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


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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.
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SCIeNTIFIC REPoRTS | (2019) 9:200 | DOI:10.1038/s41598-018-37570-y
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 worldwide15. 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:
Received: 23 August 2018
Accepted: 23 November 2018
Published: xx xx xxxx
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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)
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
disappeared Improvement No change or
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.
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
Screening 207
188 in
treatment and
179 ongoing
1 switched
-8 stopped
-17 Transferred
from a different
-2 refused
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) system1116 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 patients 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)
2 (2.2) 1 (1.1)
75 (80.6) 21 (22.6)
3 (3.2) 2 (2.2)
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
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.
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
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
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
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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Tikun Olam LTD. supported the study.
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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
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
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Supplementary resource (1)

... We identified five published studies evaluating the efficacy of CBP in children and/or adolescents with ASD. These include three before-after observational studies with no control group [41][42][43] and two case reports [44,45] ( Table 1). The symptoms that improved most often across the studies were maladaptive behaviours (e.g., aggression, irritability, and hyperactivity), and core impairments of ASD (social skills, social communication, and repetitive behaviours). ...
... Adverse effects were mostly mild to moderate and transient. Concomitant medications were reported in four of the five studies, in about two-thirds of the cohort [41][42][43][44][45] (Online Resource 2). ...
... In the three before-and-after observational studies [41][42][43] and a case report [45] whole plant extracts with high doses of CBD and THC or CBD and THC isolates were used ( Table 1). The three observational studies included administration of whole plant extract (n = 60) [41], cannabis oil (n = 188) [42] and cannabis Sativa extract (CE) (n = 18) [43], CBD/THC ratios were: 20:1; 20:1; and 75:1, respectively. ...
Full-text available
A better understanding of the endocannabinoid system and a relaxation in regulatory control of cannabis globally has increased interest in the medicinal use of cannabinoid-based products (CBP). We provide a systematic review of the rationale and current clinical trial evidence for CBP in the treatment of neuropsychiatric and neurodevelopmental disorders in children and adolescents. A systematic search of MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Trials was performed to identify articles published after 1980 about CBP for medical purposes in individuals aged 18 years or younger with selected neuropsychiatric or neurodevelopmental conditions. Risk of bias and quality of evidence was assessed for each article. Of 4466 articles screened, 18 were eligible for inclusion, addressing eight conditions (anxiety disorders (n = 1); autism spectrum disorder (n = 5); foetal alcohol spectrum disorder (n = 1); fragile X syndrome (n = 2); intellectual disability (n = 1); mood disorders (n = 2); post-traumatic stress disorder (n = 3); and Tourette syndrome (n = 3)). Only one randomised controlled trial (RCT) was identified. The remaining seventeen articles included one open-label trial, three uncontrolled before-and-after trials, two case series and 11 case reports, thus the risk of bias was high. Despite growing community and scientific interest, our systematic review identified limited and generally poor-quality evidence for the efficacy of CBP in neuropsychiatric and neurodevelopmental disorders in children and adolescents. Large rigorous RCTs are required to inform clinical care. In the meantime, clinicians must balance patient expectations with the limited evidence available.
... In the United Kingdom, CBMPs may be considered for these symptoms if licensed treatments have failed to produce a sufficient clinical response or are not tolerated. 15 In 2019, Schleider et al. 16 published a series of outcomes from 188 children and adolescents treated with CBMPs. In this study they demonstrated an improvement in quality of life, mood, sleep and challenging behaviours. ...
... However, they did not utilise any validated measures to assess for symptom prevalence and change over time. 16 At present, there is a paucity of randomised controlled trials and other high-quality evidence on the efficacy and safety of CBMPs in the treatment of ASDassociated symptoms. Importantly, there are no published clinical studies of the outcomes of adult patients treated with CBMPs. ...
Antiseizure medications (ASMs) are the second most widely prescribed psychotropic for people with intellectual disabilities in England. Multiple psychotropic prescribing is prevalent in almost half of people with intellectual disabilities on ASMs. This analysis identifies limited evidence of ASM benefit in challenging behaviour management and suggests improvements needed to inform clinical practice
... Estudo prospectivo avaliou a eficácia e segurança da Cannabis medicinal como tratamento adjuvante em pacientes com transtorno do espectro autista (média de idade de 12,9 anos; n=188) (Schleider et al., 2019). ...
... Cannabis is of increasing interest in this area, though most studies to date have looked at shared pathological symptoms such as hyperactivity, sleep and communication. Thus far results have been mixed, in part due to wide variation in cannabis composition and dosage (172)(173)(174)(175). GABAergic agents are of increasing interest due to the theory of excitatory inhibitory imbalance (which I will explore later in this introduction) and Bumetanide has also recently shown efficacy in symptom reduction (176). ...
Full-text available
Autism Spectrum Disorder (ASD) is a common neurodevelopmental condition typically diagnosed at 2-4 years of age when deficits in social interaction and communication are noted by carers. Our knowledge of ASD is advancing with greater awareness of the needs of autistic children and adults and a move towards improving services for these patients. The underlying neurobiology of ASD is a unifying aetiological agent, likely altered through both genetic and environmental influences. There is compelling evidence to suggest that abnormalities in Excitatory (E) glutamate and inhibitory (I) Gamma-Aminobutyric Acid (GABA) signalling in the brain may underpin ‘atypical’ development. Therefore I chose to examine relationships within the glutamatergic system in the striatum. First I looked at metabotropic glutamate receptor 5 (mGluR5) in adults with and without ASD and found higher levels of mGluR5 among autistic participants. This is consistent with other recent studies. Despite the close functional ties between mGluR5 and E/I signalling, no-one had directly examined the relationship between mGluR5 and glutamate or GABA in vivo in the human brain of autistic individuals. I found a strong negative relationship between GABA+ and mGluR5. I then looked at mGluR5 in three animal models associated with ASD to see whether any of these models might explain the greater availability of mGluR5 in autism. CNTNAP2 KO mice had significantly higher mGlu5 receptor binding in the striatum (caudate-putamen) as compared to wild-type (WT) mice. Given that CNTNAP2 is associated with a specific striatal deficit of parvalbumin positive GABA interneurons and ‘autistic’ features, this finding suggests that an increase in mGluR5 in ASD may relate to developmental GABAergic interneuron abnormalities. Neurodevelopment requires careful coordination of neuronal and glial processes spanning proliferation, differentiation, myelination and pruning. Disruption to this process can result in neurodevelopmental difficulties and disorders such as ASD. Therefore I conducted early life studies examining the relationship between subcortical Glx (Glutamate and Glutamine), N-acetylaspartate (a marker of neuronal health) and myo-Inositol (a marker of glial activity) at three early life time points: in utero, within 4 weeks of birth (neonatal time point) and at 4-6-months of age (‘infant’ time point). I compared these to later neurodevelopmental outcomes finding that higher neonatal NAA concentrations corresponded to better general neurodevelopmental scores and lower ADOS-2 scores. As NAA is a marker of neuronal health this implies that we can mark neuronal health at birth and demonstrate that this correlates with neurodevelopmental outcomes. I then went on to examine these same relationships at the 4-6-month timepoint. Higher levels of myo-Inositol (and therefore greater glial activity) corresponded to poorer general and social developmental outcomes. Higher levels of Glx and therefore excess excitation predicted greater social deficits. This is in keeping with the theory of E/I imbalance.
... [1][2][3][4][5][6][7][8][9] The intensified production and medical use of cannabis inflorescences has required laboratories worldwide to explore alternative, quick, cost-effective, and accurate analytical methods for cannabinoid quantification and the classification of cannabis cultivars, the latter being essential for authentication purposes. 2,[4][5][6][7][8][10][11][12][13][14][15][16][17][18][19] At present, the most common techniques for elucidating cannabinoid composition involve laborious, time-consuming, and expensive technologies, such as high-pressure liquid chromatography (HPLC) coupled with photodiode array (PDA) or mass spectrometry coupled with gas chromatography (GC-MS). 2,[20][21][22][23][24][25] Despite the fact that cannabinoids are fluorescent, the application of fluorescencebased detectors for their identification and quantification is surprisingly rare, even though fluorescence-based detectors are more sensitive than UV-based detectors and the emission and excitation spectra may convey more information about the compounds in a sample. ...
Introduction: Cannabis sativa L. inflorescences are rich in secondary metabolites, particularly cannabinoids. The most common techniques for elucidating cannabinoid composition are expensive technologies, such as high-pressure liquid chromatography (HPLC). Objectives: We aimed to develop and evaluate the performance of a novel fluorescence spectroscopy-based method coupled with N-way partial least squares regression (N-PLS-R) and partial least squares discriminant analysis (PLS-DA) models to replace the expensive chromatographic methods for preharvest cannabinoid quantification. Methodology: Fresh medicinal cannabis inflorescences were collected and ethanol extracts were prepared. Their excitation-emission spectra were measured using fluorescence spectroscopy and their cannabinoid contents were determined by HPLC-PDA. Subsequently, N-PLS-R and PLS-DA models were applied to the excitation-emission matrices (EEMs) for cannabinoid concentration prediction and cultivar classification, respectively. Results: The N-PLS-R model was based on a set of EEMs (n = 82) and provided good to excellent quantification of (-)-Δ9-trans-tetrahydrocannabinolic acid, cannabidiolic acid, cannabigerolic acid, cannabichromenic acid, and (-)-Δ9-trans-tetrahydrocannabinol (R2 CV and R2 pred > 0.75; RPD > 2.3 and RPIQ > 3.5; RMSECV/RMSEC ratio < 1.4). The PLS-DA model enabled a clear distinction between the four major classes studied (sensitivity, specificity, and accuracy of the prediction sets were all ≥0.9). Conclusions: The fluorescence spectral region (excitation 220-400 nm, emission 280-550 nm) harbors sufficient information for accurate prediction of cannabinoid contents and accurate classification using a relatively small data set.
... In addition, previous studies on autism spectrum disorders have shown that CBD products have a sedative effect. 19 Therefore, it is reasonable to assume that the improvement in daytime activity and vigor in this study was secondary to the reduction in seizures. A total of 46.4% of the patients felt that their QOL had improved, and 50.0% of the caregivers felt that their QOL had improved. ...
Full-text available
Purpose of study: Despite very strict cannabis regulations in Japan, some cannabidiol (CBD) products have been legally distributed since 2013 and taken by some epilepsy patients. However, its efficacy and safety have not been evaluated. Basic procedures: A self-administered questionnaire was sent to 38 patients with intractable epilepsy who were taking CBD. The questionnaire sought information on patient background (sex, age) and medical history (diagnosis, type of seizures), characteristics of CBD use (frequency, route of administration), and the safety of CBD use (adverse events, side effects). Patients were also asked about changes in seizure frequency, intensity, and duration; effect on sleep; effect on daytime activity/vitality; increase/decrease in antiepileptic drugs dosage; quality of life (QOL); and caregiver-assessed QOL. Findings: Responses were received from 28 of 38 patients. The median CBD intake was 12.0 mg/kg/day. Nine patients (32.1%) were suspected of having an adverse event, but all were mild and no patients discontinued CBD due to adverse events. Fifteen patients (53.6%) reported a decrease in seizure frequency, and 2 patients (7.1%) showed complete resolution of seizures. No significant correlation was found between the patient’s diagnosis and the seizure type or efficacy. Conclusions: This is the first cross-sectional study of CBD users in Japan, suggesting that CBD may be an effective option for Asian patients with refractory epilepsy, regardless of diagnosis or seizure type.
... The increased worldwide production and medical application of cannabis inflorescence has led scientist to explore novel, cost-effective, fast and reliable techniques for cannabinoids identification and quantification as well as cannabis cultivar classification [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. ...
Cannabinoids are commonly identified and quantified using chromatographic based methods. In the present study, fluorescence spectroscopic method coupled with Parallel Factor Analysis (PARAFAC) modeling was developed and validated as a simple and fast alternative technique for identification and quantification of major cannabinoids. A PARAFAC model was built on a set of excitation-emission matrices, yielding an optimal quantitative and qualitative performance using five components, which were identified as (-)-Δ9-trans-tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), cannabichromenic acid (CBCA) and (-)-Δ9-trans-tetrahydrocannabinol/cannabidiol/cannabigerol (THC/CBD/CBG). The identity of the major acidic components, THCA, CBDA and CBGA was verified by the correlation between PARAFAC model scores and their corresponding concentrations measured by HPLC as well as by the similarity between the excitation-emission spectral loadings of each PARAFAC component and the excitation-emission spectra of pure cannabinoids standards. Moreover, the PARAFAC model scores of each component were plotted against the cannabinoids actual concentrations in the extracts to evaluate the performance of the model for predicting the concentration of each compound. All three major acidic cannabinoids revealed good to excellent linear correlations (R2 > 0.7) between the model scores and measured concentrations according to the model calibration, cross-validation and prediction performance criteria. On the other hand, components 4 and 5 identified as CBCA and THC/CBD/CBG, respectively, revealed weaker linear correlation between the PARAFAC scores to the measured concentrations. These findings pave the way for a more comprehensive assessment of cannabis excitation-emission matrices (EEMs) as a cheaper and fast alternative for commonly used chromatographic-based quantification methods.
Maternal stress can result in changes in the hypothalamic-pituitary-adrenal (HPA) axis and lead to stress-related behaviours in offspring. Under physiological conditions, delta-9 tetrahydrocannabinol (THC) appears to be detrimental for fertility. However, cannabis is also commonly used for stress-relief. THC acts on the endocannabinoid receptors in granulosa cells (GCs), which affects oocyte competency. The objective of this study was to evaluate the effects of THC on in vitro bovine granulosa cell viability, apoptosis, and stress response pathway. GCs were cultured in vitro in the presence of clinically relevant therapeutic and recreational plasma doses of THC. Cortisol doses reflecting normal and elevated plasma levels were used to evaluate the effects of THC under induced stress in vitro. No effect of THC was observed on cell viability or apoptosis. High and low cortisol concentrations caused significant increases in 11β-HSD1 mRNA expression (n = 6, p < 0.0001). Interestingly, when combined with high [THC], there was a significant decrease in 11β-HSD1 expression compared to high and low cortisol treatments alone (p < 0.001, p < 0.05). GR expression was unaffected by cortisol treatments, and low [THC] treatment maintained increased expression in the presence of high and low cortisol treatments (n = 6, p < 0.01, p < 0.0001). Our findings represent a foundation to obtain useful data for evaluating THC potential therapeutic benefit.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder, onset in early childhood and associated with cognitive, social, behavioral, and sensory impairments. The pathophysiology is still unclear, and it is believed that genetic and environmental factors are fully capable of influencing ASD, especially cell signaling and microglial functions. Furthermore, the endocannabinoid system (ECS) participates in the modulation of various brain processes and is also involved in the pathophysiological mechanisms of this condition. Due to the health and quality of life impacts of autism for the patient and his/her family and the lack of effective medications, the literature has elucidated the possibility that Cannabis phytocannabinoids act favorably on ASD symptoms, probably through the modulation of neurotransmitters, in addition to endogenous ligands derived from arachidonic acid, metabolizing enzymes and even transporters of the membrane. These findings support the notion that there are links between key features of ASD and ECS due to the favorable actions of cannabidiol (CBD) and other cannabinoids on symptoms related to behavioral and cognitive disorders, as well as deficits in communication and social interaction, hyperactivity, anxiety and sleep disorders. Thus, phytocannabinoids emerge as therapeutic alternatives for ASD.
Autism spectrum disorder (ASD) is a pervasive developmental disorder that is thought to affect 52 million people globally. Individuals are commonly affected by comorbid behavioural difficulties and psychiatric conditions. However, when considering the tolerability of currently available licensed medications, there are limited treatments for ASD. Cannabis-based medicinal products (CBMPs) have been proposed as a potential novel therapeutic for ASD based on the pre-clinical evidence of the effects of cannabinoids on anxiety, mood, behaviour and motor skills. However, clinical translation has been limited. Moreover, studies suggest that CBMPs are well tolerated by those with ASD. While randomised controlled trials are still necessary, those with ASD can be considered for treatment with CBMPs if they have failed to respond to licensed therapies following assessment at a specialist clinic, such as Sapphire Medical Clinics.
Full-text available
Autism spectrum disorder (ASD) defines a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction with restricted or repetitive motor movements, frequently associated with general cognitive deficits. Although it is among the most severe chronic childhood disorders in terms of prevalence, morbidity, and impact to the society, no effective treatment for ASD is yet available, possibly because its neurobiological basis is not clearly understood hence specific drugs have not yet been developed. The endocannabinoid (EC) system represents a major neuromodulatory system involved in the regulation of emotional responses, behavioral reactivity to context, and social interaction. Furthermore, the EC system is also affected in conditions often present in subsets of patients diagnosed with ASD, such as seizures, anxiety, intellectual disabilities, and sleep pattern disturbances. Despite the indirect evidence suggestive of an involvement of the EC system in ASD, only a few studies have specifically addressed the role of the EC system in the context of ASD. This review describes the available data on the investigation of the presence of alterations of the EC system as well as the effects of its pharmacological manipulations in animal models of ASD-like behaviors.
Full-text available
Since the documented observations of Kanner in 1943, there has been great debate about the diagnoses, the sub-types, and the diagnostic threshold that relates to what is now known as autism spectrum disorder (ASD). Reflecting this complicated history, there has been continual refinement from DSM-III with ‘Infantile Autism’ to the current DSM-V diagnosis. The disorder is now widely accepted as a complex, pervasive, heterogeneous condition with multiple etiologies, sub-types, and developmental trajectories. Diagnosis remains based on observation of atypical behaviors, with criteria of persistent deficits in social communication and restricted and repetitive patterns of behavior. This review provides a broad overview of the history, prevalence, etiology, clinical presentation, and heterogeneity of ASD. Factors contributing to heterogeneity, including genetic variability, comorbidity, and gender are reviewed. We then explore current evidence-based pharmacological and behavioral treatments for ASD and highlight the complexities of conducting clinical trials that evaluate therapeutic efficacy in ASD populations. Finally, we discuss the potential of a new wave of research examining objective biomarkers to facilitate the evaluation of sub-typing, diagnosis, and treatment response in ASD.
Full-text available
Significance We present evidence that an oxytocin-dependent endocannabinoid signal contributes to the regulation of social reward. The results provide insights into the functions of oxytocin, a neuropeptide crucial for social behavior, and its interactions with other modulatory systems that regulate the rewarding properties of social behavior. They further suggest that oxytocin-driven anandamide signaling may be defective in autism spectrum disorders, and that correcting such deficits might offer a strategy to treat these conditions.
Full-text available
To compare the annual prevalence of the autism symptom phenotype and of registered diagnoses for autism spectrum disorder during a 10 year period in children. Population based study. Child and Adolescent Twin Study and national patient register, Sweden. 19 993 twins (190 with autism spectrum disorder) and all children (n=1 078 975; 4620 with autism spectrum disorder) born in Sweden over a 10 year period from 1993 to 2002. Annual prevalence of the autism symptom phenotype (that is, symptoms on which the diagnostic criteria are based) assessed by a validated parental telephone interview (the Autism-Tics, ADHD and other Comorbidities inventory), and annual prevalence of reported diagnoses of autism spectrum disorder in the national patient register. The annual prevalence of the autism symptom phenotype was stable during the 10 year period (P=0.87 for linear time trend). In contrast, there was a monotonic significant increase in prevalence of registered diagnoses of autism spectrum disorder in the national patient register (P<0.001 for linear trend). The prevalence of the autism symptom phenotype has remained stable in children in Sweden while the official prevalence for registered, clinically diagnosed, autism spectrum disorder has increased substantially. This suggests that administrative changes, affecting the registered prevalence, rather than secular factors affecting the pathogenesis, are important for the increase in reported prevalence of autism spectrum disorder. © Lundström et al 2015.
Conference Paper
Objective: This retrospective study assessed safety, tolerability and efficacy of cannabidiol (CBD) based medical cannabis, as an adjuvant therapy, for refractory behavioral problems in children with ASD. Background: Anecdotal evidence of successful cannabis treatment in children with autism spectrum disorder (ASD) are accumulating but formal studies are lacking. Design/Methods: Sixty children with ASD (age = 11.8± 3.5, range 5.0–17.5; 77% low functioning; 83% boys) were treated with oral CBD and tetrahydrocannabinol (THC) at a ratio of 20:1. The dose was up-titrated to effect (maximal CBD dose − 10mg/kg/d). Tolerability and efficacy were assessed using a modified Liverpool Adverse Events Profile, the Caregiver Global Impression of Change (CGIC) scale, the Home Situations Questionnaire–Autism Spectrum Disorder (HSQ-ASD) and the Autism Parenting Stress Index (APSI). Results: Following the cannabis treatment, behavioral outbreaks were much improved or very much improved (on the CGIC scale) in 61% of patients. The anxiety and communication problems were much or very much improved in 39% and 47% respectively. Disruptive behaviors, were improved by 29% from 4.74±1.82 as recorded at baseline on the HSQ-ASD to 3.36±1.56 following the treatment. Parents reported less stress as reflected in the APSI scores, changing by 33% from 2.04±0.77 to 1.37±0.59. The effect on all outcome measures was more apparent in boys with non-syndromic ASD. Adverse events included sleep disturbances (14%) irritability (9%) and loss of appetite (9%). Conclusions: This preliminary study support the feasibility of CBD based medical cannabis as a promising treatment option for refractory behavioral problems in children with ASD. Based on these promising results, we have launched a large, double blind, placebo controlled cross-over trial with 120 participants (NCT02956226).
The reported effectiveness of these home preparations, especially those with high cannabidiol (CBD) concentrations, has garnered the attention of the medical community. In particular cannabis sativa, known for its lack of a psychoactive effect and high CBD content, has become a target of medical research. The shift in public and political interest to medicinal applications of CBD demands renewed research into its efficacy. Pediatric populations in particular stand to benefit significantly from a better understanding of the safety and efficacy of this novel treatment. This review discusses the current state of CBD research and identifies areas that require further investigation as they pertain to pediatric epilepsy populations. It will especially cover those suffering from refractory epilepsies for which other methods of remediation have not sufficed.
Autism is a neurodevelopmental disorder characterized by dysfunction in three core symptom domains: speech and communication deficits, repetitive or compulsive behaviors with restricted interests, and social impairment. The neuropeptide oxytocin, along with the structurally similar peptide arginine vasopressin, may play a role in the etiology of autism, and especially in the social impairment domain. Oxytocin is a nonapeptide (i.e., it has nine amino acids). It is synthesized in magnocellular neurons in the paraventricular nucleus and the supraoptic nucleus of the hypothalamus and is released into the bloodstream by way of axon terminals in the posterior pituitary. Oxytocin is released both peripherally, where it is involved in milk letdown and the facilitation of uterine contractions, and centrally, where it acts as a neuromodulator along with arginine vasopressin. Here, we discuss relevant translational research pertaining to the role of oxytocin in social and repetitive behaviors and consider clinical implications. We also discuss current research limitations, review recent preliminary findings from studies involving oxytocin in autism spectrum disorder patient populations, and point to possible directions for future research.
Objective: To evaluate the effectiveness of dronabinol (delta-9-THC) as supplementary therapy in a child with autistic disorder. Methods: A child who met the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) criteria for a diagnosis of autistic disorder and who took no other medication during the observa-tion time was included in an open and uncontrolled study. Symptom assessment was performed using the Aberrant Behavior Checklist (ABC) before and after six months of medical treatment. Result: Compared to baseline, significant improvements were observed for hyperactivity, leth-argy, irritability, stereotypy and inappropriate speech at follow-up (p=0.043). Conclusion: This study showed that the use of dronabinol may be able to reduce the symptoms of autism.