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Abbreviations: ASD, autism spectrum disorder; CBD, cannabidiol; THC, Δ9-tetrahydrocannabinol.
Citation: Aran A, Cayam-Rand D. Medical Cannabis in Children. Rambam Maimonides Med J 2020;11 (1):e0003.
Review. doi:10.5041/RMMJ.10386
Copyright: © 2020 Ayan and Cayam-Rand. This is an open-access article. All its content, except where otherwise noted,
is distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
Conflict of interest: Adi Aran reports receiving personal fees and stock options for advisory roles at BOL Pharma. No
potential conflict of interest relevant to this article was reported for Dalit Cayam-Rand.
* To whom correspondence should be addressed. E-mail: aaran@szmc.org.il
Rambam Maimonides Med J | www.rmmj.org.il 1 January 2020 Volume 11 Issue 1 e0003
Special Issue on Cannabis in Medicine with Guest Editor Michael Dor, M.D.
Medical Cannabis in Children
Adi Aran, M.D.* and Dalit Cayam-Rand, M.D.
Neuropediatric Unit, Shaare Zedek Medical Center, Jerusalem, Israel
ABSTRACT
The use of medical cannabis in children is rapidly growing. While robust evidence currently exists only for
pure cannabidiol (CBD) to treat specific types of refractory epilepsy, in most cases, artisanal strains of CBD-
rich medical cannabis are being used to treat children with various types of refractory epilepsy or irritability
associated with autism spectrum disorder (ASD). Other common pediatric disorders that are being
considered for cannabis treatment are Tourette syndrome and spasticity. As recreational cannabis use
during youth is associated with serious adverse events and medical cannabis use is believed to have a
relatively high placebo effect, decisions to use medical cannabis during childhood and adolescence should
be made with caution and based on evidence. This review summarizes the current evidence for safety,
tolerability, and efficacy of medical cannabis in children with epilepsy and in children with ASD. The main
risks associated with use of Δ9-tetrahydrocannabinol (THC) and CBD in the pediatric population are
described, as well as the debate regarding the use of whole-plant extract to retain a possible “entourage
effect” as opposed to pure cannabinoids that are more standardized and reproducible.
KEY WORDS: Autism, cannabis, CBD, children, epilepsy, THC
NEUROACTIVITY OF CANNABIS
The cannabis plant has a substantial effect on social
behavior in humans.1 It enhances interpersonal
communication2 and decreases hostile feelings.3
Similar to other plants, cannabis contains hundreds
of compounds, including terpenes and flavonoids,
many of which have a known or presumed neurol-
ogical effect.4 Cannabis also contains over a hundred
unique compounds called phytocannabinoids (plant-
derived cannabinoids).
The two main phytocannabinoids are cannabidiol
(CBD) and Δ9-tetrahydrocannabinol (THC). These
Medical Cannabis in Children
Rambam Maimonides Medical Journal 2 January 2020 Volume 11 Issue 1 e0003
compounds were characterized in 1963 and 1964,
respectively, by Professor Raphael Mechoulam and
colleagues from Israel.5,6 Mechoulam found that THC
is the plant’s main psychoactive component, respon-
sible for the feeling of a “high.” This effect in the
brain is mediated by an abundant G-protein-coupled
receptor, which he named cannabinoid type 1 recep-
tor (CB1R). A second receptor that is also directly
activated by THC was isolated later from macro-
phages in the spleen and was named cannabinoid
type-2 receptor (CB2R).7 Accordingly, the main
effect mediated by CB2R is immunomodulation. This
receptor is not significantly expressed in the brain
under normal conditions but can be found on glial
cells in various brain pathologies.
The two main endogenous ligands of the can-
nabinoid receptors (“endocannabinoids”) are N-
arachidonoylethanolamine (AEA or anandamide)
and 2-arachidonoylglycerol (2-AG).
Figure 1 demonstrates the endocannabinoid sys-
tem. Endocannabinoids are produced “on demand”
in postsynaptic neurons and act as retrograde sig-
naling messengers in overactive brain circuits. By
activating CB1R in presynaptic neurons, they modu-
late the synaptic release of neurotransmitters into
the synaptic cleft and attenuate the synaptic activity
in that circuit.8 After reuptake of the endocanna-
Figure 1. Biosynthesis, Degradation, and Receptor Binding of AEA and 2-AG.
AEA is synthesized from membrane phospholipids in the postsynaptic neuron by NAPE-PLD. It crosses the synapse
“against the traffic” and activates CB1R and TRPV1 on the presynaptic neuron. Following reuptake to the
presynaptic neuron by the EMT, AEA activates nuclear receptors—PPARs—and is degraded by FAAH.
THC directly activates CB1R; CBD inhibits FAAH and EMT (increasing AEA levels), the endogenous ligand of CB1R. Like
AEA, CBD activates PPARs and TRPV1.
2-AG, 2-arachidonoylglycerol (blue ellipses and related lines); AA, arachidonic acid (green ellipses); AEA, ananda-
mide (purple ellipses and related lines); CB1R, cannabinoid type 1 receptor; CBD, cannabidiol; DAGL, diacylglycerol
lipase; EMT, endocannabinoid membrane transporter (green tubes); FAAH, fatty acid amide hydrolase; GPR55, G
protein-coupled receptor 55; MAGL, monoacylglycerol lipase; NAPE-PLD, N-acylphosphatidylethanolamine-specific
phospholipase D; PPARs, peroxisome proliferator-activated receptors; THC, Δ9-tetrahydrocannabinol; TRPV1,
transient receptor potential channels of vanilloid type-1. Broken lines = inhibition; half ellipses ( ) = receptors;
hexagons = enzymes; yellow mesh = cell membrane. Thicker lines and half ellipses are of greater importance than
the thinner ones. Black lines, other pathways; red lines, phytocannabinoid pathways.
Medical Cannabis in Children
Rambam Maimonides Medical Journal 3 January 2020 Volume 11 Issue 1 e0003
binoids to the presynaptic neuron by the endocan-
nabinoid membrane transporter, they are immedi-
ately hydrolyzed.
While THC directly activates the endocannabi-
noid system through CB1R, CBD does not activate
CB1R directly and is not psychoactive.9 Cannabidiol
has a relatively high toxicity threshold and appears
to have anxiolytic, antipsychotic, and neuroprotec-
tive properties that may be mediated through
receptors such as serotonin 5-HT1A, glycine α3 and
α1, TRPV1, GPR55, and PPARγ, and by inhibiting
adenosine reuptake.10–13 Cannabidiol also inhibits
the enzyme fatty acid amide hydrolase (FAAH) that
degrades anandamide, the endogenous ligand of
CB1R, and hence can indirectly activate the endo-
cannabinoid system (Figure 1).
While 99% pure cannabinoids are more repro-
ducible and standardized than whole-plant extract
and thus preferred as a study drug, several studies
suggest a synergistic effect for the numerous canna-
bis compounds in the whole-plant extract.4,14–19 This
so-called “entourage effect” remains controversial.20
Future studies should directly assess the effects
of pure cannabinoids versus whole-plant extracts in
various disorders among different target popula-
tions.
MAIN RISKS OF CANNABIS IN CHILDREN
The current knowledge on the long-term side-effects
of cannabinoids is based mainly on longitudinal
follow-up of recreational cannabis users.21–23 Several
large studies have demonstrated that the main risks
of decreased motivation,24–26 addiction,27 mild cog-
nitive decline,23,25,28,29 and schizophrenia25,30–32 are
directly related to the THC and CBD concentrations
in the strain used,33 i.e. the higher the ratio of THC
to CBD, the greater the risk. The risk is also elevated
among those with younger onset of use (<18 years)
and in the presence of other risk factors, such as a
family history of schizophrenia and concomitant use
of alcohol and tobacco.33,34 Notably, these studies
contained very few participants under 10 years old
and did not assess daily use of medical cannabis.
Longitudinal follow-up studies in children with
epilepsy receiving pure CBD suggest high tolerability
and safety,35–37 but these studies included very few
participants younger than 5 years old.
Animal studies suggest that using pure CBD and
its analogue cannabidivarin (CBDV) during early
development is relatively safe38,39 while the use of
THC, with or without CBD, during early develop-
ment was found to impair brain structure and
function.40–43
Short-term adverse events of pure CBD or CBD-
rich whole-plant extracts include somnolence, weight
loss, and increased liver transaminases.35,36,44–47
MEDICAL CANNABIS FOR CHILDREN
WITH EPILEPSY
Epilepsy is a common neurological disorder, affect-
ing 0.5%–1% of the world’s population.48 Despite
the availability of many effective antiepileptic drugs,
about one-third of epileptic patients will continue to
have treatment-refractory seizures.49 If a patient
continues to have seizures despite appropriate treat-
ment trials with three medications, the probability
of achieving seizure freedom with subsequent medi-
cations is less than 3.5%.49 In such cases, treatment
options include epileptic surgery, vagal nerve stimu-
lation, or ketogenic diet. However, for the numerous
patients who are not eligible for surgery or do not
respond to these treatments, medical cannabis may
offer more hope for seizure reduction compared
with other pharmacological interventions.
Cannabis treatment for seizures has a long his-
tory; it has been used as an anticonvulsant in the
ancient Middle East and India for at least 4000
years.50 More recently, leading nineteenth-century
neurologists Sir John Russell Reynolds and Sir
William Richard Gowers sporadically used THC-rich
cannabis to treat seizures. The use of cannabis for
epilepsy gradually ceased following the introduction
of phenobarbitone in 1912 and phenytoin in 1937.
Small studies, mainly of THC-rich cannabis for
children with epilepsy, re-emerged in the 1970s with
mixed results. Following the discovery of the endo-
cannabinoid system in the 1990s and its major role
in neuromodulation, including the attenuation of
overactive brain circuits, studies in animal models
and anecdotes of successful treatment in refractory
epilepsy cases began to accumulate. However, larger-
scale clinical studies of cannabinoids in epilepsy
were only conducted in recent years.50 These studies
focus on the safer cannabinoid, CBD, which seems
to have more of an antiepileptic effect than THC in
preclinical studies.
A plant-derived pure CBD compound (brand
name: Epidiolex) was approved by the US Food and
Drug Administration (FDA) in 2018 for treating two
severe forms of epilepsy—Dravet and Lennox–
Gastaut syndromes51—following a series of successful
safety and efficacy studies.36,52–54
Medical Cannabis in Children
Rambam Maimonides Medical Journal 4 January 2020 Volume 11 Issue 1 e0003
A recent systematic review and meta-analysis of
the efficacy and tolerability of pure CBD and CBD-
rich medical cannabis revealed that CBD is more
effective than placebo for treatment-resistant epilep-
sy, regardless of the etiology of the epileptic syn-
drome.37 Adverse events included somnolence,
decreased appetite and weight, irritability, increased
seizure frequency, and diarrhea (in some of the
studies). Laboratory abnormalities included eleva-
tion of liver transaminases in patients who also
received valproic acid. Short-term adverse events
were found to be similar for pure CBD and CBD-rich
medical cannabis. Adverse events were more fre-
quent at treatment onset compared with long-term
follow-up.37 Clinicians should also be aware of cross-
reactivity between CBD or CBD-rich medical canna-
bis and antiepileptic medications that are also me-
tabolized by the cytochrome P450 complex. Notably,
active metabolites of benzodiazepines significantly
increase with concomitant use of CBD and CBD-rich
medical cannabis.
MEDICAL CANNABIS FOR CHILDREN
WITH AUTISM SPECTRUM DISORDER
Autism spectrum disorder (ASD) affects up to 2.5%
of children worldwide and is a major public health
challenge.55 Individuals with ASD have social and
communication difficulties, stereotyped or repetitive
behaviors and interests, sensory problems, and, in
many cases, cognitive impairment and disruptive
behaviors. These deficits are present in early child-
hood and lead to significant disability.56
Approximately 50% of children and adolescents
with ASD demonstrate behavioral difficulties, in-
cluding tantrums, non-compliance, aggression, and
self-injury.57–59 This rate is higher than in any other
neurodevelopmental disorder.60–65 The behavioral
difficulties of children with ASD increase their social
isolation66,67 and often cause more distress to care-
givers than the core autistic symptoms.68–70 Maladap-
tive behaviors also limit the child’s ability to benefit
from intervention efforts, thereby impairing the long-
term prognosis.71
Standard treatment for these problems is based
on behavioral interventions71–75 combined with med-
ications,76,77 particularly atypical antipsychotics78–84
and mood stabilizers.85 However, both the efficacy
and tolerability of pharmacotherapy in children with
ASD are less favorable than among typically devel-
oping children with similar symptoms.86
As a result, despite extensive behavioral and
medical treatment, 40% of the children and youth
with ASD suffer from maladaptive behavior87 that
severely impacts their quality of life and takes a
heavy toll on their families.69,88 The frustration from
current medical treatment leads to an exceptionally
high percentage of parents seeking help from com-
plementary and alternative medicine.89,90
Epilepsy is one of the most common comorbid
conditions in ASD, affecting 10%–30% of children
and youth with ASD,91 and several pathophysiologi-
cal processes are implicated in both disease process-
es.92 Hence, the positive effect of cannabinoids in re-
fractory patients is relevant for individuals with ASD.
The CB1R is highly expressed in the frontal cortex
and subcortical areas associated with social func-
tioning.93,94 The CB1 receptors and their endogenous
ligands anandamide and 2-AG regulate social play
and social anxiety in animal models95–100 and in
humans.101–103
Activation of the endocannabinoid system in the
nucleus accumbens (anandamide mobilization and
consequent activation of CB1 receptors) driven by
oxytocin, a neuropeptide that reinforces social bond-
ing, was demonstrated to be necessary and sufficient
to express the rewarding properties of social interac-
tion.104 Reduced endocannabinoid activity was dem-
onstrated in several animal models of ASD,105
including monogenic (fragile-X,106 neuroligin 3107),
polygenic (BTBR105), and environmental (rat valproic
acid108) models. Activation of the endocannabinoid
system105–108 and administration of CBD105 have been
shown to restore social deficits in some models. A
single oral administration of 600 mg CBD to 34 men
(17 neurotypicals and 17 with ASD) increased pre-
frontal gamma-aminobutyric acid (GABA) activity in
neurotypicals and decreased GABA activity in those
with ASD.109 Additionally, children with ASD have
been found to have lower peripheral endocannabi-
noid levels.110,111
Therefore, dysregulation of the endocannabinoid
system may play an important role in ASD patho-
physiology and may represent a target for phar-
macological intervention.112
Four uncontrolled case-series, including 60, 188,
53, and 18 children with ASD and severe behavioral
problems, reported high tolerability and efficacy of
artisanal CBD-rich cannabis strains.44–47 In the
largest cohort, data collection was partial, and there
was also an unknown overlap between the first three
Medical Cannabis in Children
Rambam Maimonides Medical Journal 5 January 2020 Volume 11 Issue 1 e0003
cohorts. Most participants were followed for at least
6 months, and the retention rate was about 80%.
The treatment was reported to substantially
decrease the irritability and anxiety in most of the
participants and to improve the social deficits in
about half of the subjects, but these results should
be interpreted cautiously.
Cannabinoid treatment is associated with a rela-
tively high placebo effect, compared with other
pharmacological treatments.113 Placebo effect is ex-
pected to be even higher in ASD studies which use
subjective behavioral assessments.114 Hence, placebo-
controlled studies are required even for a prelimi-
nary assessment of efficacy. To date, only one con-
trolled study was completed (NCT02956226) and
another is ongoing (NCT03202303).
NCT02956226 was a phase 2, proof-of-concept
trial, conducted in a single referral center, Shaare
Zedek Medical Center, Jerusalem, Israel. In this
double-blind, placebo-controlled trial, 150 children
(age 5–21 years) with ASD and behavioral problems
(Clinical Global Impression of Severity ≥4), were
randomized (in a 1:1:1 ratio) to receive either pla-
cebo or one of two cannabinoid solutions for 12
weeks. The cannabinoid solutions were: (1) whole-
plant cannabis extract containing cannabidiol (CBD)
and Δ9-tetrahydrocannabinol (THC) in a 20:1 ratio;
and (2) purified CBD and THC in the same ratio and
dose, without other components of the cannabis
plant such as minor cannabinoids, terpenes, and
flavonoids which may also contribute to the thera-
peutic effect in an entourage effect.4 The rationale
for THC use was previous experience with similar
cannabis strains in open-label studies44–46 and the
known effects of THC on social behavior.115 The
taste, smell, and texture of the three study interven-
tions were carefully adjusted for similarity, which
was approved by a professional taster. Participants
received either placebo or cannabinoids for 12 weeks
to test efficacy, followed by a 4-week washout, and
crossed-over to receive another treatment for 12
weeks to further assess tolerability. The treatments
were given orally as an add-on to any pre-existing
treatment, with an average CBD dose of 5.5
mg/kg/day, divided into three daily doses. There
were no serious treatment-related adverse events.
The most prevalent adverse events were somnolence
and loss of appetite. In some of the measures, can-
nabinoids reduced the irritability and even the core
symptoms of autism significantly more than place-
bo, with no advantage of the whole-plant extract
over the pure cannabinoids.
MEDICAL CANNABIS FOR CHILDREN
WITH SPASTICITY AND OTHER
INDICATIONS
An open-label study of 25 children (age 1–17 years)
with a complex motor disorder116 demonstrated im-
provement in spasticity and dystonia, sleep diffi-
culties, pain severity, and quality of life. The partici-
pants received one of two artisanal strains of CBD-
rich cannabis for 5 months: either a 20:1 CBD:THC
ratio or a 6:1 ratio. No significant differences were
found between the two strains. Two case series, one
with 12 children with treatment-refractory spasticity
related to developmental disorders117 and one with 7
children with pantothenate kinase-associated neuro-
degeneration (PKAN),118 reported improvement in
the spasticity and dystonia in some of the children
after treatment with dronabinol, a synthetic form of
THC (spasticity) or various cannabis strains (PKAN).
Case reports of children who received cannabis for
other indications119 included cases of: neuropathic
pain and comorbid major depressive disorder (dro-
nabinol, n=2), anxiety and sleep in PTSD (CBD, n=1),
and Tourette syndrome (THC, n=1). Larger open-
label studies and randomized studies are required
prior to clinical use of cannabis for these indications.
DISCUSSION
Public interest in cannabis-based treatment is rapid-
ly growing, especially in disorders with substantial
unmet needs such as pediatric ASD and refractory
epilepsy. This review summarizes current knowl-
edge on the neuroactivity of cannabinoids, potential
risks, and evidence of efficacy and tolerability in epi-
lepsy and ASD. While most patients receive a variety
of artisanal strains, only pure CBD for epilepsy has
been rigorously evaluated in controlled trials thus
far, with modest but significant improvement in
motor seizures and acceptable tolerability. Adverse
events included somnolence and reduced appetite.
Important interactions with antiepileptic drugs in-
clude an increased risk of hepatotoxicity with val-
proic acid and an increased level of active metabo-
lites with benzodiazepines, contributing to somno-
lence and potentially to efficacy.
While some studies suggest that artisanal strains
with a very high ratio of CBD:THC (e.g. 20:1) are as
safe and potent as pure CBD, this issue should be
evaluated in future studies. Notably, artisanal prep-
arations, if used, should be obtained from
government-controlled sources (preferably good
manufacturing practices-approved) as several studies
Medical Cannabis in Children
Rambam Maimonides Medical Journal 6 January 2020 Volume 11 Issue 1 e0003
demonstrated significant inconsistency between
product labels and actual content in many cases.
In ASD, the gap between published evidence and
public beliefs is much wider. Preclinical studies and
case series, reporting successful treatment with
artisanal CBD-rich cannabis strains in children with
ASD and severe irritability, have triggered wide-
spread use of various cannabis strains in children
with ASD, despite a lack of published controlled
studies. Moreover, parents often request medical
cannabis to treat the core autistic symptoms—not
the associated irritability—and this request often
comes from parents of children younger than 5
years. Some parents prefer to try medical cannabis
for irritability as a first-line treatment, as it is
perceived as natural and hence safer, compared with
the FDA-approved antipsychotics, risperidone and
aripiprazole. Many families are interested in
products with a relatively high content of THC,
which carries a higher risk of severe neurobehav-
ioral comorbidities in this vulnerable population
compared with the general population.
In our opinion, the use of medical cannabis in
ASD should be currently limited to clinical trials and
highly selected cases of treatment-resistant severe
irritability.
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