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

Abstract

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.

Full text

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SCIeNTIFIC REPoRTS | (2019) 9:200 | DOI:10.1038/s41598-018-37570-y
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Real life Experience of Medical
Cannabis Treatment in Autism:
Analysis of Safety and Ecacy
Lihi Bar-Lev Schleider
1,2, Raphael Mechoulam3, Naama Saban2, Gal Meiri4,5 &
Victor Novack1
There has been a dramatic increase in the number of children diagnosed with autism spectrum disorders
(ASD) worldwide. Recently anecdotal evidence of possible therapeutic eects 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 ecacy. 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 eects 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 signicant 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 eect; the
most common was restlessness (6.6%). Cannabis in ASD patients appears to be well tolerated, safe and
eective option to relieve symptoms associated with ASD.
ere has been a 3-fold increase during the last 3 decades in the number of children diagnosed with autism spec-
trum disorders worldwide1–5. No specic treatments are currently available and interventions are focussing on
lessening of the disruptive behaviors, training and teaching self-help skills for a greater independence6.
Recently, CBD enriched cannabis has been shown to be benecial for children with autism7. In this retrospec-
tive 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. e rationale for this
treatment is based on the previous observations and theory that cannabidiol eects might include alleviation of
psychosis, anxiety, facilitation of REM sleep and suppressing seizure activity8. A prospective single-case-study
of Dronabinol (a THC-based drug) showed signicant improvements in hyperactivity, lethargy, irritability,
stereotypy and inappropriate speech at 6 month follow-up9. Furthermore, Dronabinol treatment of 10 ado-
lescent patients with intellectual disability resulted in 8 patients showing improvement in the management of
treatment-resistant self-injurious behaviour10.
In 2007, e Israel Ministry of Health began providing approvals for medical cannabis, mainly for symp-
toms palliation. In 2014, e Ministry of Health began providing licenses for the treatment of children with
epilepsy. Aer 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 signicant lack of knowl-
edge regarding the safety prole and the specic symptoms that are most likely to improve under cannabis treat-
ment. erefore, the aim of this study was to characterize the patient population receiving medical cannabis
treatment for autism and to evaluate the safety and ecacy of this therapy.
1Clinical Cannabis Research Institute, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion
University of the Negev, Be’er-Sheva, Israel. 2Research Department, Tikun Olam LTD, Tel Aviv-Yafo, Israel. 3Institute
for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel. 4Negev Autism
Centre, Ben-Gurion University of the Negev, Beer Sheva, Israel. 5Soroka University Medical and Faculty of Health
Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel. Correspondence and requests for materials should
be addressed to V.N. (email: VictorNo@clalit.org.il)
Received: 23 August 2018
Accepted: 23 November 2018
Published: xx xx xxxx
OPEN
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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 certied 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. e 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%) suered
from epilepsy and 7 patients (3.7%) from Attention Decit 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 inorescence. 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. e cannabis dose was not signif-
icantly associated with weight (r correlation coecient = −0.13, p = 0.30), age (r correlation coecient = −0.10,
p = 0.38), or gender (p = 0.38).
Follow-up, one month. Aer one month, out of 188 patients, 8 (4.2%) stopped treatment, 1 (0.5%) switched
to a dierent 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 signicant improvement, 37
Total (188)
Mean age (SD) 12.9 (7.0)
Gender (male), No. (%) 154 (81.9)
Mean body mass index (SD) 29.0 (5.3)
Previous experience with cannabis (Yes), No. (%) 19 (10.1)
Comorbidities:
Epilepsy, No. (%) 27 (14.4)
Attention Decit Hyperactivity Disorder, No. (%) 7 (3.7)
Tourette syndrome, No. (%) 4 (2.1)
Celiac Disease, No. (%) 3 (1.6)
Anxiety Disorder, No. (%) 3 (1.6)
Table 1. Demographic and clinical characteristics of patients at intake.
Intake prevalence
Total (188)
Change at six months
Symptom
disappeared Improvement No change or
deterioration
Restlessness, No. (%) 170 (90.4) 1 (1.2) 71 (89.8) 7 (8.8)
Rage attacks, No. (%) 150 (79.8) 1 (1.3) 65 (89.0) 7 (9.5)
Agitation, No. (%) 148 (78.7) 1 (1.4) 57 (83.8) 10 (14.7)
Sleep problems, No. (%) 113 (60.1) 9 (19.5) 27 (58.6) 10 (21.7)
Speech Impairment, No. (%) 113 (60.1) —15 (30) 35 (70)
Cognitive impairment, No. (%) 91 (48.4) —15 (27.2) 40 (72.7)
Anxiety, No. (%) 69 (36.7) —24 (88.8) 3 (11.1)
Incontinence, No. (%) 51 (27.1) 2 (9.0) 7 (31.8) 13 (59.0)
Seizures, No. (%) 23 (12.2) 2 (15.3) 11 (84.6) —
Limited Mobility, No. (%) 17 (9.0) 2 (18.1) —9 (81.8)
Constipation, No. (%) 15 (8.0) 1 (12.5) 6 (62.5) 2 (25)
Tics, No. (%) 15 (8.0) 1 (20.0) 4 (80.0) —
Digestion Problems, No. (%) 14 (7.4) 1 (12.5) 5 (62.5) 2 (25.0)
Increased Appetite, No. (%) 14 (7.4) 1 (33.3) 1 (33.3) 1 (33.3)
Lack of Appetite, No. (%) 14 (7.4) 2 (40.0) 1 (20.0) 2 (40.0)
Depression, No. (%) 10 (5.3) —5 (100.0) —
Table 2. Symptom prevalence and change. Symptom prevalence at intake in 188 patients assessed at intake and
change at six months in patients responding to the six-month questionnaire.
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(31.1%) moderate improvement; 7 patients (5.9%) experienced side eects and 17 (14.3%) reported that the
cannabis did not help them.
e reported side eects at one month were: sleepiness (1.6%), bad taste and smell of the oil (1.6%), restless-
ness (0.8%), reux (0.8%) and lack of appetite (0.8%).
Follow-up, six months. Aer 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 dierent 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 signicant 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 signicant.
To assess the potential response bias, we have compared baseline characteristics between 93 respondents and
62 non-respondents to the 6-month questionnaire. e former group was slightly older (13.7 ± 0.8 vs. 10.8 ± 0.5,
p = 0.004).
Quality of Life. Quality of life, mood and ability to perform activities of daily living were assessed before the
treatment and at six months. Good quality of life was reported by 31.3% of patients prior to treatment initiation
while at 6 months good quality of life was reported by 66.8% (p < 0.001, Supplementary Fig.S2). Positive mood
was reported by the parents on 42% before treatment and 63.5% aer 6 months of treatment (p < 0.001). e
ability to dress and shower independently was signicantly improved from 26.4% reported no diculty in these
activities prior to the treatment to 42.9% at six months (p < 0.001). Similarly, good sleep and good concentra-
tion were reported by 3.3% and 0.0% (respectively) before the treatment and on 24.7% (p < 0.001) and 14.0%
(p < 0.001) during an active treatment (Table3).
e 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; restless-
ness and rage attacks were improved in 72 patients (91.0%) and 66 (90.3%) respectively (Table2).
Medications Use. e 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 Eects. e most common side eects, reported at six months by 23 patients (25.2%, with at least one
side eect) were: restlessness (6 patients, 6.6%), sleepiness (3, 3.2%), psychoactive eect (3, 3.2%), increased appe-
tite (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. e reasons for the treatment discontinuation were: no therapeutic eect (70.6%, twelve patients)
and side eects (29.4%, ve patients). However, 41.2% (seven patients) of the patients who discontinued the treat-
ment 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
eective option to relieve symptoms, mainly: seizures, tics, depression, restlessness and rage attacks. e com-
pliance 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 signicant or moderate improvement in the child
global assessment.
Six-month follow-up
One-month follow-up
Intake
Screening 207
188 in
treatment and
responded
179 ongoing
treatment
155ongoing
treatment
9switched
supplier
-15stopped
treatment
1 switched
supplier
-8 stopped
treatment
-17 Transferred
from a different
supplier
-2 refused
treatment
119 responded
93 responded
Figure 1. e study population in the three follow-up periods, at intake, aer one month and aer six months
of medical cannabis treatment.
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e exact mechanism of the cannabis eects in patients with ASD is not fully elucidated. Findings from ASD
animal models indicate a possible dysregulation of the endocannabinoid (EC) system11–16 signalling behaviours,
a dysregulation that was suggested to be also present in ASD patients17. Mechanism of action for the eect 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 dierent brain structures18.
e EC system is involved in modulating imbalanced GABAergic19 and glutamatergic transmission20.
Other mechanism of action can be through oxytocin and vasopressin, neurotransmitters that act as important
modulators of social behaviours21. Administration of oxytocin to patients with ASD has been shown to facilitate
processing of social information, improve emotional recognition, strengthen social interactions, reduce repetitive
behaviours22 and increase eye gaze23. Cannabidiol was found to enhance oxytocin and vasopressin release during
activities involving social interaction16.
Two main active ingredients (THC and CBD) can have dierent 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 depression24, following THC administration, as well as
improved mood and better quality of life in general25. In patients suering from anxiety, THC led to improved
anxiety levels compared to placebo26 and in dementia patients, it led to reduction in nocturnal motor activi-
ty,violence27,28 behavioural and severity of behavioural disorders29. Moreover, cannabis was shown to enhances
interpersonal communication30 and decrease hostile feelings within small social groups31.
In our study we have shown that a CBD enriched treatment of ASD patients can potentially lead to an
improvement of behavioural symptoms. ese ndings are consistent with the ndings of two double-blind,
placebo-controlled crossover studies demonstrating the anxiolytics properties of CBD in patients with anxiety
disorder32,33. In one, CBD had a signicant eect on increased brain activity in the right posterior cingulate cor-
tex, which is thought to be involved in the processing of emotional information32, and in the other, simulated pub-
lic speaking test was evaluated in 24 patients with social anxiety disorder. e CBD treated group had signicantly
lower anxiety scores than the placebo group during simulated speech, indicating reduction in anxiety, cognitive
impairment, and discomfort factors33.
e cannabis treatment appears to be safe and side eects reported by the patients and parents were moderate
and relatively easy to cope with. e most prevalent side eects reported at six months was restlessness, appear-
ing 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 eects. We believe that the careful titration schedule especially in the
ASD paediatric population is important for maintaining a low side eects rate and increase of the success rate.
Furthermore, we believe that a professional instruction and detailed parents’ training sessions are highly impor-
tant for the increasing of eect to adverse events ratio.
e present ndings 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 specic disease (self-selection bias). We have not formally conrmed the ASD diag-
nosis, however all the children included in the study were previously diagnosed with ASD by certied neurologist
or psychiatrist, as required by Ministry of Health prior to the initiation of the cannabis-based treatment.
is study was based on a subjective self-report of the patient’s parent’s observation and not by the patients
themselves. ese reports, with subjective variables such as quality of life, mood, and general eects, may be
Sleep Eating with Appetite Concentration on daily tasks Bowel Activity
Before During p value Before During p value Before During p value Before During p value
Severe diculty 44 (47.3) 2 (2.2)
<0.001
2 (2.2) 1 (1.1)
0.751
75 (80.6) 21 (22.6)
<0.001
3 (3.2) 2 (2.2)
0.242
Moderate diculty 18 (19.4) 27 (29.0) 6 (6.5) 13 (14.0) 11 (11.8) 41 (44.1) 13 (14.0) 17 (18.3)
No diculty 28 (30.1) 39 (41.9) 59 (63.4) 47 (50.5) 2 (2.2) 11 (11.8) 71 (76.3) 54 (58.1)
Good 2 (2.2) 15 (16.1) 10 (10.8) 16 (17.2) 010 (10.8) 5 (5.4) 13 (14.0)
Very Good 1 (1.1) 8 (8.6) 16 (17.2) 14 (15.1) 03 (3.2) 1 (1.1) 4 (4.3)
Table 3. Assessment of daily activities. Ability to perform activities of daily living was assessed prior to and six
months aer initiation of cannabis treatment. Numbers in parenthesis represent the % of patients.
Medication family
Intake Change at six months follow-up
Tot a l Stopped taking
this medication Dosage
decreased Has not
changed Dosage
increased New
medication
Antipsychotics, n (%) 55 11 (20) 3 (5) 41 (75) 0 0
Antiepileptics, n (%) 46 6 (13) 035 (76) 2 (4.5) 3 (6.5)
Antidepressants, n (%) 10 3 (30) 04 (40) 1 (10) 2 (20)
Hypnotics and sedatives, n (%) 10 2 (20) 1 (10) 7 (70) 0 0
Anxiolytics, n (%) 72 (28) 05 (72) 0 0
Table 4. Concomitant medications. Concomitant medications use at the baseline and six months follow up in
patients responding to the six-month questionnaire.
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biased by the parent’s opinion of the treatment. Moreover, even though the eect was assessed at six months,
the possibility of the inated expectations of the novel treatment “miracle” eect cannot be excluded. e ques-
tionnaire response rate at 6 months was 60%, thus the estimates of the ecacy 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 understand-
ing of the cannabis eect on ASD patients.
Methods
Study Population. ere 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. is 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. e patient’s parents were interviewed by the nurse and lled a medical
questionnaire, which included the following domains: demographics, comorbidities, habits, concomitant medi-
cations, measurements of quality of life and a detailed symptoms check-list. Following intake, the nurse advised
on the treatment plan.
Treatment Regiment. e 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. e 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, <1.5% CBC,
0.5% CBG, <0.5% CBDV and <0.1% CBN. e remaining ingredients were terpenes, avonoids, waxes and
chlorophyll
In patients who reported high sensitivity to previously used medications, the treatment started with oil con-
taining 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 signicant aggressive or violent behaviour, 3%
THC oil was added.
e dose was increased gradually for each patient depending on the eect 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.
Aer 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 eects and quality of life.
Study outcomes. For safety analysis we have assessed the frequency of the following side eects at one and
at six months: physiological eects – 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 eects – restlessness, fear, psycho-active eect,
hallucinations, confusion and disorientation, decreased concentration, decreased memory or other. e patient
parents were asked to provide details of the incidence, duration and severity of the reported side eect.
For the ecacy analysis we used the global assessment approach where the patient parents were asked: “How
would you rate the general eect of cannabis on your child condition?” the options were: signicant improve-
ment, moderate improvement, slight improvement, no change, slight deterioration, moderate deterioration and
signicant 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
good34.
e 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. e
non-parametric Mann-Whitney U test and paired Wilcoxon test was used whenever parametric assumptions
could not be satised.
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 reected in the intake form.
P value < 0.05 was considered to be statistically significant. All analyses were performed at the Clinical
Research Centre, Soroka University Medical Centre, Beer-Sheva, Israel using IBM SPSS version 22 (SPSS,
Chicago, IL).
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Declarations. e study was approved by Soroka University Medical Center Ethics Committee (study num-
ber: SCRC-0415-15) and the need for informed consent was waived due to the retrospective nature of the data
analysis.
Availability of Data
e data set generated and/or analysed during the current study are not publicly available due to medical con-
dentiality but are available from the rst author on reasonable request summarized form pending the approval
of the IRB.
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Acknowledgements
Tikun Olam LTD. supported the study.
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7
SCIeNTIFIC REPoRTS | (2019) 9:200 | DOI:10.1038/s41598-018-37570-y
Author Contributions
L.B.L.S., V.N. and R.M. planned the study; N.S. collected the data, L.B.L.S. and V.N. analysed the data, L.B.L.S.
wrote the manuscript, V.N. and G.M. reviewed and approved the manuscript.
Additional Information
Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-018-37570-y.
Competing Interests: L.B.L.S. and N.S. are employees of Tikun-Olam Ltd. V.N. is a paid member of the Tikun
Olam Ltd. scientic advisory board. R.M. and G.M. have no conicts of interest pertaining to the current
manuscript.
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