ArticlePDF AvailableLiterature Review

Medical Cannabis in Children

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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.
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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 receptorsPPARsand 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.1013 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.4,1419 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.2123 Several
large studies have demonstrated that the main risks
of decreased motivation,2426 addiction,27 mild cog-
nitive decline,23,25,28,29 and schizophrenia25,3032 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,3537 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.4043
Short-term adverse events of pure CBD or CBD-
rich whole-plant extracts include somnolence, weight
loss, and increased liver transaminases.35,36,4447
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 epilepsyDravet and Lennox
Gastaut syndromes51following a series of successful
safety and efficacy studies.36,5254
Medical Cannabis in Children
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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.5759 This rate is higher than in any other
neurodevelopmental disorder.6065 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.6870 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 interventions7175 combined with med-
ications,76,77 particularly atypical antipsychotics7884
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 models95100 and in
humans.101103
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
system105108 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.4447 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 521 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 studies4446 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 117 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 symptomsnot
the associated irritabilityand 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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... Cannabis is a highly complex plant with up to three species, at least 100 chemical compounds, and more than 700 cultivars (Aran & Cayam-Rand, 2020;Gloss, 2015;Jarvis, 2017;Pollio, 2016). Cannabis, which can often be erroneously referred to interchangeably as Docusign Envelope ID: E2A48C58-B45E-4BE7-BE92-AB30F6CF19AD "marijuana", is the taxonomic term that refers to a genus of plants in the Cannabaceae Family. ...
... Differentiation of the subspecies of cannabis is imperative for both agricultural and law enforcement purposes (Aran & Cayam-Rand, 2020;Simiyu et. al., 2022). ...
... The call to investigate came with various research findings leading to the discovery of the ECS in the late 1980s to early 1990s (Crocq, 2020;Pertwee, 2006). More recently research has led to the discovery of a phenomenon called "The Entourage Effect" which has significant medical implications when attempting to balance the medical benefits and side effects caused by cannabis (Aran & Cayam-Rand, 2020). ...
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This doctoral project examines the implementation and effects of youth medical marijuana programs. The study systematically reviews existing literature, focusing on key aspects such as the educational and support needs for minor patients and their caregivers, the effects of medical cannabis on pediatric health, and the current state of professional guidance in the field. The primary problem under investigation is the lack of structured support and education for children and adolescents using medical cannabis, which potentially exposes them to health risks. The study utilizes a meta-ethnographic approach to synthesize qualitative research, examining studies published from 2018 to 2023 in North America. Results indicate significant gaps in caregiver and professional education regarding pediatric medical cannabis use, highlighting the necessity for comprehensive educational programs and consistent follow-up care. The study emphasizes the importance of integrating informed decision-making practices and transformative learning approaches to enhance the efficacy and safety of medical cannabis programs for minors. This research underscores the critical need for regulated practices to safeguard the health and well-being of pediatric patients.
... Despite its psychoactive and seizure-inducing effects, another reason why THC is not recommended for paediatric patients is because THC can adversely impact brain development [83,84]. In early childhood, significant brain development occurs in which one million synapses are formed each second [85]. ...
... In early childhood, significant brain development occurs in which one million synapses are formed each second [85]. During the first few years of life, THC exposure can lead to abnormal brain structure and function, as well as unfavourable neurodevelopmental outcomes [83,84]. THC activates CB1 receptors in a nonspecific manner and interferes with the ECS, which can prevent synaptic connections from forming, especially in the prefrontal cortex and hippocampus [86]. ...
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Paediatric epilepsies are especially concerning as they can be resistant to standard antiepileptic drugs and have high mortality rates. Moreover, young children are naturally at an increased risk of developing epilepsy. In early life, the depolarizing effect of γ-aminobutyric acid (GABA) renders immature neurons incapable of adequate inhibition which predisposes them to becoming hyperexcitable. Until recently, the search has been ongoing for a suitable therapy that would work more effectively in severe childhood epilepsies. Fortunately, cannabidiol (CBD), the non-psychoactive part of cannabis, has recently surfaced as a successful anticonvulsant in rare and severe paediatric epilepsy disorders. CBD circumvents normal endocannabinoid signalling in which endogenous cannabinoids are released by a postsynaptic neuron to silence the activity of a presynaptic neuron at a synapse. Instead, CBD exerts its anticonvulsant effects by acting on a number of non-cannabinoid targets, namely the transient receptor potential vanilloid 1 channel, G protein-coupled receptor 55, and equilibrative nucleoside transporter 1. In clinical trials, CBD lowered seizure frequency in paediatric patients who had Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), tuberous sclerosis complex (TSC), and other epilepsy syndromes. For the past few decades, the illegalization of cannabis has halted research into cannabinoids, and we are only now starting to study cannabis further despite knowing for centuries that it relieves a variety of conditions. The Food and Drug Administration and European Medicines Agency have recently approved CBD as an additive treatment option for DS, LGS, and TSC patients. Our society is becoming more open to the prospect of cannabis’ therapeutic potential. This is particularly promising for children suffering from severe forms of epilepsy in which most of our current antiepileptic drugs are often ineffective.
... Це свідчить про поступову інтеграцію України до глобальної системи охорони здоров'я та уніфікацію медичних стандартів. Згідно з науковими дослідженнями, лікарський канабіс містить від 80 до 100 каннабіноїдів, серед яких ключову роль відіграють тетрагідроканабінол (TГК) та каннабідіол (CBD) [6]. ТГК є основним психоактивним компонентом, що впливає на психоемоційний стан, тоді як CBD здійснює імуномодулюючу дію. ...
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This chapter is the “meat and potatoes” of medical cannabis care for the modern clinician. It will provide insight and discussion of common concerns and potential myths about providing medical cannabis education or care to patients. It will explore the common concerns about risks, including the risk of addiction, psychosis, cannabis use during pregnancy, and other vulnerable patient groups. A proposed approach to a medical visit with a patient interested in using medical cannabis is included, along with language for safe counseling and education.
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Data addressing safety concerns related to potential drug interactions between cannabis‐derived products and pharmaceutical medications in the pediatric population are lacking. In this study, we retrieved case reports through a published literature search using PubMed and spontaneous reporting data using the Food and Drug Administration's Adverse Event Reporting System (FAERS) to identify potential cannabis– and cannabinoid–drug interactions in individuals younger than 18 years old. To evaluate the published case reports, we used the Drug Interaction Probability Scale (DIPS), a 10‐item questionnaire designed to discern the causal relationship between a potential drug interaction and adverse drug reactions (ADRs). FAERS reports were deduplicated and analyzed to gather information regarding patient demographics, associated drugs, nature of the ADRs, outcomes, professions of the reporters, and reporting timelines. Seven published case reports and 9142 FAERS ADRs reports were included in the final analysis. Based on the findings, caution is warranted when cannabis or cannabinoids are used in combination with prescribed medications, including methadone, everolimus, fluoxetine, and paroxetine. Cannabinoids may inhibit drug‐metabolizing enzymes, including several cytochrome P450s, leading to increased drug exposure and potentially, an increased risk for ADRs.
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Purpose of the review Cannabis is one of the most commonly used psycho-active substances in the world. It has been used for medicinal and recreational purposes, with use frequently initiated during adolescence. Although once thought to be harmless, a growing body of evidence has associated adolescent cannabis use with adverse outcomes. A comprehensive literature review was conducted including cross-sectional and prospective studies examining the risk factors and potential impact of adolescent cannabis use. Recent findings The findings of this review indicated that demographic variables such as age, male sex, and low socioeconomic status may predict the initiation of cannabis use during adolescence, as well as symptoms of anxiety and depression, impulsivity, and cannabis use of other family members and friends. Adverse consequences of adolescent cannabis use include depression, psychosis, suicidality, as well as negative impacts on overall functioning, cognition, and educational achievement. Summary Although this area of research continues to be affected by numerous methodological limitations, there is strong evidence indicating a myriad of potential harms associated with the use of cannabis during adolescence.
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BACKGROUND AND OBJECTIVES: Klippel-Trenaunay syndrome (KTS) is a rare congenital disease that manifests at birth or in childhood and has an unknown etiology, with no ethnic or gender predilection. Pain management, common in many cases, is challenging due to the complexity of the factors involved. The aim of this report is to demonstrate the effective use of a multimodal approach, including medicinal cannabis, in the treatment of pain in a child with KTS. CASE REPORT: this is the case of a child suffering from CTS who had severe chronic pain, significantly compromising his quality of life. The pain was managed with pharmacological therapies, including the use of medicinal cannabis as a therapeutic alternative when conventional treatments proved insufficient. The multimodal approach, which included the use of tetrahydrocannabinol, led to a reduction in pain and an improvement in the patient’s quality of life. Medical cannabis therapy proved to be an effective option, especially in cases of pain refractory to other interventions. CONCLUSION: The treatment of pain in patients with KTS should be multimodal, with an emphasis on non-invasive approaches. The use of medicinal cannabis is a viable and safe alternative, particularly in situations where conventional treatments do not provide adequate relief. Keywords: analgesic pain management; cannabidiol; chronic pain; medicinal cannabis; tetrahydrocannabinol
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Autism Spectrum Disorders comprise conditions that may affect cognitive development, motor skills, social interaction, communication, and behavior. This set of functional deficits often results in lack of independence for the diagnosed individuals, and severe distress for patients, families, and caregivers. There is a mounting body of evidence indicating the effectiveness of pure cannabidiol (CBD) and CBD-enriched Cannabis sativa extract (CE) for the treatment of autistic symptoms in refractory epilepsy patients. There is also increasing data support for the hypothesis that non-epileptic autism shares underlying etiological mechanisms with epilepsy. Here we report an observational study with a cohort of 18 autistic patients undergoing treatment with compassionate use of standardized CBD-enriched CE (with a CBD to THC ratio of 75/1). Among the 15 patients who adhered to the treatment (10 non-epileptic and five epileptic) only one patient showed lack of improvement in autistic symptoms. Due to adverse effects, three patients discontinued CE use before 1 month. After 6–9 months of treatment, most patients, including epileptic and non-epileptic, showed some level of improvement in more than one of the eight symptom categories evaluated: Attention Deficit/Hyperactivity Disorder; Behavioral Disorders; Motor Deficits; Autonomy Deficits; Communication and Social Interaction Deficits; Cognitive Deficits; Sleep Disorders and Seizures, with very infrequent and mild adverse effects. The strongest improvements were reported for Seizures, Attention Deficit/Hyperactivity Disorder, Sleep Disorders, and Communication and Social Interaction Deficits. This was especially true for the 10 non-epileptic patients, nine of which presented improvement equal to or above 30% in at least one of the eight categories, six presented improvement of 30% or more in at least two categories and four presented improvement equal to or above 30% in at least four symptom categories. Ten out of the 15 patients were using other medicines, and nine of these were able to keep the improvements even after reducing or withdrawing other medications. The results reported here are very promising and indicate that CBD-enriched CE may ameliorate multiple ASD symptoms even in non-epileptic patients, with substantial increase in life quality for both ASD patients and caretakers.
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Mood disorders are the most prevalent mental conditions encountered in psychiatric practice. Numerous patients suffering from mood disorders present with treatment-resistant forms of depression, co-morbid anxiety, other psychiatric disorders and bipolar disorders. Standardized essential oils (such as that of Lavender officinalis) have been shown to exert clinical efficacy in treating anxiety disorders. As endocannabinoids are suggested to play an important role in major depression, generalized anxiety and bipolar disorders, Cannabis sativa, was suggested for their treatment. The endocannabinoid system is widely distributed throughout the body including the brain, modulating many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. CB1 and CB2 receptors primarily serve as the binding sites for endocannabinoids as well as for phytocannabinoids, produced by cannabis inflorescences. However, ‘cannabis’ is not a single compound product but is known for its complicated molecular profile, producing a plethora of phytocannabinoids alongside a vast array of terpenes. Thus, the “entourage effect” is the suggested positive contribution derived from the addition of terpenes to cannabinoids. Here we review the literature on the effects of cannabinoids and discuss the possibility of enhancing cannabinoid activity on psychiatric symptoms by the addition of terpenes and terpenoids. Possible underlying mechanisms for the anti-depressant and anxiolytic effects are reviewed. These natural products may be an important potential source for new medications for the treatment of mood and anxiety disorders.
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Mixtures of different Cannabis sativa phytocannabinoids are more active biologically than single phytocannabinoids. However, cannabis terpenoids as potential instigators of phytocannabinoid activity have not yet been explored in detail. Terpenoid groups were statistically co-related to certain cannabis strains rich in Δ9-tetrahydrocannabinolic acid (THCA) or cannabidiolic acid (CBDA), and their ability to enhance the activity of decarboxylase phytocannabinoids (i.e., THC or CBD) was determined. Analytical HPLC and GC/MS were used to identify and quantify the secondary metabolites in 17 strains of C. sativa, and correlations between cannabinoids and terpenoids in each strain were determined. Column separation was used to separate and collect the compounds, and cell viability assay was used to assess biological activity. We found that in “high THC” or “high CBD” strains, phytocannabinoids are produced alongside certain sets of terpenoids. Only co-related terpenoids enhanced the cytotoxic activity of phytocannabinoids on MDA-MB-231 and HCT-116 cell lines. This was found to be most effective in natural ratios found in extracts of cannabis inflorescence. The correlation in a particular strain between THCA or CBDA and a certain set of terpenoids, and the partial specificity in interaction may have influenced the cultivation of cannabis and may have implications for therapeutic treatments.
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Background Pantothenate kinase–associated neurodegeneration is characterized by severe, progressive dystonia. This study aims to describe the reported usage of cannabis products among children with pantothenate kinase–associated neurodegeneration. Methods A cross-sectional, 37-item survey was distributed in April 2019 to the families of 44 children who participate in a clinical registry of individuals with pantothenate kinase–associated neurodegeneration. Results We received 18 responses (40.9% response rate). Children were a mean of 11.0 (SD 4.3) years old. The 15 respondents with dystonia or spasticity were on a median of 2 tone medications (range 0-9). Seven children had ever used cannabis (38.9%). The most common source of information about cannabis was other parents. Children who had ever used cannabis were on more tone medications, were more likely to have used opiates, were less likely to be able to roll, and less likely to sit comfortably, than children who had never used cannabis. Four children reported moderate or significant improvement in dystonia with cannabis. Other areas reported to be moderate or significantly improved were pain (n = 3), sleep (n = 4), anxiety (n = 3), and behavior (n = 2). Adverse effects included sadness (n = 1), agitation/behavior change (n = 1), and tiredness (n = 1). Conclusion Cannabis use was commonly reported among children with pantothenate kinase–associated neurodegeneration whose parents responded to a survey, particularly when many other dystonia treatments had been tried. Physicians should be aware that parents may treat their child with severe, painful dystonia with cannabis. Placebo-controlled studies of products containing cannabidiol and 9-tetrahydrocannabinol are needed for pediatric tone disorders.
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This paper aimed to systematically examine the efficacy and adverse event (AE) profile of cannabidiol and medicinal cannabis by analyzing qualitative and meta-analytic data. We used the terms ("Cannabidiol" OR "Cannabis") AND "Epilepsy" AND ("Treatment" OR "Therapeutics") as keywords to retrieve studies indexed on PubMed, ScienceDirect, and CENTRAL databases. The inclusion criteria were as follows: clinical studies with a longitudinal observational design and intervention using cannabinoid derivatives, especially cannabidiol and medicinal cannabis, whereby some results involved the frequency of epileptic seizures. We used Cochrane Collaboration's Review Manager software (RevMan 5.1.6) for the meta-analysis and dichotomized the articles to a confidence interval of 95%. From 236 articles, we selected 16 for descriptive analysis; we selected only 4 for the meta-analysis. According to the results, a statistically meaningful effect of cannabidiol compared with placebo was observed (p < 0.00001). When comparing treatment with cannabidiol or medicinal cannabis, significance was not found for the AE profile (p = 0.74). As AEs for cannabidiol were more common under short-term than under long-term treatment (p < 0.00001), this approach was favorable in the long term. Furthermore, cannabidiol is more effective than placebo, regardless of the etiology of epileptic syndromes and dosage. Overall, the AE profile did not differ across treatments with cannabidiol or medicinal cannabis, though it did differ favorably for long-term than for short-term treatment.
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Adolescence is the transitional period between childhood and adulthood, during which extensive brain development occurs. Since this period also overlaps with the initiation of drug use, it is important to consider how substance use during this time might produce long-term neurobiological alterations, especially against the backdrop of developmental changes in neurotransmission. Alcohol, cannabis, nicotine, and opioids all produce marked changes in the expression and function of the neurotransmitter and receptor systems with which they interact. These acute and chronic alterations also contribute to behavioral consequences ranging from increased addiction risk to cognitive or neuropsychiatric behavioral dysfunctions. The current review provides an in-depth overview and update of the developmental changes in neurotransmission during adolescence, as well as the impact of drug exposure during this neurodevelopmental window. While most of these factors have been studied in animal models, which are the focus of this review, future longitudinal studies in humans that assess neural function and behavior will help to confirm pre-clinical findings. Furthermore, the neural changes induced by each drug should also be considered in the context of other contributing factors, such as sex. Further understanding of these consequences can help in the identification of novel approaches for preventing and reversing the neurobiological effects of adolescent substance use.
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Cannabis exposure during the perinatal period results in varied and significant consequences in affected offspring. The prevalence of detrimental outcomes of perinatal cannabis exposure is likely to increase in tandem with the broadening of legalization and acceptance of the drug. As such, it is crucial to highlight the immediate and protracted consequences of cannabis exposure on pre- and postnatal development. Here, we identify lasting changes in neurons' learning flexibility (synaptic plasticity) and epigenetic misregulation in animal models of perinatal cannabinoid exposure (using synthetic cannabinoids or active components of the cannabis plant), in addition to significant alterations in social behavior and executive functions. These findings are supported by epidemiological data indicating similar behavioral outcomes throughout life in human offspring exposed to cannabis during pregnancy. Further, we indicate important lingering questions regarding accurate modeling of perinatal cannabis exposure as well as the need for sex- and age-dependent outcome measures in future studies.
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Background: Cannabis usage is increasing with its widespread legalization. Cannabis use by mothers during lactation transfers active cannabinoids to the developing offspring during this critical period and alters postnatal neurodevelopment. A key neurodevelopmental landmark is the excitatory to inhibitory gamma-aminobutyric acid (GABA) switch caused by reciprocal changes in expression ratios of the K+/Cl- transporters potassium-chloride cotransporter 2 (KCC2) and sodium-potassium-chloride transporter (NKCC1). Methods: Rat dams were treated with Δ9-tetrahydrocannabinol or a synthetic cannabinoid during the first 10 days of postnatal development, and experiments were then conducted in the offspring exposed to these drugs via lactation. The network influence of GABA transmission was analyzed using cell-attached recordings. KCC2 and NKCC1 levels were determined using Western blot and quantitative polymerase chain reaction analyses. Ultrasonic vocalization and homing behavioral experiments were carried out at relevant time points. Results: Treating rat dams with cannabinoids during early lactation retards transcriptional upregulation and expression of KCC2, thereby delaying the GABA switch in pups of both sexes. This perturbed trajectory was corrected by the NKCC1 antagonist bumetanide and accompanied by alterations in ultrasonic vocalization without changes in homing behavior. Neurobehavioral deficits were prevented by CB1 receptor antagonism during maternal exposure, showing that the CB1 receptor underlies the cannabinoid-induced alterations. Conclusions: These results reveal how perinatal cannabinoid exposure retards an early milestone of development, delaying the trajectory of GABA's polarity transition and altering early-life communication.