment outcomes, in the treatment group.  
3) Correlations between change in ‘biomarkers’ from baseline to 8 weeks and treatment 
outcomes, in the treatment group, in the placebo group, and in the entire cohort. 
4)  Correlations between ‘child characteristics’ at baseline [age, sex, level of function (DSM-5 
levels of support required, CARS, VABS, CGI-S, ABC-I, SRS, NVIQ), etiological factors, 
comorbidities, history of autistic regression, diet, behavioral treatments and impact of high 
fever on social deficits status], and treatment outcomes, in the treatment group.  
5) Correlations between ‘child characteristics’ at baseline and ‘biomarkers’ at baseline. 
6) Effects of the treatment compared to placebo on ‘biomarkers’ - change from baseline to week 
8. 
7) Correlations between plasma levels of 7-carboxy-CBD at 8 weeks and change in 
‘biomarkers’ from baseline to 8 weeks, in the treatment group.  
8) Correlations between levels of 7-carboxy-CBD at 8 weeks, and ‘biomarkers’ at 8 weeks, in 
the treatment group.  
9) Correlations between ‘biomarkers’ at baseline and levels of 7-carboxy-CBD at 8 weeks, in 
the treatment group.  
10) Correlations among ‘biomarkers’ [markers of the endocannabinoid system, transcriptome, 
proteome, and gut microbiota]: at baseline (entire cohort), at 8 weeks (active treatment group, 
placebo group, and entire cohort), and when combining data from baseline and 8 weeks 
(entire cohort). 
11) Correlations between each ‘biomarker’ and each behavioral assessment score (i.e., symptom 
severity) at baseline (entire cohort), at 8 weeks (active treatment group, placebo group, and 
entire cohort), and when combining data from baseline and 8 weeks (entire cohort). 
12) Longitudinal changes in gut microbiota in the study group and in the placebo group and 
correlations with longitudinal changes in the behavioral assessments in these time points.  
13) Cross-sectional correlations between gut microbiota and behavioral assessments at baseline 
(entire cohort) and at week 8 (active treatment group, placebo group, entire cohort) and when 
combining all time points (entire cohort). 
14) Correlations between treatment outcomes in the placebo group (‘placebo response’) and the 
family characteristics: ‘child characteristics’ (age, IQ, severity of core symptoms, experience 
with previous oral treatments and perceived ability to understand the study goals) and ‘parent 
characteristics’ (age, education, and parental expectations and believes regarding 
pharmacological and natural treatments as assessed by the parental expectations and believes 
29-item questionnaire). 
15) Correlations between gut microbiota and gastrointestinal symptoms as assessed by the 30-
item Health State Questionnaire (adverse events questionnaire) – when combining all time 
points (entire cohort). 
16) Correlations among all assessments including: ‘treatment outcomes’, ‘child characteristics’, 
and ‘parent characteristics’ (e.g., child QOL, parent QOL, severity of ASD symptoms, etc.).    
17) Correlations between ‘child characteristics’, ‘treatment outcomes’, and ‘biomarkers’ assessed 
in this study, and polymorphism in genes that compose the endocannabinoid system and the 
‘methionine and methylation cycle’ for participants in whom this data will be available 
(genetic assessments will not be performed as part of this study). 

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Table 2: Assessment Schedule during the first phase 
 
$ A diagnosis of ASD based on DSM criteria and CARS-2, core symptoms cannot be explained by the level of intellectual 
disability (NVIQ), age 4-12 years, weight 12.5-57.49 kg, CGI-S ≥4, ABCI-I score ≥18, SRS-2 total score ≥ 66, predicted 
compliance with study requirements including blood tests and tolerability to taste and smell of the study interventions. 
 
* CBC, liver transaminases, total bilirubin; Plasma levels of 7-carboxy-CBD; Serum endocannabinoid levels, relative mRNA 
expression levels of components of the eCB system in whole blood (real-time PCR), RNA-sequencing of whole blood 
samples, and plasma proteome. 
Visit Number 
1 
 
Screening 
2 
 
Baseline 
 
a 
 
 b 
End of 
Titration 
 
c 
3 
 
4W 
 
d 
 4 
  
8W    
Day Number (Visit Window) 
-90 to 1 
1 
4±2 
8±2 
12±2 28±3 42±3 56±3 
Informed consent/assent 
X 
 
 
 
 
 
 
 
Eligibility criteria$ 
X 
X 
 
 
 
 
 
 
Demographics & Medical history 
X 
 
 
 
 
 
 
 
ASD criteria      
- 
DSM-5 
X 
 
 
 
 
 
 
 
- 
CARS-2 
X 
 
 
 
 
 
 
 
Overall severity – CGI-S 
X 
 
 
 
 
 
 
 
Behavioral problems: ABC-I 
X 
X 
 
 
 
X 
 
X 
Core symptoms: SRS-2 
X 
X 
 
 
 
X 
 
X 
Nonverbal IQ 
X 
 
 
 
 
 
 
 
Vital signs 
X 
X 
 
 
 
 
 
X 
Physical exam (including BMI) 
X 
X 
 
 
 
 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Parent expectations and believes 
 
X 
 
 
 
 
 
 
Adverse Events  
 
X 
X 
X 
X 
X 
X 
X 
Compliance with Intervention 
 
 
X 
X 
X 
X 
X 
X 
Blood sampling*  
 
X 
 
 
 
 
 
X 
Gut microbiota  
 
X 
 
 
 
 
 
X 
Socialization – VABS-3 
 
X 
 
 
 
 
 
X 
QOLA; EDI; AIM 
 
X 
 
 
 
 
 
X 
BRIEF, MAP-DB, GI problems 
 
X 
 
 
 
 
 
X 
Sleep Habits – CSHQ 
 
X 
 
 
 
X 
 
X 
Physician impression of overall 
change - CGI-I 
 
 
 
 
 
 
 
X 
Caregiver impression of overall 
change – CGIC 
 
 
 
 
 
 
 
X 
Assessment of Blinding 
Questionnaire 
 
 
 
 
 
 
 
X 

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Figure 4: Study Flow Chart 
  

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Statistical Analyses 
 
A detailed statistical plan is provided in the Statistical Analyses Plan (SAP).  
 
Based on previously reported placebo effects on ABC-I scores in other ASD trials74,95,96 and 
allowing for a slightly greater placebo effect due to higher expectations associated with cannabis 
treatment, we estimate that participants assigned to the placebo group will exhibit a mean 20% 
reduction from baseline ABC-I scores. Based on our preliminary results, we assume a small-to-
medium effect size (0.35) for the study treatment—terpenes-enriched cannabis oil (T1/C28). 
Consequently, a sample size of 34 participants per group is required to achieve 80% power, using 
a mixed model of repeated measures (MMRM). To account for early withdrawals, an additional 
15% will be recruited, resulting in a total of 39 participants per group. 
This sample size is expected to provide sufficient power to detect differences in the primary 
outcome. However, an adaptive design with interim analysis by an external, non-blinded 
biostatistician will determine the final sample size. 
For secondary and exploratory efficacy analyses, nominal p-values will be presented for 
informational purposes only. 
The primary report will focus on odds ratios (OR) and 95% confidence intervals (CI). 
Additionally, a secondary analysis will evaluate the proportion of participants achieving the 
minimal clinically important difference (MCID) using a chi-square test or logistic regression 
analysis to compare proportions between groups. The analysis of the Vineland Adaptive Behavior 
Scales, Third Edition (VABS-III), will utilize Growth Scale Values (GSV), with adjustments for 
participants transitioning between age categories during the study. 
All efficacy analyses will be based on an intent-to-treat (ITT) population, defined as all 
randomized subjects who receive at least one dose of the study medication and have post-baseline 
efficacy data available. For the primary efficacy outcome and key secondary outcomes, a per-
protocol (PP) population will also be defined, consisting of ITT participants who substantially 
adhere to the study protocol. 
The primary analysis assumes that ABC-I scores are missing at random (MAR), an assumption 
deemed reasonable for this study. Missing data are unlikely to differ systematically from 
observed values for unknown reasons. 
The primary endpoint will be assessed using a Mixed Model for Repeated Measures (MMRM), 
implemented in SAS (PROC MIXED), R (lme4 package), or equivalent statistical software. 
Sensitivity analyses will include per-protocol analysis and may utilize multiple imputations to 
confirm the robustness of findings 
Secondary analyses will be conducted using the same methodology as the primary ABC-I 
endpoint for each treatment sequence. 
 
 
 

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Data Management and Confidentiality 
Identifiers- We will use a mathematic manipulation on the participants’ ID number (Xor with a 
4-digit secret code) to assign a unique ‘participant number’. We will use the participant number to 
avoid exposing personally identifiable information (PII). Only the Principal Investigator and data 
coordinating manager will have the list connecting the identified data with the participant 
number. The list will be kept in a locked desktop computer protected by two passwords and in a 
locked safe in Shaare Zedek Medical Center. Representatives of the IRB and MOH may have 
access to this identified list upon specific request. 
 
Confidentiality: To protect the privacy of human subjects and maintain the confidentiality of 
study data we will use a strict separation between identified and non-identified data.  
Identified data: consent forms and contact information will not contain ‘participant number’. It 
will be kept in a locked cabinet at Shaare Zedek Medical Center- SZMC. Electronic files of 
contact information and scans of consent forms will be kept in a locked desktop computer 
protected by two passwords.  
ADOS-2 assessments (if performed) will be videotaped (with legal guardians’ consent) to allow 
evaluation by two independent ratters. Files will be kept in external hard disks at a locked safe. 
All video files will be completely removed within 12 months after study completion. 
All other data, records, and biological samples will be captured and stored un-identified, using the 
participant number as the sole identifier.  
Hard copies of all outcome questionnaires and assessment tools will be stored un-identified 
(participant number only) in locked cabinets at the study site (SZMC). Biological samples (sera, 
plasma, and stool samples) will be stored un-identified (participant number only) in locked 
freezers at the study site. Identified and non-identified data will be kept in different rooms. Only 
the study PI and the data coordinating manager will have access to study records, data, and 
specimens. Representatives of the IRB, and MOH are eligible to review study records.  
 
Data capture, verification, and disposition: Study data will be captured using paper and pencil 
forms that will not contain identified data. Forms will be uploaded to the web application 
REDCap. REDCap is a secure web application for building and managing online surveys and 
databases. It can be used to collect any type of data including 21 CFR Part 11, FISMA, and 
HIPAA-compliant environments. REDCap supports online and offline data capture for research 
studies and the REDCap Consortium is composed of thousands of active institutional partners in 
over one hundred countries.    
All data (hard copy and electronic) will be stored for 15 years.  
 
Sharing study results:  The results of all baseline assessments (CARS-2, nonverbal IQ), blood 
work, and other data regarding study participation (including study assignments and individual 
results) will be shared with the primary care providers. 
 
Procedures Description:  
 
The principal investigator (PI) for the clinical investigation is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported in the eCRFs and in all other reports 
during the clinical investigation 
 
The Site Clinical Coordinator for the clinical investigation is responsible for: 
1 
Maintaining all of the study-related files: This includes maintaining all logs such as: 

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- 
Ethics Approvals and all communications with the ethic committees (such as protocol 
amendments and serious adverse events reports)  
- 
Protocol Deviation Log 
- 
Subject Informed Consent (SIC) Signature Log 
- 
Investigation Team Log 
2 
Correct filling of the eCRFs based on source documentation and live documentation 
3 
Maintaining contact with study subjects, and coordinating study visits  
 
At the start of the clinical study, the Clinical Coordinator will make sure that all study files for the 
following: 
- 
IRB/EC/Helsinki Committee Documents.All IRB Correspondence is on file.The study 
staff are IRB approved prior to performing any study procedures.Adverse events and 
deviation procedures for reporting to IRB per current guidelines are in place.All versions 
of the IRB protocols and informed consent forms are on file.Signed Good Clinical 
Practice compliance form, financial disclosure and CV for the PI and sub investigators. 
Other documents: 
- 
CVs for all study staff are on file and updated within the last 2 years 
- 
Medical licenses for the Sub-Investigators are on file and updated prior to the expiration 
- 
Delegation Log is updated and procedures for updating the log with new staff are in place 
- 
All other essential documents have been prepared and completed as appropriate 
 
Before, during, and at the close of the study period, study documentation will be monitored by the 
Clinical Coordinator for the following: 
- 
Informed Consent Form (ICF) 
o Ensure that subject identification is on all pages of the ICF, if applicable 
o Documentation of subject receiving a copy of the consent form is present 
o Clinic note documents informed consent process 
o The parents or a legal guardian of the subject and study representative signed and 
dated the consent form for their self  
o Note to file completed for any informed consent deviations.   
o Ensure a valid (current version date) copy of the consent form was used 
 
Protocol: 
- 
Confirm that the study staff is conducting the study in compliance with the protocol 
approved by IRB/CE/Helsinki Committee and are trained in Good Clinical Practices 
(GCP). 
- 
The protocol deviations (exceptions and violations) are documented in the subject chart 
and reported to IRB/CE/Helsinki Committee as required. 
- 
Ensure any deviations are logged in the form ‘Protocol Deviations’ 
 
Source Documents: 
- 
Review subject charts to ensure accuracy, completeness, and legibility of the data 
- 
Any correction made to the source documents is dated, initialed, and explained. The 
original entry should not be obscured. 
- 
The protocol-specific source documents are on file. 
- 
Source documents are completed in ink or electronically. 
- 
Note to files are generated for missing or incomplete data, and to explain any discrepancies 
or additional comments. 
 
Case Report Forms: 

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- 
Ensure that the data reported on the CRF is consistent with the source documents. 
- 
Discrepancies between the source documents and eCRF are explained in a note to file or 
captured in a comment in the eCRF. 
 
 
Biological samples 
Biological samples will be labeled with participant numbers and stored in locked freezers. The 
legal guardians will decide in the consent form if the samples will be kept after the termination of 
the study for possible use in further studies or be destroyed upon termination of the study. 
 
Blood samples 
Blood (6 ml in tubes with procoagulant, 6 ml in tubes with EDTA, and 3 ml in Tempus™ Blood 
RNA Tube) will be collected at the baseline (9-11 AM) and at 2-month (on 9:00- 11:00 AM, 3-4 
hours post treatment administration). 
Assessments will include: 
- 
Plasma levels of 7-carboxy-CBD  
- 
Serum endocannabinoid levels 
- 
Relative mRNA expression levels of components of the eCB system (CB1R, CB2R, 
NAPE-PLD, FAAH, DAGL, and MAGL) normalized to GAPDH in whole blood. 
- 
RNA-sequencing of whole blood samples (transcriptome), and plasma proteomics will be 
performed pre and post-treatment to discover treatment-responsive biomarkers which 
correlate with behavioral improvement.  
 
Stool samples 
Stool samples will be collected using OMNIgene GUT sample collection kit (DNA Genotek, 
Canada). This kit homogenizes the sample and stabilizes the DNA for up to 60 days at room 
temperature. Participants will receive the kits in advance: a first kit during the screening visit, a 
second kit during the 2nd or 3rd. Participants will be instructed to use the kits within 2 weeks prior 
to their next visit (baseline, 8 weeks) and bring them with them to the next visit. Stool samples 
will not be collected if the participant had received any antibiotic treatment during the 4 weeks 
prior to the sampling day. Any antibiotic treatment, special diets, and use of probiotics during the 
4 to 8 weeks prior to the sampling day - will be documented. 
 
 
 

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Informed Consent Process 
Subjects’ legal guardians interested in having their children participate in the clinical 
investigation will be screened by the participating physician. 
Subjects’ legal guardians will then be given a copy of the Patient Informed Consent with ample 
time to read and review the document and ask questions before signing. 
Subjects will meet with one of the investigators to discuss investigational participation and any 
questions they may have regarding the investigation, the investigational device, and the informed 
consent. 
The informed consent will be signed by the legal guardian, during the meeting with one of the 
participating investigators. 
A photocopy of the signed patient informed consent form will be provided to the legal guardian 
prior to the procedure. 
Subjects requesting to withdraw consent will be disqualified from the investigation at no cost or 
consequence 
 
All subjects in this study are pediatric subjects (4-12) with ASD and are therefore unable to sign 
an informed consent.  A legal guardian will sign the informed consent. Assent form will be 
obtained from any participant who is able to give it. 
 
Vulnerable Population 
This clinical investigation will be conducted on pediatric (4-12 years old) ASD populations.  
Vulnerable patients’ legal guardians will be responsible for patient informed consent. 
 
Data and Safety Monitoring Board (DSMB) 
An independent Data and Safety Monitoring Board (DSMB) will oversee the conduct of the trial. 
The DSMB is responsible for monitoring study progress, including data quality, recruitment, 
retention, and the overall risk–benefit balance. It will also consider external developments 
relevant to participant safety and research ethics. The DSMB will review interim analyses as 
needed, although no formal stopping rules are defined for this study, and will ensure that all trial 
data remain confidential. The DSMB will provide regular reports to the Bazelet Group regarding 
participant safety and trial progress, and will make recommendations on whether the study should 
continue as planned, be modified, or be terminated. In addition, the DSMB will advise the 
Bazelet Group on issues related to study conduct, enrollment, or data integrity. The DSMB will 
conclude its responsibilities upon completion of follow-up for the final participant. 
 
 

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Randomization and blinding 
 
Eligible subjects will be assigned an enrollment number in sequential order beginning with 01. 
Allocation to the treatment arm will be based on a randomization list. A randomization scheme 
will be generated by an external unblinded biostatistician. The blocked randomization will be 
performed using SAS statistical software V9.4 via the plan procedure with a fixed block size. 
The randomization scheme and lists will be sent to the study site. The randomization list will 
include sequential numbers and assigned 4-letter codes. Randomization will be kept at a 1:1 ratio. 
The randomization list will be encrypted by password and will be sent prior to first dosing to the 
principal investigator. 
The study active treatments as well as the placebo treatments will be packed in similar bottles and 
packages and will have similar appearance, taste, and smell . 
 
CBD-predominant cannabis oils and matched placebo will be prepared, bottled, and labeled by 
the Bazelet Group (Or Akiva, Israel). CBD, terpenes, and THC (when applicable), together with a 
taste and odor mixture, will be dissolved in olive oil to yield a concentration of 28% CBD (280 
mg/g, equivalent to 256 mg/mL, or 8.96 mg per 0.035-mL drop) and 9 mg THC/mL (0.32 mg per 
0.035-mL drop). An international company (dsm-firmenich) designed the taste and odor mixture 
to ensure that all three treatments (study drug, terpene-enriched CBD oil, and placebo) are 
indistinguishable. 
 
The code key for the active/ placebo labels will be kept by the external biostatistical until study-
end. Neither the principal investigator nor any other team member or individual will have access 
to the codes until study-end.  
 
 
To assess the blinding state, caregivers, participants (when applicable) and researchers will 
complete an Assessment of Blinding Questionnaire at the end of the randomized study.   
 
 
 
 

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Study Interventions 
CBD-predominant cannabis oil (CBD 3.6 mg/kg twice daily; THC 0.128mg/kg twice daily, and 
terpenes 0.25mg/kg twice daily) will be administered orally as an add-on to any existing 
treatment. 
 
Dose Justification 
The target dose of 7.2mg CBD/kg/d and 0.257mg THC/kg/d divided into 2 daily doses is based 
on the results of the randomized study that was completed recently50 in which the target dose was 
10mg CBD/kg/d and 0.5mg THC/kg/d and on our clinical experience in recent years in more than 
400 children. Notably, ongoing clinical trials of CBD for children with ASD use 3-20mg/kg/d, 
and most are using 10mg/kg/d.51 The safety of plant-derived CBD isolate at doses of 10-
50mg/kg/d was demonstrated in multiple placebo-controlled studies in children with epilepsy and 
lower doses are associated with fewer AEs.97-101 At a dose of 7.2mg/kg/d we expect no treatment 
related adverse events.  
 
 
Administration 
CBD rich oil will be administered by drops containing 0.035 ml / 8.96 mg CBD each. 
The CBD dose will be up-titrated over 8 days: 
Days 1-4: 0.1 drops per Kilogram of Bodyweight (rounded number)– twice daily (1.8 mg/kg/d)  
Days 5-8: 0.2 drops per Kilogram of Bodyweight (rounded number – twice daily (3.6 mg/kg/d) 
Days 9-56: 0.4 drops per Kilogram of Bodyweight (rounded number – twice daily (7.2 mg/kg/d) 
 
The CBD dose will be down-titrated at the end of the randomized study over 7 days: 
Days 57-60: 0.2 drops per Kilogram of Bodyweight (rounded number – twice daily (3.6 mg/kg/d) 
Days 61-64: 0.1 drops per Kilogram of Bodyweight – twice daily (1.8 mg/kg/d) 
 
On day 65, the parents or legal guardian will decide if the treatment will be discontinued or be 
switched to a second treatment (either terpenes enrich CBD isolate or CBD-predominant oil) at 
the same dose for 4 days followed by 0.2 drops per Kg X 2/d for another 4 days and 0.4 drops/kg 
X2/d until the end of the second phase. 
 
 
 
 
 
 

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Amendments to the Protocol 
The study coordinator will ensure that  
1 
Amendments to the Clinical Investigation Plan are documented, using the form 
‘Amendment and Revision Sheet’ 
2 
Approval is documented, using form ‘Clinical Investigation Document Approval Log’’ 
The amended protocol is sent to all investigators and the EC/IRB/Helsinki Committee after 
approval 
 
Deviations from the Protocol 
Neither the Principal Investigator nor any of the sub-investigators are authorized to deviate from 
the protocol, except as specified in 4.5.4 b of ISO 14155:2011 and 21 CFR 812.150 (a)(4), 
specifically requests for deviations, and reports of deviations, if the deviation affects subject’s 
rights, safety, and wellbeing, or the scientific integrity of the clinical investigation. 
Under emergency circumstances, deviations from the protocol to protect the rights, safety, and 
well-being of human subjects may proceed without prior approval of the sponsor and the 
EC/IRB/Helsinki Committee. Such deviations shall be documented and reported to the sponsor 
and the EC/IRB/Helsinki Committee as soon as possible. 
The research coordinator will prepare the EC/IRB /Helsinki Committee Notifications letter using 
the EC Notification Form if any reportable serious deviations or adverse events were recorded 
and send them to the Ethics Committee/Institutional Review Board/Helsinki Committee and 
Principal Investigator, according to this protocol. 
All notifications will be carried out within the time frames specified by local regulatory 
authorities. 
 

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Statements Of Compliance 
1 This clinical investigation will be conducted in accordance with ethical principles stated in the 
Declaration of Helsinki and in compliance with all national and local regulatory requirements for the 
safety and protection of human subjects.  
2 This clinical investigation will be implemented only upon receiving all final notification/authorizations 
from local and national regulatory and Helskinki/EC/IRB authorities, as appropriate. 
3 This clinical investigation will comply with any additional requirements set forth by the 
Helsinki/EC/IRB and/or regulatory authorities. 
4 This clinical investigation provides clinical study medical insurance for study participants as required 
by local and national regulatory authorities. 
5 This protocol was written in accordance with the ISO 14155:2011 Standard for Clinical investigation 
of medical devices for human subjects – Good Clinical Practice 
 
 
Early Termination or Suspension of the Clinical Investigation 
Grounds for suspension or premature termination of the clinical investigation include but are not 
limited to: 
- 
Non-compliance of the investigational site personnel to the protocol and or 
investigational procedures 
- 
Serious Adverse Events that demonstrate danger to the patient population 
- 
Unethical performance on the part of any of the investigators 
- 
Failed audit of investigation with serious flaws to study design, performance or outcomes 
- 
Business/Financial issues that cannot be resolved 
- 
Other unforeseen events that give the PI reasonable doubts to the safety of the 
participants which cannot be resolved in a reasonable time 
 
Publication Policy 
The results of this clinical investigation may be published in a mainstream peer-reviewed 
professional journal as per Chapter I. of the agreement between the Shaare Zedek Medical Center 
and the Sponsor   
 
 
 

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Adverse Events 
 
An adverse event is any undesirable or unintentional or unexpected event (sign, symptom, 
illness, abnormal laboratory value, or other medical events) that occurs during the course of the 
study, whether or not considered related to the study interventions. This definition includes events 
related to the investigational treatments and also includes events related to the procedures 
involved.   
 
Regardless of the relationship to the investigational treatments, all moderate to serious adverse 
events occurring from the time that the informed consent is signed must be recorded in the 
patient’s CRF.  
 
A mild adverse event is one that the symptom does not influence performance, require drug 
treatment or prevent the patient from carrying on with normal life activities. 
A moderate adverse event is one that the symptoms make the patient uncomfortable and causes 
some impairment to normal life activities and require treatment for symptom(s). 
A serious adverse event is an adverse event that: 
- 
Led to death 
- 
Led to a serious deterioration in the health of the subject, that either resulted in 
o A life-threatening illness or injury, or 
o A permanent impairment of a body structure or body function, or 
o In-patient or prolonged hospitalization, or 
o Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function 
 
 
In the event of an emergency resulting from the clinical investigation, all emergency treatment 
will be provided at no cost to the patient.  Clinical Investigation Insurance has been provided to 
ensure all costs be covered if necessary. 
 
The principal investigator will notify the sponsor immediately (within 24 hours) of any serious 
adverse event.  All reports to the appropriate authorities will be made by the principal investigator 
as set forth in the standard clinical practices outlined in the   21 CFR (§ 812.150(a)(1), § 
812.46(b) and § 812.150(b)(1))/ MEDDEV 2.7/3 Dec 2010 and ICH-GCP Guidelines. 
 
Adverse Events will be reported and treated as per the standard clinical   practices outlined   in   
the   21 CFR (§ 812.150(a)(1), § 812.46(b) and § 812.150(b)(1))/ MEDDEV 2.7/3 Dec 2010 and 
ICH-GCP Guidelines 
 
Anticipated adverse events include rare insomnia, irritability, and intolerance of the taste and 
smell. 
 
 

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Appendix 1 – non-generic questionnaires  
 
The Hebrew version of the following questionnaires appears in the investigator brochure. 
 
 
Demographics and medical history questionnaire………….………….31 
Health State Questionnaire (adverse events) ……………...…………...34 
Parental expectations and beliefs……………………………...…...……35 
Assessment of Blinding Questionnaire …………………………………36 
Gastrointestinal signs and symptoms inventory …………………….....37 
 
 
 

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Cannabinoid treatment in children with ASD – Demographic questionnaire 
 
Date: _______________ GUID: ______________ Informant: Mothe / Father / Guardian 
 
1. Has your child regressed in his/her development or communication? No/Yes 
Please describe at which age and the nature of the regression: ___________________ 
________________________________________________________________________ 
 
2. When your child has a high temperature, does she/ he have a substantial 
improvement in communication? No/Yes (Please specify) ____________________ 
____________________________________________________________________ 
 
3. Has your child had a genetic testing? No/Yes 
             CMA (chip) - No/Yes /unknown; Exome sequencing - No/Yes /unknown  
  
4. Does your child have a genetic diagnosis? No/Yes __________________________ 
 
5. Does your child suffer from a syndromic ASD? (Such as Down syndrome or 
Angelman syndrome, or substantial deficits in motor function or cardiac problems, or 
unusual facial features) – No/Yes (Please specify __________________________  
 
6. Does your child have a sibling or an uncle with ASD (even mild)?   No/Yes (Please 
specify) ______________________________________________________ 
 
7. Does your child have a sibling or an uncle with intellectual disability? No/Yes 
(Please specify) _______________________________________________________ 
 
8. Birth week:  _______: Normal    /    35-36/   32-34/     29-31/ 23-28 
 
9. Birth weight: ______________ Appropriate for Gestational Age /  
Small for Gestational age/    Large for Gestational age 
 
10. Curse of delivery: Normal / Cesarean / Vacuum/ Forceps, APGAR: __________ 
 
11. Was your child transferred to NICU after the labor?  No / Yes-less than 24 hours / 2-
7 days / 8-13 days / 2-4 weeks / longer than 4 weeks ___________ 
 
12.  Was you child ever hospitalized in ICU:  No/Yes (Please specify) 
_____________________________________________________________ 
 
13. Was there a serious problem in pregnancy or childbirth or a serious illness / 
accident in the first two years of life? (Severe complications of prematurity, meningitis 
or encephalitis with prolonged hospitalization in intensive care, drowning or suffocation, 
severe accident) No / Yes__________________________________  
 
14. How old was your child when he was first diagnosed with ASD? _____________ 
 
15. How old was your child when he/she started attending a special education program? 
____________________ 
 

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16.  Did your child suffer (for more than 6 months) from any of the following problems?  
(Please mark all that applies) 
Significant behavioral difficulties / Anxiety/ Significant sleep disorder / ADHD / 
Epilepsy / High sensitivity to noise, smell or touch /Unusual seeking of stimulations: 
smell, touch, sight / Low motor skills / GI problems / Food allergy / Food sensitivity  
 
17. Does your child have any other chronic diseases?  No/Yes _______________ 
 
18. Has your child ever taken any medications on a regular basis (for more than a 
month)?  No/Yes (Please mark all that applies) 
 
Antipsychotics: Neuleptil (Pericyazine) / Rispond, Risperdal (Risperidone) / Abilify, 
Ariply (Aripiprazole)
 
   / Entumine (Clothiapine) / Zyprexa (Olanzapine) / Promethazine 
(Prothiazin) / Seroquel (quetiapine) / Ziprasidone (Geodon) / 
Nozinan (levomepromazine) / clozapine 
 
Stimulants: Ritalin, Concerta, Focalin
   
    / Attent, Vyvanse 
 
SNRI: Atomic, Strattera 
 
alpha-2 agonists: Clonirit (clonidine), Intuniv (Guanfacine) 
 
Mood stabilizers: Depalept (Valproic acid) / Tegratol, Timonil (Carbamazepine)   
 
Benzodiazepines: Rivotril, Clonex (Clonazepam) / Xanax (alprazolam) 
 
SSRIs: Cipralex, Lexapro (escitalopram), Prozac, Prizma, Flutine (fluoxetine), Favoxil 
(fluvoxamine), Seroxat (paroxetine), Lustral, Serenada, Zoloft (sertraline) 
 
Other: _______________________________________________________________ 
 
19. Is your child currently taking any medications on a regular basis? No/Yes  
 
1.Name: ____________________ daily dose ___________ since ___________________ 
2.Name: ____________________ daily dose ___________ since ___________________  
3.Name: ____________________ daily dose ___________ since ___________________   
4.Name: ____________________ daily dose ___________ since ___________________   
5.Name: ___________ _________ daily dose ___________ since ___________________  
 
20. Has your child ever taken any nutritional supplements (for more than a month)? 
No/Yes (Please mark all that applies) 
 
Vitamins: Folic Acid / Folinic Acid / B12 / B6 / Vitamin D 
Minerals: Magnesium / Iron / Calcium 
Other: Carnitine (L-carnitine, Acetyl carnitine) / Sulforaphane, Glucoraphanin  
Other: Melatonin / Probiotics/ Omega – 3 
Other: ________________________________________________________ 
 
21. If any of the mentioned nutritional supplements were discontinued in the past 3 
months, please specify which and when: __________________________________ 
 
22. Has your child received antibiotics in the past two months?  
No/Yes (Please specify Name, daily dosage and for how long) __________________ 
____________________________________________________________________ 

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23. Has your child currently taking any nutritional supplements?  No/Yes  
 
1.Name: ____________________ daily dose ___________ since ___________________ 
       2.Name: ____________________ daily dose ___________ since ___________________  
       3.Name: ____________________ daily dose ___________ since ___________________   
       4.Name: ____________________ daily dose ___________ since ___________________   
       5.Name: ____________________ daily dose ___________ since __________________  
 
24. Please specify the amount of cow milk (not dairy products but actual milk) that your 
child consumes per day:  
Not at all / Up to half a glass / about one glass / about two glasses / 3 glasses or more 
 
25. Is your child currently on a special diet? (Gluten-free / Low Gluten / Lactose free / 
Low Carbs (modified Atkins) 
 
             No/Yes (Please specify Which and for how long) _____________________________ 
             _____________________________________________________________________ 
 
26.  Has your child ever taken medical Cannabis / CBD / Cannabis products?  
 
No/Yes (Please specify for how long he/she took it and when was it discontinued)  
 
1. Licensed Medical Cannabis which mostly contains CBD (20:1, 15:3, 24:0, 28:1)     
for _______ months. Discontinued _________ years and _____months ago. 
 
2. Medical Cannabis which mostly contains THC (such as: night oil, Erez, Alaska)     
for _______ months.  Discontinued _________ years and _____months ago. 
 
3. Other: __________________________________________________________      
for _______ months.  Discontinued _________ years and _____months ago. 
 
 
27. Is your child currently receiving behavioral/emotional therapy?   No/Yes 
 
1. ___________________________. Hours per week: _____. Since ___________ 
2. ___________________________. Hours per week: _____. Since ___________ 
3. ___________________________. Hours per week: _____. Since ___________ 
4. ___________________________. Hours per week: _____. Since ___________ 
5. ___________________________. Hours per week: _____. Since ___________ 
 
28. Please specify all the schools/ education programs your child attended: 
 
Age __________.  Program: ______________________________________________ 
Age __________.  Program: ______________________________________________ 
Age __________.  Program: ______________________________________________ 
Age __________.  Program: ______________________________________________ 
Age __________.  Program: ______________________________________________ 
Age __________.  Program: ______________________________________________ 
Age __________.  Program: ______________________________________________ 
 
29. Parents education (years):  Mother: ________________     Father: ______________ 
 
30. Parents occupation:  Mother: ___________________     Father: ________________ 

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Health State Questionnaire (modified Dosage Record Treatment Emergent Symptom Scale) 
 
Date: _______________ GUID: ______________ Informant: Mothe / Father / Guardian 
  
During the last 2 weeks (or 4 days, if at study onset), has your child had any of the problems listed? 
If you didn’t mark ‘No’, please indicate if the problem was mild, moderate, or severe. If you think that this 
problem is related to the study treatment, please mark it as well. 
 
 
Health Problem 
No 
Rarely 
Sometimes 
Always    mild 
moderate 
Severe 
Treatment 
related 
1 
Dizziness  
 
 
 
 
 
 
 
 
2 
Drowsiness 
 
 
 
 
 
 
 
 
3 
Restlessness  
 
 
 
 
 
 
 
 
4 
Aggression  
 
 
 
 
 
 
 
 
5 
Increased tantrums 
 
 
 
 
 
 
 
 
6 
Emotional liability 
 
 
 
 
 
 
 
 
7 
Hair loss  
 
 
 
 
 
 
 
 
8 
Rash  
 
 
 
 
 
 
 
 
9 
Blurred vision  
 
 
 
 
 
 
 
 
10 
Nausea  
 
 
 
 
 
 
 
 
11 
Vomiting 
 
 
 
 
 
 
 
 
12 
Abdominal pain 
 
 
 
 
 
 
 
 
13 
Concentration problem 
 
 
 
 
 
 
 
 
14 
Dry mouth 
 
 
 
 
 
 
 
 
15 
Tremors  
 
 
 
 
 
 
 
 
16 
Headache 
 
 
 
 
 
 
 
 
17 
Insomnia 
 
 
 
 
 
 
 
 
18 
Involuntary movements 
 
 
 
 
 
 
 
 
19 
Depression  
 
 
 
 
 
 
 
 
20 
Memory problems  
 
 
 
 
 
 
 
 
21 
Constipation 
 
 
 
 
 
 
 
 
22 
Loss of appetite 
 
 
 
 
 
 
 
 
23 
Gain of appetite 
 
 
 
 
 
 
 
 
24 
Diarrhea 
 
 
 
 
 
 
 
 
25 
Nasal congestion 
 
 
 
 
 
 
 
 
26 
Sweating 
 
 
 
 
 
 
 
 
27 
Weakness 
 
 
 
 
 
 
 
 
28 
Increased salivation 
 
 
 
 
 
 
 
 
29 
Increased anxiety 
 
 
 
 
 
 
 
 
30 
Confusion 
 
 
 
 
 
 
 
 
31 
Suicidal thoughts 
 
 
 
 
 
 
 
 
 
During the last 2 weeks (or 4 days, if at study onset) Please indicate: 
Any other important health problems: __________________________________________________________ 
Any use of medical services: _________________________________________________________________ 
Any change in the study treatment dose: ________________________________________________________ 
Any change in the regular medications: _________________________________________________________ 
Any change in the regular diet or intake of food supplements (including probiotics): _____________________ 
Any change in the home or school routine or in the behavioral/ emotional treatments: ____________________ 
 
Do you think the current treatment is helpful: Yes / No 
If you answered Yes, please specify in what way: ______________________________________________ 

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Parental expectations and beliefs  
 
The following table presents various statements. Please indicate to what extent do you agree with each 
statement (your answers will have no effect on your participation in the study) 
 
# 
Statements 
Strongly 
Agree 
Quite 
agree 
Not so 
agree 
Not at 
all agree 
1 
When I give my child medicine (for example to relieve pain) he/she usually understands 
that the treatment may help him/her. 
 
 
 
 
2 
My child can understand that the treatment given in the study may improve his / her 
behavior. 
 
 
 
 
3 
My child can understand that the treatment given in the study may improve his / her 
communication difficulties. 
 
 
 
 
4 
My child's condition in the last month is worse compared to his average condition 
 
 
 
 
5 
It is hard for me to deal with my child's behavioral difficulties (I am losing patience) 
 
 
 
 
6 
When I am calm and patient my child is usually calmer too 
 
 
 
 
7 
I believe that the treatment given in the study may greatly improve my child's 
communication difficulties. 
 
 
 
 
8 
I believe that the treatment given in the study may greatly improve my child's 
behavioral difficulties 
 
 
 
 
9 
I personally know a family that treatment similar to the one given in the study - helped 
her a lot. 
 
 
 
 
10 
In the last year, my child received natural or medicinal therapy that helped him/ her 
with his/ her behavioral difficulties. 
 
 
 
 
11 
In the last year, my child received natural or medicinal therapy that helped him/ her 
with his/ her communication difficulties. 
 
 
 
 
12 
In the last year my child received natural or medicinal treatment for the behavioral 
difficulties which was discontinued due to side effects 
 
 
 
 
13 
My child is relatively sensitive to side effects of medications 
 
 
 
 
 
  
   Questions for the child participating in the study 
 
  What do you see in the picture? 
  Why do you think the child is taking medicine? (Maybe his tummy hurts and they want to help him feel better, maybe he 
has trouble behaving nicely and they want to help him) 
  How can the medicine help the child? 
  Do you sometimes have trouble behaving nicely? 
  We want to give you a treatment that will help you feel calmer and behave more nicely. Do you think that will help you? 
  We also believe the treatment can help you with your communication, like talking, understanding, and playing with others. 
Do you think that will help you? 
 
Rank (from 1-10): 
A. The child's ability to understand that the medicine given to him will improve his behavioral difficulties ________ 
B. The child's expectations that the treatment will help with his behavior problems _                     _ 
 
 
 

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Assessment of Blinding Questionnaire  
 
1) Please select the option that best reflects your beliefs regarding the treatment that 
your child received in the study: 
A) I am convinced that the treatment was 'real treatment' 
B) It seems to me that the treatment was 'real treatment' 
C) It seems to me that the treatment was 'placebo' 
D) I am convinced that the treatment was 'placebo' 
E) I really do not know 
 
 
2) If you chose A, B, C, or D, please tell us why you chose this option (you can choose 
more than one option) 
A) Due to the appearance, smell, or texture of the treatment. please specify: __________ 
____________________________________________________________________ 
B) Due to the effectiveness of the treatment 
C) Due to the inefficiency of the treatment 
D) Due to the side effects of the treatment. Please indicate which side effects: ________ 
___________________________________________________________________ 
E) I have such a feeling but I cannot point to the reason 
 
 

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Gastrointestinal signs and symptoms inventory (modified GISSI-17) 
           
  Participant research ID_________________ 
   
Your relationship to this child: Mother   
Father    
Other: _______________________ 
 
 
Most of the questions on this form are about THE LAST SIX WEEKS.  
Please put a check (V) in the box that best describes your child. 
 
In the last 6 weeks, has your child experienced any of the following gastrointestinal (tummy) 
symptoms: 
                                                                                                         Yes           No            Unsure 
1. Abdominal (belly) pain 
2. Nausea  
 
3. In the last 6 weeks, how often did your child usually have BMs? 
a.       Less than once a week 
b.       1-2 times a week 
c.       3-6 times a week 
d.       Once a day 
e.        2-3 Times a day 
f.        More than 3 times a day 
g.       Unsure 
 
4. In the last 6 weeks, what were your child’s BMs usually like? 
a.     Very hard 
b.     Hard 
c.    Not too hard and not too soft 
d.    Very soft or mushy 
e.     Watery 
f.    Unsure 
 
In the last 6 weeks, did your child:                                   Yes         No           Unsure 
 
5. Appear to feel pain when having a BM? 
6. Have to rush to the bathroom for a BM? 
 
 
In the last 6 weeks, has your child:                                   Yes             No        Unsure 
 
7. Spit up ≥ 2x per day? 
8. Experienced retching? 
9. Tilted his/her head to the side and arched back? 
 
 

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In the last 6 weeks, has your child missed activities due to:            Yes             No           Unsure 
 
10. pain and/or discomfort? 
 
11. Vomiting 
 
12. problems with BMs 
 
13. In the last 6 weeks, did your child push his abdomen with his/her hands or your hands, push 
his/her abdomen against or lean forward over furniture? 
 
14. In the last 6 weeks, did your child choke, gag, cough, or sound wet during or after 
swallowing or with meals? 
 
15. In the last 6 weeks, has your child started to refuse many foods that he or she would eat in 
the past? 
 
 
 
                                                             
 
 

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Appendix 2  
Placebo-controlled clinical trials of cannabinoid therapy in ASD with published results  
Study  
Treatment 
Target daily 
dose  
Participants 
& design 
Primary 
outcome/s 
Key Secondary 
outcomes 
Results 
Aran et 
al. [50]  
CBD-rich cannabis 
extract, 1 CBD:THC 
ratio = 20:1; 
Pure CBD&THC, 2 
CBD:THC = 20:1 
10mg CBD 
per kg of 
body weight, 
divided into 3 
daily doses  
N=150; age 
5-21 years; 
Cross-over; 
Two 12-
week periods 
Behavioral 
improvement at 
week 12:  
1. CGI-I 3  
2. HSQ-ASD 4 
1. Social 
Responsiveness 
Scale (SRS-2) 
2. Autism Parental 
Stress Index (APSI) 
3. Safety 
Both cannabinoids 
were superior to 
placebo in 2 out of 4 
assessments: CGI-I 3 
and SRS-2. No severe 
adverse events  
Silva et 
al. [102]  
CBD-rich cannabis 
extract 5 CBD:THC 
ratio = 9:1 
Variable dose: 
1.0-11.6 mg 
CBD (total) 
divided into 2 
daily doses 
N=60; age 5-
11 years; 
Parallel 
groups;  
12 weeks 
Primary Vs Secondary outcomes were not 
specified. 1. A semi-structured interview 
prepared by the authors.   2. Autism 
Treatment Evaluation Checklist (ATEC).  
3. Childhood Autism Rating Scale (CARS) 
Superior to placebo 
in 3 out of 9 
symptoms assed by 
the interview but not 
on ATEC or CARS 
 
1 BOL-DP-O-01-W, a whole-plant cannabis extract containing CBD and THC at a 20:1 ratio 
2 BOL-DP-O-01, purified CBD + purified CBD at a 20:1 ratio 
3 CGI-I: Clinical Global Impression-Improvement was used to measure improvement in 
disruptive behaviors by incorporating anchoring instructions related to behavioral 
difficulties. 
4 HSQ-ASD: Home Situations Questionnaire-ASD, a parent-rated measure of noncompliant 
behavior in children with ASD 
5 CBD-rich cannabis extract containing CBD and THC at a 9:1 ratio, supplied at a very low 
concentration (5mg/mL) by the Associação Brasileira de Apoio Cannabis Esperança 
(ABRACE) 
 

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Scahill L, Jeon S, Boorin SJ, et al. Weight Gain and Metabolic Consequences of 
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8. 
Spanagel R, Bilbao A. Approved cannabinoids for medical purposes - 
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and Adolescents with Autism Spectrum Disorder: Effects on Sleep Parameters as 
Measured by the CSHQ. Biomedicines. Jul 13 
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10. 
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