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Real life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy

There has been a dramatic increase in the number of children diagnosed with autism spectrum disorders (ASD) worldwide. Recently anecdotal evidence of possible therapeutic effects of cannabis products has emerged. The aim of this study is to characterize the epidemiology of ASD patients receiving medical cannabis treatment and to describe its safety and efficacy. We analysed the data prospectively collected as part of the treatment program of 188 ASD patients treated with medical cannabis between 2015 and 2017. The treatment in majority of the patients was based on cannabis oil containing 30% CBD and 1.5% THC. Symptoms inventory, patient global assessment and side effects at 6 months were primary outcomes of interest and were assessed by structured questionnaires. After six months of treatment 82.4% of patients (155) were in active treatment and 60.0% (93) have been assessed; 28 patients (30.1%) reported a significant improvement, 50 (53.7%) moderate, 6 (6.4%) slight and 8 (8.6%) had no change in their condition. Twenty-three patients (25.2%) experienced at least one side effect; the most common was restlessness (6.6%). Cannabis in ASD patients appears to be well tolerated, safe and effective option to relieve symptoms associated with ASD.

Introduction

There has been a 3-fold increase during the last 3 decades in the number of children diagnosed with autism spectrum disorders worldwide 1,2,3,4,5 . No specific treatments are currently available and interventions are focussing on lessening of the disruptive behaviors, training and teaching self-help skills for a greater independence 6 .

Recently, CBD enriched cannabis has been shown to be beneficial for children with autism 7 . In this retrospective study on 60 children, behavioural outbreaks were improved in 61% of patients, communication problems in 47%, anxiety in 39%, stress in 33% and disruptive behaviour in 33% of the patients. The rationale for this treatment is based on the previous observations and theory that cannabidiol effects might include alleviation of psychosis, anxiety, facilitation of REM sleep and suppressing seizure activity 8 . A prospective single-case-study of Dronabinol (a THC-based drug) showed significant improvements in hyperactivity, lethargy, irritability, stereotypy and inappropriate speech at 6 month follow-up 9 . Furthermore, Dronabinol treatment of 10 adolescent patients with intellectual disability resulted in 8 patients showing improvement in the management of treatment-resistant self-injurious behaviour 10 .

In 2007, The Israel Ministry of Health began providing approvals for medical cannabis, mainly for symptoms palliation. In 2014, The Ministry of Health began providing licenses for the treatment of children with epilepsy. After seeing the results of cannabis treatment on symptoms like anxiety, aggression, panic, tantrums and self-injurious behaviour, in children with epilepsy, parents of severely autistic children turned to medical cannabis for relief.

Although many with autism are being treated today with medical cannabis, there is a significant lack of knowledge regarding the safety profile and the specific symptoms that are most likely to improve under cannabis treatment. Therefore, the aim of this study was to characterize the patient population receiving medical cannabis treatment for autism and to evaluate the safety and efficacy of this therapy.

Results

Patient population

During the study period, 188 ASD patients initiated the treatment. Diagnosis of ASD was established in accordance with the accepted practice in Israel; six board certified paediatric psychiatrists and neurologists were responsible for treatment of 125 patients (80.6%), the remaining 30 children were referred by 22 other physicians. Table 1 shows demographic characteristics of the patient population. The mean age was 12.9 ± 7.0 years, with 14 (7.4%) patients being younger than the age of 5, 70 patients (37.2%) between 6 to 10 years and 72 (38.2%) aged 11 to 18. Most of the patients were males (81.9%). Twenty-seven patients (14.4%) suffered from epilepsy and 7 patients (3.7%) from Attention Deficit Hyperactivity Disorder (ADHD).

At baseline parents of 188 patients reported on average of 6.3 ± 3.2 symptoms. Table 2 shows the prevalence of symptoms with most common being restlessness (90.4%), rage attacks (79.8%) and agitation 78.7%.

Cannabis products recommended to the patients were mainly oil applied under the tong (94.7%). Seven patients (3.7%) received a license to purchase oil and inflorescence and three patients (1.5%) received a license to purchase only inflorescence. Most patients consumed oil with 30% CBD and 1.5% THC, on average 79.5 ± 61.5 mg CBD and 4.0 ± 3.0 mg THC, three times a day (for a more detailed distribution of CBD/THC consumptions see Supplementary Fig. S1). Insomnia recorded in 46 patients (24.4%) was treated with an evening does of 3% THC oil with on average additional 5.0 ± 4.5 mg THC daily. All the products content was validated by HPLC (High Performance Liquid Chromatography) in each production cycle. The cannabis dose was not significantly associated with weight (r correlation coefficient = −0.13, p = 0.30), age (r correlation coefficient = −0.10, p = 0.38), or gender (p = 0.38).

Follow-up, one month

After one month, out of 188 patients, 8 (4.2%) stopped treatment, 1 (0.5%) switched to a different cannabis supplier, and 179 patients (94.6%) continued active treatment (Fig. 1). Of the latter group, 119 (66.4%) responded to the questionnaire with 58 patients (48.7%) reporting significant improvement, 37 (31.1%) moderate improvement; 7 patients (5.9%) experienced side effects and 17 (14.3%) reported that the cannabis did not help them.

The study population in the three follow-up periods, at intake, after one month and after six months of medical cannabis treatment.

The reported side effects at one month were: sleepiness (1.6%), bad taste and smell of the oil (1.6%), restlessness (0.8%), reflux (0.8%) and lack of appetite (0.8%).

Follow-up, six months

After six months, of the 179 patients assessed in the one-month follow-up, 15 patients (8.3%) stopped treatment, 9 (4.9%) switched to a different cannabis supplier and 155 patients (86.6%) continued treatment (Fig. 1). Of the latter group, 93 (60.0%) responded to the questionnaire with 28 patients (30.1%) reporting a significant improvement, 50 patients (53.7%) moderate improvement, 6 patients (6.4%) slight improvement and 8 (8.6%) having no change in their condition. None of the variables entered to the multivariate analysis to predict treatment success was statistically significant.

To assess the potential response bias, we have compared baseline characteristics between 93 respondents and 62 non-respondents to the 6-month questionnaire. The former group was slightly older (13.7 ± 0.8 vs. 10.8 ± 0.5, p = 0.004).

Quality of Life

The improved symptoms at 6 months included seizures, of the 13 patients on an active treatment at six months 11 patients (84.6%) reported disappearances of the symptoms and two patients reported improvement; restlessness and rage attacks were improved in 72 patients (91.0%) and 66 (90.3%) respectively (Table 2).

Medications Use

The most common concomitant chronic medications on the intake were antipsychotics (56.9%), antiepileptics (26.0%), hypnotics and sedatives (14.9%) and antidepressants (10.6%). Out of 93 patients responding to the follow-up questionnaire, 67 reported use of chronic medications at intake. Overall, six patients (8.9%) reported an increase in their drugs consumption, in 38 patients (56.7%) drugs consumption remained the same and 23 patients (34.3%) reported a decrease, mainly of the following families: antipsychotics, antiepileptics antidepressants and hypnotics and sedatives (Table 4). Antipsychotics, the most prevalent class of medications taken at intake (55 patients, 33.9%); at 6 months it was taken at the same dosage by 41 of them (75%), 3 patients (5.4%) decreased dosage and 11 patients (20%) stopped taking this medication (Table 4).

Side Effects

The most common side effects, reported at six months by 23 patients (25.2%, with at least one side effect) were: restlessness (6 patients, 6.6%), sleepiness (3, 3.2%), psychoactive effect (3, 3.2%), increased appetite (3, 3.2%), digestion problems (3, 3.2%), dry mouth (2, 2.2%) and lack of appetite (2, 2.2%).

Out of 23 patients who discontinued the treatment, 17 (73.9%) had responded to the follow-up questionnaire at six months. The reasons for the treatment discontinuation were: no therapeutic effect (70.6%, twelve patients) and side effects (29.4%, five patients). However, 41.2% (seven patients) of the patients who discontinued the treatment had reported on intentions to return to the treatment.

Discussion

Cannabis as a treatment for autism spectrum disorders patients appears to be well-tolerated, safe and seemingly effective option to relieve symptoms, mainly: seizures, tics, depression, restlessness and rage attacks. The compliance with the treatment regimen appears to be high with less than 15% stopping the treatment at six months follow-up. Overall, more than 80% of the parents reported at significant or moderate improvement in the child global assessment.

The exact mechanism of the cannabis effects in patients with ASD is not fully elucidated. Findings from ASD animal models indicate a possible dysregulation of the endocannabinoid (EC) system 11,12,13,14,15,16 signalling behaviours, a dysregulation that was suggested to be also present in ASD patients 17 . Mechanism of action for the effect of cannabis on ASD may possibly involve GABA and glutamate transmission regulation. ASD is characterized by an excitation and inhibition imbalance of GABAergic and glutamatergic signalling in different brain structures 18 . The EC system is involved in modulating imbalanced GABAergic 19 and glutamatergic transmission 20 .

Other mechanism of action can be through oxytocin and vasopressin, neurotransmitters that act as important modulators of social behaviours 21 . Administration of oxytocin to patients with ASD has been shown to facilitate processing of social information, improve emotional recognition, strengthen social interactions, reduce repetitive behaviours 22 and increase eye gaze 23 . Cannabidiol was found to enhance oxytocin and vasopressin release during activities involving social interaction 16 .

Two main active ingredients (THC and CBD) can have different psychoactive action mechanisms. THC was previously shown to improve symptoms characteristic to ASD patients in other treated populations. For example, patients reported lower frequency of anxiety, distress and depression 24 , following THC administration, as well as improved mood and better quality of life in general 25 . In patients suffering from anxiety, THC led to improved anxiety levels compared to placebo 26 and in dementia patients, it led to reduction in nocturnal motor activity,violence 27,28 behavioural and severity of behavioural disorders 29 . Moreover, cannabis was shown to enhances interpersonal communication 30 and decrease hostile feelings within small social groups 31 .

In our study we have shown that a CBD enriched treatment of ASD patients can potentially lead to an improvement of behavioural symptoms. These findings are consistent with the findings of two double-blind, placebo-controlled crossover studies demonstrating the anxiolytics properties of CBD in patients with anxiety disorder 32,33 . In one, CBD had a significant effect on increased brain activity in the right posterior cingulate cortex, which is thought to be involved in the processing of emotional information 32 , and in the other, simulated public speaking test was evaluated in 24 patients with social anxiety disorder. The CBD treated group had significantly lower anxiety scores than the placebo group during simulated speech, indicating reduction in anxiety, cognitive impairment, and discomfort factors 33 .

The cannabis treatment appears to be safe and side effects reported by the patients and parents were moderate and relatively easy to cope with. The most prevalent side effects reported at six months was restlessness, appearing in less than 6.6% of patients. Moreover, the compliance with the treatment was high and only less than 5% have stopped the treatment due to the side effects. We believe that the careful titration schedule especially in the ASD paediatric population is important for maintaining a low side effects rate and increase of the success rate. Furthermore, we believe that a professional instruction and detailed parents’ training sessions are highly important for the increasing of effect to adverse events ratio.

The present findings should be interpreted with caution for several reasons. Firstly, this is an observational study with no control group and therefore no causality between cannabis therapy and improvement in patients’ wellbeing can be established. Children of parents seeking cannabis therapy might not constitute a representative sample of the patient with the specific disease (self-selection bias). We have not formally confirmed the ASD diagnosis, however all the children included in the study were previously diagnosed with ASD by certified neurologist or psychiatrist, as required by Ministry of Health prior to the initiation of the cannabis-based treatment.

This study was based on a subjective self-report of the patient’s parent’s observation and not by the patients themselves. These reports, with subjective variables such as quality of life, mood, and general effects, may be biased by the parent’s opinion of the treatment. Moreover, even though the effect was assessed at six months, the possibility of the inflated expectations of the novel treatment “miracle” effect cannot be excluded. The questionnaire response rate at 6 months was 60%, thus the estimates of the efficacy and safety of the treatment can be biased. However, high compliance (above 80%) with the treatment provides a good evidence of the patients and parents satisfaction with the treatment.

While this study suggest that cannabis treatment is safe and can improve ASD symptoms and improve ASD patient’s quality of life, we believe that double blind placebo-controlled trials are crucial for a better understanding of the cannabis effect on ASD patients.

Methods

Study Population

There are currently over 35,000 patients approved for medical cannabis use in Israel and 15,000 (~42.8%) of them receive treatment at Tikun-Olam Ltd. (TO), the largest national provider of medical cannabis. This study included all patients receiving cannabis license at TO with the diagnosis of autism in the years 2015–2017.

During the routine treatment process at the cannabis clinic, all willing patients underwent an extensive initial evaluation and their health status was periodically assessed by the treating team. At the intake session, the nurse assessed a complete medical history. The patient’s parents were interviewed by the nurse and filled a medical questionnaire, which included the following domains: demographics, comorbidities, habits, concomitant medications, measurements of quality of life and a detailed symptoms check-list. Following intake, the nurse advised on the treatment plan.

Treatment Regiment

The treatment in majority of the patients was based on cannabis oil (an extract of a high CBD strain dissolve in olive oil in a ratio THC:CBD of 1:20, 30% CBD and 1.5% THC), and underwent an individualized titration. The starting dose was one sublingual drop three times a day with one oil drop (0.05 ml) containing 15 mg CBD and 0.75 mg Δ9-THC. Oil contained 45% olive oil, 30% CBD, 1.5% THC,

In patients who reported high sensitivity to previously used medications, the treatment started with oil containing 1:20 15% CBD and 0.75% THC. In patients with severe sleep disturbances, following the initial treatment phase, 3% THC oil was added to the evening dose. In cases with a significant aggressive or violent behaviour, 3% THC oil was added.

The dose was increased gradually for each patient depending on the effect of the cannabis oil on the targeted symptoms according to the treatment plan and the tolerability of each patient. Finding of the optimal dose could take up to two months and dosage range is wide: from one drop three times a day to up to 20 drops three times a day of the same product.

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After one month, the treating team contacted the parents to follow-up on the treatment progression. At six months patients underwent an additional assessment of the symptom intensity, side effects and quality of life.

Study outcomes

For safety analysis we have assessed the frequency of the following side effects at one and at six months: physiological effects – headaches, dizziness, nausea, vomiting, stomach ache, heart palpitation, drop in blood pressure, drop in sugar, sleepiness, weakness, chills, itching, red/irritated eyes, dry mouth, cough, increased appetite, blurred vision, slurred speech; cognitive side effects – restlessness, fear, psycho-active effect, hallucinations, confusion and disorientation, decreased concentration, decreased memory or other. The patient parents were asked to provide details of the incidence, duration and severity of the reported side effect.

For the efficacy analysis we used the global assessment approach where the patient parents were asked: “How would you rate the general effect of cannabis on your child condition?” the options were: significant improvement, moderate improvement, slight improvement, no change, slight deterioration, moderate deterioration and significant deterioration. Autism symptoms severity assessment included the following items: restlessness, rage attacks, agitation, speech impairment, cognitive impairment, anxiety, incontinence, depression and more. Quality of life was assessed on a Likert scale ranging from very poor to poor, neither poor nor good and good to very good 34 .

The study was approved by Soroka University Medical Centre Ethics Committee and due to the nature of the data analysis based on the routinely obtained clinical data, it was determined that no informed consent is required. All methods were performed in accordance with the relevant institutional and international research guidelines and regulations.

Statistical analysis

Continuous variables with normal distribution were presented as means with standard deviation. Ordinary variables or continuous variables with non-normal distribution were presented as medians with an interquartile range (IQR). Categorical variables were presented as counts and percent of the total.

We used t-test and paired t-test for the analysis of the continuous variables with normal distribution. The non-parametric Mann-Whitney U test and paired Wilcoxon test was used whenever parametric assumptions could not be satisfied.

We utilized logistic regression for the multivariate analysis of factors associated with treatment success. We have included the following variables into the models based on clinical considerations: age, gender, number of chronic medications, number of total symptoms, and the three most prevalent symptoms: restlessness, rage attacks and agitation (as a dichotomous variable- yes/no), as reflected in the intake form.

Declarations

The study was approved by Soroka University Medical Center Ethics Committee (study number: SCRC-0415-15) and the need for informed consent was waived due to the retrospective nature of the data analysis.

Availability of Data

The data set generated and/or analysed during the current study are not publicly available due to medical confidentiality but are available from the first author on reasonable request summarized form pending the approval of the IRB.

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Cannabinoid treatment for autism: a proof-of-concept randomized trial

Endocannabinoid dysfunction in animal models of autism spectrum disorder (ASD) and accumulating, albeit anecdotal, evidence for efficacy in humans motivated this placebo-controlled double-blind comparison of two oral cannabinoid solutions in 150 participants (age 5–21 years) with ASD.

Methods

We tested (1) BOL-DP-O-01-W, a whole-plant cannabis extract containing cannabidiol and Δ9-tetrahydrocannabinol at a 20:1 ratio and (2) BOL-DP-O-01, purified cannabidiol and Δ9-tetrahydrocannabinol at the same ratio. Participants (N = 150) received either placebo or cannabinoids for 12-weeks (testing efficacy) followed by a 4-week washout and predetermined cross-over for another 12 weeks to further assess tolerability.

Registered primary efficacy outcome measures were improvement in behavioral problems (differences between whole-plant extract and placebo) on the Home Situation Questionnaire-ASD (HSQ-ASD) and the Clinical Global Impression-Improvement scale with disruptive behavior anchor points (CGI-I). Secondary measures were Social Responsiveness Scale (SRS-2) and Autism Parenting Stress Index (APSI).

Results

Changes in Total Scores of HSQ-ASD (primary-outcome) and APSI (secondary-outcome) did not differ among groups. Disruptive behavior on the CGI-I (co-primary outcome) was either much or very much improved in 49% on whole-plant extract (n = 45) versus 21% on placebo (n = 47; p = 0.005). Median SRS Total Score (secondary-outcome) improved by 14.9 on whole-plant extract (n = 34) versus 3.6 points after placebo (n = 36); p = 0.009). There were no treatment-related serious adverse events. Common adverse events included somnolence and decreased appetite, reported for 28% and 25% on whole-plant extract, respectively (n = 95); 23% and 21% on pure-cannabinoids (n = 93), and 8% and 15% on placebo (n = 94).

Lack of pharmacokinetic data and a wide range of ages and functional levels among participants warrant caution when interpreting the results.

Conclusions

This interventional study provides evidence that BOL-DP-O-01-W and BOL-DP-O-01, administrated for 3 months, are well tolerated. Evidence for efficacy of these interventions are mixed and insufficient. Further testing of cannabinoids in ASD is recommended.

Trial registration ClinicalTrials.gov: NCT02956226. Registered 06 November 2016, https://clinicaltrials.gov/ct2/show/NCT02956226

Background

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]; the efficacy and tolerability of pharmacotherapies addressing comorbid disruptive behaviors are relatively low [2].

Consumption of cannabis is reported to enhance interpersonal communication [3] and decrease hostile feelings [4]. The main components of the cannabis plant (phytocannabinoids) are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC activates the type-1 cannabinoid receptor (CB1R) in the brain; it is psychoactive and can lead to anxiety and psychosis [5]. CBD, on the other hand, is an allosteric modulator of the CB1R and might decrease the effects of CB1R agonists such as THC. It is not psychoactive and has a relatively high toxicity threshold [5]. While THC consumption, especially at a young age, can lead to addiction, cognitive decline, motivational loss, and psychosis, co-consumption of CBD might reduce these risks [6].

CBD also appears to have anxiolytic, antipsychotic, antiepileptic, and neuroprotective properties that may be mediated through receptors such as serotonin 5-HT1A, glycine α3 and α1, TRPV1, GPR55, GABAA, and PPARγ, and by inhibiting adenosine reuptake [7,8,9,10,11]. A single oral administration of 600 mg CBD to 34 men (17 neurotypicals and 17 with ASD) increased prefrontal GABA activity in neurotypicals and decreased GABA activity in those with ASD [12].

Epidiolex is a cannabis-derived pure CBD compound which was approved by the U.S. FDA in 2018 for the treatment of two severe forms of epilepsy [13]. This may be relevant for patients with ASD, as 10–30% also have epilepsy, and several pathophysiological pathways are implicated in both disorders [11, 14].

The endocannabinoid system is a cell-signaling system composed of the cannabinoid receptors, their endogenous ligands (endocannabinoids, mainly anandamide and 2-AG), transporters, and enzymes which produce and degrade the endocannabinoids [15].

Studies in animal models suggest a reduced endocannabinoid tone in ASD [16,17,18,19]. Stimulation of the endocannabinoid system [16,17,18,19] and administration of CBD [17] have improved social deficits in some models. Additionally, children with ASD have been found to have lower peripheral endocannabinoid levels [20, 21].

These preclinical data and case-series, reporting treatment with artisanal CBD-rich, cannabis strains [22,23,24,25,26] have triggered widespread use of various cannabis strains in children with ASD, despite a lack of controlled studies. Furthermore, the cannabis plant contains a wide range of minor cannabinoids, terpenes, and flavonoids which differ by strain. These components have also been reported to impact human behaviour [27, 28]. Various combinations of these components have been proposed to have a synergistic pharmacological effect (‘the entourage effect’) [29]. Whether presumed effects of cannabis in ASD should be attributed to CBD or THC, or whether minor cannabinoids, terpenes, and flavonoids also contribute therapeutically remains unclear. Accordingly, we performed a proof-of-concept, placebo-controlled trial of whole-plant extract and pure cannabinoids in children and adolescents with ASD. We hypothesized that whole-plant extract, per the entourage effect, would be more effective than placebo for disruptive behaviors; assessing this hypothesis was our primary objective. A secondary objective was to assess the efficacy of pure cannabinoids which are more standardized and repeatable than whole-plant extracts and hence more suitable for pharmacotherapy.

Methods

Standard protocol approvals, registrations, and patient consents

NCT02956226 was approved by the Institutional Review Board at Shaare Zedek Medical Center and the Israeli Ministry of Health prior to participant enrollment. Participants’ parents provided written informed consent and written assent was obtained from participants when appropriate.

Study design

This proof-of-concept, randomized, double-blind, placebo-controlled trial was conducted in a single referral center—Shaare Zedek Medical Center, Jerusalem, Israel. Eligible participants were children and adolescents (5–21 years old) with an ASD diagnosis per DSM-5 criteria, confirmed by Autism Diagnostic Observation Schedule (ADOS-2), and moderate or greater behavioral problems (rating ≥ 4) on the Clinical Global Impression (CGI)-Severity scale (Table 1). Anchoring instructions (provided in the Additional file 1) were used so that the CGI-S would quantify behavioral difficulties rather than overall ASD severity.

Participants were randomly assigned (1:1:1 ratio) to 1 of 3 treatments for 12-weeks. Treatments were: (1) oral placebo, (2) whole-plant cannabis extract containing CBD and THC at a 20:1 ratio, and (3) pure CBD and pure THC at the same ratio and concentration. Randomization and blinding processes are described in the Additional file 1.

The primary objective was to evaluate whether whole-plant cannabis extract would induce a significant improvement in behavioral assessments compared to placebo. We used the same CBD: THC ratio as in previous open-label case series [22,23,24]. We did not use a ‘CBD only’ arm in this initial study, as we hypothesized that the CBD-THC combination would be more efficacious because of direct effects of THC on the endocannabinoid system.

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For ethical reasons, we used a crossover design in which all participants would receive cannabinoids at least once: after 12-weeks of treatment (‘Period-1’) and a 4-week washout period, participants crossed-over to a predetermined second 12-week treatment (‘Period-2’; Fig. 1). The cross-over design was intended to allow within-participant analyses, comparing the two treatments that each participant received. As we had noted a substantial improvement in our open observational study with whole-plant extract [22], we ordered treatments a priori to minimize the likelihood of substantial improvement of severe disruptive behaviors in the first period and deterioration in the second period. As we hypothesized that whole-plant extract would be more effective than pure cannabinoids, we excluded the sequence of whole-plant extract followed by placebo.

Preliminary analyses revealed a treatment order effect: change from baseline was greater in the first period than in the second, suggesting a greater initial placebo effect. As a treatment order effect impairs the validity of within-participant analyses, we decided to evaluate between-group efficacy only during the first period. Data from both periods were examined for safety and tolerability. For transparency, we present within-participant analyses and between-participant analyses of period-2 (Additional file 1).

Intervention

Cannabis plants (Topaz strain; BOL Pharma, Israel) were subjected to CO2 extraction. The extract was either immediately dissolved in olive oil (BOL-DP-O-01-W) or underwent further purification to 99% pure CBD and then was dissolved in olive oil (BOL-DP-O-01). The final concentrations of CBD and THC in both solutions were 167 mg/ml CBD and 8.35 mg/ml THC. Flavorings were added to all three solutions to make taste and scent uniform.

In each treatment period, starting dose was 1 mg/kg/d CBD (and 0.05 mg/kg/d THC). The dose was increased by 1 mg/kg/d CBD (and 0.05 mg/kg/d THC) every other day up to 10 mg/kg body weight per day CBD (and 0.5 mg/kg/d THC) for children weighing 20–40 kg or 7.5 mg/kg/d CBD (and 0.375 mg/kg/d THC) for weight > 40 kg (to a maximum of 420 mg CBD and 21 mg THC per day) divided into 3 daily doses. Treatments were given orally (sublingual whenever possible) as an add-on to any ongoing stable medication. At the end of each treatment period, the study treatment was gradually decreased over 2 weeks.

Baseline evaluations

Baseline assessments included: ADOS-2 [30], a standardized assessment of communication, social interaction, play, and imaginary use of materials; Vineland Adaptive Behavior Scales (VABS) [31], a caregiver interview assessing Communication, Socialization, and Daily Living Skills; and Childhood Autism Rating Scale-Second edition (CARS2-ST) [32], a quantitative measure of direct behavior observation.

Outcomes

Primary outcomes: We designated two co-primary outcome measures to assess ASD associated disruptive behaviors: Home Situations Questionnaire-ASD (HSQ-ASD) and CGI-Improvement (CGI-I) targeting behavioral problems.

HSQ-ASD [33] is a 24-item parent-rated measure of noncompliant behavior in children with ASD. The scale yields per-item mean scores of 0 to 9 (higher is worse) [33].

CGI-I [34] was used to measure improvement in disruptive behaviors from baseline by incorporating anchoring instructions related to behavioral difficulties (Anchors appear in the Additional file 1). As in the standard CGI-I, scores ranged from 1 (very much improved) through 4 (unchanged) to 7 (very much worse). Scores of 1 or 2 (much improved) were defined as a positive response; all others indicated a negative response [34]. CGI-I was assessed at the end of each treatment period. The same clinician (AA) assessed and rated the CGI-S and CGI-I of all participants.

Secondary outcomes included the Social Responsiveness Scale-2nd edition (SRS-2), the Autism Parenting Stress Index (APSI), and adverse events.

SRS-2: [35] this 65-item, caregiver questionnaire quantifies autism symptom severity (total scores range from 0 to 195; higher is worse).

APSI: [36] this 13-item parent-rated measure assesses parenting stress in three categories: core social disability, difficult-to-manage behavior, and physical issues.

Adverse events were assessed using a modified Liverpool Adverse Events Profile (LAEP) including the 19 original LAEP [37] items plus 15 items covering all significant adverse effects of CBD and THC reported in prior pediatric studies.

Statistical analyses

The primary aim of this study was to test the superiority of whole-plant-extract over placebo in treating ASD associated behavioral problems, using the HSQ-ASD and the CGI-I for disruptive behaviors. The comparison between pure-cannabinoids and placebo was registered as a secondary outcome. Sample size calculation was based on an effect size of f = 0.67 (in total HSQ-ASD score) [38] and standard deviation of 3 points in the within-participant difference between placebo and whole-plant extract conditions. To achieve 80% power with 2.5% alpha (adjusted for two co-primary endpoints) requires a sample of 43 patients per group. To account for attrition, an additional 15% were enrolled. A total of 50 participants per arm was set to test primary study endpoints. Analyses were performed using JMP version 14 (SAS Institute, Cary, NC, USA). All P values were two-sided. Specific statistical tests used and corrections applied for multiple comparisons are indicated in figure/table legends.

For details on the cannabinoid preparations, randomization process, important changes to methods after trial commencement, anchoring instructions for rating the CGI-S and CGI-I, and the CONSORT checklist, see Additional file 2.

Results

Between 11 January 2017 and 12 April 2018, 150 children and adolescents (mean age 11.8 ± 4.1 years, median 11.25, range 5.1–20.8; 80% boys) entered the trial. ASD symptoms were ‘severe’ in 78.7% per ADOS-2 (Comparison Score = 8–10) [30] and adaptive level was ‘low’ (Standard Score ≤ 70) in 88% per Vineland Behavior Scales [31].

Screening, randomization and attrition are shown in Fig. 2 and participant characteristics are provided in Table 2. Fifty participants were randomly assigned to each of the 3 treatments in Period-1 and 44 per group completed the study (12% overall attrition).

Trial profile: screening, randomization and treatment periods

Safety and tolerability of cannabinoid treatment with BOL-DP-O-01-W (whole-plant extract) and BOL-DP-O-01 (pure cannabinoids)

Adverse events (AEs) were reported whenever they occurred, and caregivers were proactively asked about them at each study visit, and every 4 weeks using a structured questionnaire. AEs were documented whether considered related to study treatments or not. Reports of new adverse events or worsening of previously reported events were rated mild (present, but not problematic), moderate (problematic and leading to study drug dose decrease), or severe (posing a problem requiring medical intervention). Serious AEs were possibly life-threatening events or any requiring hospitalization. Overall, 95 participants received a whole-plant extract, 93 received pure cannabinoids, and 94 received a placebo.

There were no treatment-related severe or serious AEs. Six participants had an unrelated serious event (Additional file 1: Table S1). Overall, mild AEs were not significantly more frequent during cannabinoid treatment (mild AEs were reported 383, 388, and 353 times, in 89, 79, and 78 participants during treatment with whole-plant extract, pure cannabinoids, and placebo, respectively). Moderate AEs were reported 80, 78, and 57 times, in 44, 45, and 26 participants during treatment with whole-plant extract, pure cannabinoids, and placebo, respectively. AEs that were more common during cannabinoid treatment are presented in Table 3. The full list of adverse events and correlations with age, sex, treatment dose, and concomitant medications appears in Additional file 1: Table S2.

Impact of cannabinoid treatment with BOL-DP-O-01-W (whole-plant extract) and BOL-DP-O-01 (pure cannabinoids) on behavior

The impact of cannabinoid treatment on behavioral problems was assessed using the HSQ-ASD [33], and the CGI-I [34] (co-primary outcome measures). The APSI [36] (secondary outcome measure) also reflects the child’s behavior. HSQ-ASD total scores and APSI total scores did not differ significantly between participants who received cannabinoids and participants who received placebo (Table 4). On the CGI-I, 49% of 45 participants who received whole-plant cannabinoids responded (either much or very much improved) [34] compared with 21% of 47 on placebo (p = 0.005, Fig. 3). Of the 45 participants who received pure cannabinoids, 38% responded, which was not significantly higher than placebo (p = 0.08).

Table 4 Impact of cannabinoid treatment, as reflected by change from baseline to end of treatment period 1 in total scores of HSQ-ASD, SRS-2, and APSI

Participants (%) whose behavioral problems either much improved or very much improved on the CGI-I scale following treatment. Response to 12-week treatment using the Clinical Global Impression-Improvement (CGI-I). Positive response in this scale is defined as a rating of ‘much improved’ or ‘very much improved’ [34]. Outcome was analyzed using Likelihood ratio chi-square test. P value is unadjusted. *Remains significant after Bonferroni-correction for multiple comparisons

None of these 3 measures (HSQ-ASD, CGI-I and APSI) differed significantly between participants who received whole-plant extract versus pure cannabinoids (Table 4).

Second treatment period results are presented in Additional file 1: Table S3 and Additional file 1: Figure S2 for transparency but not further discussed because of a significant order effect.

Impact of BOL-DP-O-01-W (whole-plant extract) and BOL-DP-O-01 (pure cannabinoids) on Social Responsiveness Scale scores

ASD symptoms (secondary outcome) were assessed with the SRS-2 [35]. Improvement in SRS-2 total score was significantly higher following treatment with whole-plant extract compared with placebo (Table 4). Median total score improved by 3.6 points after placebo (n = 36) versus 14.9 on whole-plant extract (n = 34; p = 0.009) and 8.2 on pure cannabinoids (n = 28; p = 0.80). Results of the second treatment period are presented in Additional file 1: Table S3 and Additional file 1: Figure S3 for transparency.

Exploratory analyses: impact of BOL-DP-O-01-W (whole-plant extract) and BOL-DP-O-01 (pure cannabinoids) treatment on Body Mass Index (BMI)

Baseline BMIs were equivalent across treatment groups (Table 2). The BMI of participants who received cannabinoids decreased during active treatment [Median ] by − 0.45 in Period-1 (n = 44) and − 0.12 in Period-2 (n = 40)] following treatment with whole-plant extract; BMI decreased by − 0.36 in Period-1 (n = 44) and − 0.01 in Period-2 (n = 43) following treatment with pure cannabinoids. Changes in BMI following cannabinoid treatment (either whole-plant extract or pure cannabinoids) were − 0.36 in Period-1 (n = 88) and − 0.01 in Period-2 (n = 83). During treatment with placebo, changes in BMI were 0.16 in Period-1 (n = 43; p < 0.0001 versus cannabinoids) and 0.30, in Period-2 (n = 43; p = 0.002 versus cannabinoids).

Notably, participants with higher BMI at baseline had a more prominent decrease in BMI following cannabinoid treatment [The decrease in BMI was positively correlated with baseline BMI (F = 4.3, p = 0.042 in Period-1, F = 8.6, p = 0.005 in Period-2)]. Change in BMI following placebo was not significantly correlated with baseline BMI (Fig. 4).

Impact of cannabinoid treatment on BMI. Change in BMI during 12-week treatment with either cannabinoids or placebo. a Whole-plant extract versus pure cannabinoids; b Cannabinoid treatment (either whole-plant extract or pure cannabinoids) versus placebo; c Distribution of data, bars represent 10%, 25%, Median, 75% and 90%, differences between placebo and cannabinoids were analyzed using median test; d, e Change in BMI as function of baseline level, stratified by treatment (cannabinoids or placebo) and treatment period (d first period, e second period). Correlations were analyzed using linear regression

Exploratory analyses: possible moderators of treatment effects

Additional file 1: Table S4 presents possible moderators of treatment response. Severity of ASD core symptoms at baseline (as assessed by ADOS-2) and concomitant use of medications were not significantly associated with response to either pure cannabinoids or whole-plant extract, on any assessment.

Males were more likely to improve on the HSQ-ASD and SRS-2. Younger children were more likely to improve on the CGI-I and APSI. Participants who had somnolence during cannabinoid treatment were more likely to respond per the CGI-I assessment. However, treatment with the whole-plant extract remained significantly associated with improvement on the CGI-I and SRS-2 after controlling for somnolence and for concomitant use of medications during treatment [Odds Ratio of 6.08 (p = 0.003) and 3.56 (p = 0.015), respectively].

Correlations between treatment dose (per Kg of body weight) and treatment response are presented in Additional file 1: Table S5. The average treatment dose during the first period was 5.7 ± 2.6 mg/kg/d of CBD in the whole-plant extract arm and 5.9 ± 2.7 mg/kg/d of CBD in the pure cannabinoids arm. A higher dose of whole-plant extract correlated with higher behavioral improvement on the CGI-I (rs = − 0.29, n = 45, p = 0.050). Cannabinoid dose did not correlate significantly with any other endpoints for either whole-plant extract or pure cannabinoids.

Concomitant medications

Study treatments were added to ongoing behavioral or pharmacological treatments. Planned changes in such treatments or a change in the 4 weeks prior to randomization were exclusionary.

Concomitant medications were taken by 72% of participants (Table 2). Adverse events or response were not significantly associated with concomitant medication use (Additional file 1: Table S2 and S3), except for somnolence which was higher in those on chronic medications (p = 0.001).

Discussion

Currently, there are no established medications for the core autistic symptoms. Risperidone and aripiprazole have been approved by the U.S. Food and Drug Administration (FDA) to treat comorbid irritability [2] but these medications often cause obesity and metabolic syndrome [2, 39].

In this study, we have demonstrated for the first time in a placebo-controlled trial that cannabinoid treatment has the potential to decrease disruptive behaviors associated with ASD, with acceptable tolerability. This is specifically important for the many individuals with ASD who are overweight, as cannabinoid treatment was associated with net weight-loss (Fig. 4) in contrast to the substantial weight gain usually produced by antipsychotics.

Two co-primary outcomes were designated to assess improvement in disruptive behaviors following cannabinoid treatment: a parent questionnaire (HSQ-ASD) and an interview-based clinician assessment (CGI-I).

HSQ-ASD scores did not differ significantly between participants who received cannabinoids and participants who received placebo. However, as our cohort included children and adolescents with a wide range of function levels, many participants had 4 or more items which were not applicable on the HSQ-ASD, limiting sample size on this scale (Table 4).

The clinician assessment was based on a detailed description of the most bothersome behavioral problems at baseline and an extensive interview at the end of each treatment period focused on those problems. Using this patient- and family-centered tool customized for each participant, we found that 49% of participants receiving the whole-plant extract treatment responded versus 21% on placebo (p = 0.005).

Intriguingly, one of our secondary outcomes, the SRS-2, provided preliminary evidence that cannabinoid treatment might improve core symptoms of ASD (Table 4). This finding could be of high importance if confirmed in future studies, as studies exploring pharmacological interventions for the ASD core symptoms are scarce.

Although not reportable as evidence of efficacy due to crossover effects, Additional file 1: Figures S2 and S3 show that results in the second treatment period were similar to those in the first.

Other possible implications of this preliminary study for future studies and selected clinical use include feasibility of sublingual administration in children with low adaptive level, and feasibility of a starting dose of 1 mg/kg/d of CBD and a gradual increase over 2–3 weeks to a target of 5–10 mg/kg/d divided into 2–3 daily doses.

The study explored two cannabinoid compounds, differing by the absence of terpenes, flavonoids, and minor cannabinoids in the pure-cannabinoid compound. While additive and even synergistic therapeutic effects of these additional components have been suggested (‘entourage’ effect) [28, 29], we did not find clear advantages for the whole-plant extract over pure cannabinoids, suggesting that attempts to search for the optimal ‘entourage’ effect across cannabis strains with the same CBD:THC ratio are likely to be challenging. As previously reported in studies of children with refractory epilepsy [40, 41], we also found relatively high placebo effects, emphasizing the importance of placebo in studies of medical cannabis.

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Similar to these studies we also found somnolence to be the most prevalent adverse event but importantly, cannabinoid treatment remained significantly associated with a positive response on the CGI-I and SRS-2 assessments after controlling for somnolence during treatment [Odds ratio of 6.08, p = 0.003].

Cannabinoids might affect behavior and communication through several mechanisms. THC activates CB1R and has been associated with enhanced social behavior in multiple studies [42, 43]. CBD is a 5-HT1A receptor agonist, which might facilitate anxiolytic effects. Its presumed antipsychotic effect is attributed to partial agonism at dopamine D2 receptors, similar to the antipsychotic action of aripiprazole [44].

Limitations

Our study had several limitations. Although it was designed as a cross-over study, preliminary analyses revealed a treatment order effect which prevented the use of data from the second treatment period and limited sample size. As this was the first clinical study in the ASD field, we included a wide range of levels of function. Unfortunately, the standardized questionnaires contained many items that were inapplicable for some low-functioning participants, resulting in numerous invalid scores and decreased statistical power on those measures. We did not perform genetic or intelligence quotient evaluations and could not assess the effects of genetic background or cognitive level on treatment response. We did collect data on concomitant medications but were not powered to detect effects on treatment response or on adverse events. We did not obtain data on pharmacokinetics of the interventions and concomitant medications nor tests of liver enzymes and complete blood count, although we detected no clinical evidence of hepatic or hematologic dysfunction.

Conclusions

Novel pharmacological treatments for the core and comorbid symptoms of ASD are urgently needed. Preclinical studies implicate the endocannabinoid system in the pathophysiology of ASD. In a controlled study of 150 participants, we found that BOL-DP-O-01-W, a whole-plant extract which contains CBD and THC in a 20:1 ratio, improved disruptive behaviors on one of two primary outcome measures and on a secondary outcome, an index of ASD core symptoms, with acceptable adverse events. These data suggest that cannabinoids should be further investigated in ASD.

Future studies should consider recruiting participants within narrower ranges of age and functional levels, assess the long-term tolerability and safety of cannabinoid treatments, and identify target populations within the autism spectrum that might benefit most from these treatments.

Availability of data and materials

The authors declare that the data supporting study findings are available within the paper and its Additional file. The remaining data are available from the corresponding author upon reasonable request.

Abbreviations

Autism Parenting Stress Index

Autism spectrum disorder

Type-1 cannabinoid receptor

Clinical Global Impression–Severity/Improvement

Home Situations Questionnaire

Social Responsiveness Scale

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Acknowledgements

The statistical analysis was conducted by: Elliot Sprecher, PhD, Technion Faculty of Medicine, Haifa, Israel and Yishai Friedlander, M.P.H, Public Heath, Ben-Gurion University, Israel. Anchoring instructions for rating the CGI-S and CGI-I were developed in consultation with Dr. Elizabeth Berry-Kravis.

Funding

The study was funded by BOL Pharma, Revadim, Israel and the National Institute for Psychobiology in Israel (#203-17-18). The funding bodies were not involved in any way in the study design, collection, analysis and interpretation of data or in the writing of the manuscript.

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Authors and Affiliations

Neuropediatric Unit, Shaare Zedek Medical Center, 12 Bayit Street, 91031, Jerusalem, Israel

Adi Aran, Moria Harel, Hanoch Cassuto, Lola Polyansky, Aviad Schnapp & Nadia Wattad

Child Development Centers, Clalit Health Services, Tel Aviv-Yafo, Israel

Child Development Centers, Maccabi Health Services, Jerusalem, Israel

Department of Child and Adolescent Psychiatry, NYU Grossman School of Medicine, New York, NY, USA

F. Xavier Castellanos

  1. Adi Aran

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Contributions

Dr. Aran conceptualized and designed the study, recruited participants, carried out the initial analyses, drafted the initial manuscript, and reviewed and revised the manuscript. Ms. Harel collected data, carried out the initial analyses, and reviewed and revised the manuscript. Drs. Cassuto, Schnapp, Watted, Shmueli and Golan recruited participants, collected data, and reviewed and revised the manuscript. Ms. Polyansky designed the data collection instruments, collected data, carried out the initial analyses, and reviewed and revised the manuscrip. Dr. Castellanos interpreted data, drafted the initial manuscript, and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. All authors read and approved the final manuscript.

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All research procedures were approved by the Shaare Zedek Medical Center Review Board and Israeli Ministry of Health prior to participant enrollment. Participants’ parents provided written consent prior to initiation of any experimental procedures, and written assent was obtained from participants when appropriate.

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Competing interests

Adi Aran and F. Xavier Castellanos report receiving personal fees and stock options for advisory roles at BOL Pharma. The remaining authors have no conflicts of interest to disclose.

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Aran, A., Harel, M., Cassuto, H. et al. Cannabinoid treatment for autism: a proof-of-concept randomized trial. Molecular Autism 12, 6 (2021). https://doi.org/10.1186/s13229-021-00420-2

Received : 08 September 2020

Accepted : 27 January 2021

Published : 03 February 2021

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