ArticlePDF AvailableLiterature Review


Cannabis has been used for centuries to treat seizures. Recent anecdotal reports, accumulating animal model data, and mechanistic insights have raised interest in cannabis-based antiepileptic therapies. In this study, we review current understanding of the endocannabinoid system, characterize the pro- and anticonvulsive effects of cannabinoids [e.g., Δ9-tetrahydrocannabinol and cannabidiol (CBD)], and highlight scientific evidence from pre-clinical and clinical trials of cannabinoids in epilepsy. These studies suggest that CBD avoids the psychoactive effects of the endocannabinoid system to provide a well-tolerated, promising therapeutic for the treatment of seizures, while whole-plant cannabis can both contribute to and reduce seizures. Finally, we discuss results from a new multicenter, open-label study using CBD in a population with treatment-resistant epilepsy. In all, we seek to evaluate our current understanding of cannabinoids in epilepsy and guide future basic science and clinical studies.
Cannabinoids and Epilepsy
Evan C. Rosenberg
&Richard W. Tsien
&Benjamin J. Whalley
&Orrin Devinsky
#The American Society for Experimental NeuroTherapeutics, Inc. 2015
Abstract Cannabis has been used for centuries to treat sei-
zures. Recent anecdotal reports, accumulating animal model
data, and mechanistic insights have raised interest in cannabis-
based antiepileptic therapies. In this study, we review current
understanding of the endocannabinoid system, characterize
the pro- and anticonvulsive effects of cannabinoids [e.g.,
Δ9-tetrahydrocannabinol and cannabidiol (CBD)], and high-
light scientific evidence from pre-clinical and clinical trials of
cannabinoids in epilepsy. These studies suggest that CBD
avoids the psychoactive effects of the endocannabinoid
system to provide a well-tolerated, promising therapeutic for
the treatment of seizures, while whole-plant cannabis can both
contribute to and reduce seizures. Finally, we discuss results
from a new multicenter, open-label study using CBD in a
population with treatment-resistant epilepsy. In all, we seek
to evaluate our current understanding of cannabinoids in
epilepsy and guide future basic science and clinical studies.
Keywords Epilepsy .seizures .cannabinoids .cannabidiol .
THC .cannabis
Epilepsy affects 2.9 million people in the USA and 65 million
people worldwide ( One in 26 people in the
USA will develop epilepsy in their lifetime [1]. Characterized
by recurrent seizures, epilepsy encompasses multiple disor-
ders caused by varied etiologies, including genetic syndromes,
stroke, infection, and traumatic brain injury. Many patients
with epilepsy also have sensorimotor, cognitive, psychologi-
cal, psychiatric, and social impairments, as well as impaired
quality of life and an increased risk of premature death [1].
While epilepsy can affect patients of all ages, it most com-
monly affects children, the elderly, and individuals with low
socioeconomic status. The estimated direct and indirect annu-
al cost of epilepsy in the U.S. is $15.5 billion (
While many drugs can limit seizures, no drug can prevent
the underlying cause of epilepsy or the development of epi-
lepsy (epileptogenesis) in patients who are at risk (e.g., after
head trauma). A third of patients remain pharmacoresistant,
failing to achieve sustained seizure freedom after 2 or more
adequately chosen, tolerated, and appropriately used antiepi-
leptic drugs (AEDs; more accurately termed antiseizure drugs)
[24]. Patients resistant to multiple AEDs have an increased
risk for sudden unexpected death in epilepsy and other forms
of epilepsy-related mortality [5,6], as well as impairments in
psychosocial, behavioral, and cognitive functions [3,79].
For many patients, epilepsy is a progressive disorder associ-
ated with ongoing loss of brain tissue and function. Finally,
multidrug combinations and high dosages cause more severe
side effects, a particular problem in patients with treatment-
resistant epilepsies. Assessing the side effects of AEDs is es-
pecially challenging in patients on long-term AEDs as any
baselinemay be many years past and even intelligent adults,
parents, and physicians may fail to appreciate chronic adverse
Electronic supplementary material The online version of this article
(doi:10.1007/s13311-015-0375-5) contains supplementary material,
which is available to authorized users.
*Orrin Devinsky
Department of Neuroscience and Physiology, Neuroscience Institute,
NYU Langone Medical Center, New York, NY 10016, USA
School of Pharmacy, The University of Reading, Whiteknights,
Reading RG6 6AP, UK
Department of Neurology, Comprehensive Epilepsy Center, New
York University School of Medicine, New York, NY 10016, UK
DOI 10.1007/s13311-015-0375-5
effects. The available AEDs fail to meet the clinical needs for
both efficacy and safety [10], indicating a dire need for novel
therapeutics that are targeted, disease-, and age-specific.
Recently, mounting anecdotal reports and media coverage
have sparked intense interest among parents, patients, and the
scientific community regarding the potential of medical can-
nabis to treat seizures. A potential alternative or supplement to
current AEDs, the cannabis plant includes >100 diverse
phytocannabinoids that, in part, target an endogenous
endocannabinoid signaling network, as well as other net-
works. Two major phytocannabinoids derived from cannabis
are psychoactive Δ9- tetrahydrocannabinol (THC) and
nonpsychoactive cannabidiol (CBD). Both Δ9-THC and
CBD can prevent seizures and reduce mortality in animal
models of seizure with low toxicity and high tolerability
[11]. However, a systematic analysis from the American
Academy of Neurology and a Cochrane Database review both
concluded that medical cannabis is of unknown efficacyto
treat epilepsy [12,13]. In this review, we examine the history
of cannabinoids in epilepsy, discuss the effectiveness of pre
clinical seizure model studies with cannabinoids, and review
recent clinical data, including a multicenter clinical trial of
CBD for patients with treatment-resistant epilepsy.
History of Cannabis in Epilepsy
Cannabis has been used for millennia for medical, recreation-
al, and manufacturing purposes. Around 2900 BCE, the Chi-
nese Emperor Fu Hsi characterized cannabis as having sacred
yin (weak, passive forces) and yang (strong, active forces)
features, suggesting that it could restore homeostasis to an
unbalanced body. Physicians in ancient India, Egypt, Persia,
Rome, Arabia, and Greece used cannabis for spiritual and
medicinal purposes, including menstrual fatigue, gout, rheu-
matism, malaria, beriberi, constipation, pain, and absentmind-
edness [14]. Early documented uses of cannabis to treat sei-
zures include a Sumerian text from 2900 BCE and an Arabian
document from the twelfth century [15,16].
The 1854, the US Dispensatory listed cannabis to treat
neuralgia,depression, pain,muscle spasms, insomnia, tetanus,
chorea, insanity, and other disorders [17]. Cannabis was val-
ued for its analgesic, anti-inflammatory, appetite-stimulating,
and antibiotic properties. In the mid-1800s, the British sur-
geon William OShaughnessy reported cannabis therapy for
the treatment of epilepsy, recounting an alleviation of pain in
most, a remarkable increase of appetite in all, unequivocal
aphrodisia, and great mental cheerfulness[14,18]. Two of
Englands most prominent mid-to-late nineteenth- century
neurologists, J.R. Reynolds and W. Gowers, also noted the
benefits of cannabis in epilepsy [19]. Gowers reported a man
controlled on 9.8 g of Cannabis indica, dosed 3 times daily
for up to 6 months [20].
Cannabis was first regulated in the USA with the 1906
Pure Food and Drug Act. The follow-up 1937 Marijuana
Tax Act was opposed by the American Medical Association,
which considered the more severe restrictions an infringement
on physiciansfreedomtotreatpatients[17]. In 1970, the US
Comprehensive Drug Abuse Prevention and Control Act cat-
egorized marijuana as a Schedule I drug with high potential
for abuse and no accepted medicinal use. Legislation has been
introduced to the US Senate to change marijuana to a Sched-
ule II drug.
Over the last 50 years, the main chemical constituents of
cannabis have been isolated and synthesized. Δ9-THC was
isolated in 1964 and synthesized in 1971 [21,22]. CBD was
isolated in 1940 and synthesized in 1963 [23,24]. The canna-
binoid type 1 (CB
R) and type 2 (CB
R) receptors, which
bind Δ9-THC, were cloned in the 1990s [25,26], supporting
an endogenous system for this principal cannabinoidsphar-
macological activity.
The Endocannabinoid System
The discovery of the endocannabinoid system in the early
1990s revealed the neuronal mechanisms that underlie the
psychoactive effects of Δ9-THC in cannabis. Initial studies
demonstrated that brief postsynaptic depolarization re-
duced neurotransmitter release from excitatory terminals
onto Purkinje cells in the cerebellum and inhibitory termi-
nals onto pyramidal neurons in the hippocampus [27,28].
This phenomenon was termed depolarization-induced
suppression of excitation/inhibition(DSE and DSI, re-
spectively). Postsynaptic depolarization was postulated to
trigger the release of an undiscovered substance that tran-
siently limited presynaptic neurotransmitter release. Along
with the discovery of nitric oxide (NO), this paradigm-
shifting view suggested the concept of retrograde signaling
in contrast to a primarily anterograde view of synaptic sig-
naling. Application of a CB
R agonist (or antagonist) en-
hanced (or prevented) DSE and DSI, suggesting that it was
mediated by an endogenous cannabinoid ligand [2931].
These endocannabinoids were identified as the hydropho-
bic ligands N-arachidonoyl ethanolamide (anandamide)
[32] and 2-arachidonoyl glycerol (2-AG) [33,34].
Anandamide and 2-AG are synthesized from postsynaptic
membrane phospholipid precursors and released in an activi-
ty-dependent, on-demandmanner, unlike traditional vesic-
ular neurotransmitters (Fig. 1). Depolarization of the postsyn-
aptic cell or direct activation of metabotropic glutamate recep-
tors increases levels of intracellular calcium, which trigger
second messenger cascades that promote endocannabinoid
synthesis [3539]. Anandamide is synthesized via
phospholipase D-mediated hydrolysis of N-arachidonoyl-
phosphatidylethanolamine, and degraded by the fatty acid am-
ide hydrolase (FAAH) into arachidonic acid and ethanolamine
[4043]. 2-AG is synthesized via diacylglycerol (DAG) lipase
(DAGL) α-mediated hydrolysis of DAG, and degraded by
FAAH into arachidonic acid and glycerol, or by
monoacylglycerol lipase [4144]. Chronic hyperexcitability
leads to dynamic changes in the endocannabinoid pathway
(see The Endocannabinoid System:CB
Rs). Thus, the en-
zymes that regulate metabolism and cannabinoid receptors rep-
resent attractive targets to treat several neurological disorders
[45]. Accordingly, the selective CB
R blocker rimonabant was
approved in >50 countries as an anorectic to treat obesity [46],
and showed promise in helping smokers quit tobacco use [47],
but its use was suspended when postmarketing surveillance
revealed high rates of depression and suicidal ideation.
Produced in an activity-dependent manner, endocannabinoids
travel to the presynaptic cell and bind to CB
Rs. CB
Rs are G
protein-coupled receptors linked to pertussis-sensitive Gi/o α
subunits. Activation of the αsubunit triggers dissociation of
the βγ complex, which reduces adenylate cyclase production
of cyclic adenosine monophosphate [48], inhibits N- and P/Q-
type voltage-gated calcium channels [31,4952], stimulates A-
type potassium channels [5356], activates G protein-coupled
inwardly-rectifying potassium channels [5759], and inhibits
the vesicular release machinery [60]. These multiple mechanisms
reduce presynaptic cell excitability and Ca
, strongly
diminishing presynaptic neurotransmitter release. CB
Rs can al-
so regulate the presynaptic release of multiple neuromodulators
such as acetylcholine, dopamine, and norepinephrine [61]. Final-
ly, endocannabinoid signaling may modulate regional-specific
long-term synaptic plasticity, including long-term potentiation
and long-term depression (for a review, see [62,63]).
Rs are distributed primarily in axon terminals in the
neocortex (especially cingulate, frontal, and parietal re-
gions), hippocampus, amygdala, basal ganglia, thalamus,
hypothalamus, nucleus accumbens, substantia nigra, ven-
tral tegmental area, cerebellum, and brainstem [39]. CB
are most densely expressed at cortical and hippocampal
presynaptic γ-aminobutyric acid (GABA)ergic presynaptic
boutons, especially cholecystokinin-positive (CCK+) and
parvalbumin-negative GABAergic interneurons [6466].
Glutamatergic axon terminals in cortical and subcortical
neurons contain fewer presynaptic CB1 receptors than
GABAergic terminals [65,6771].
Phytocannabinoids: Classification and Function
The cannabis plant consists contains >100 C21 terpenophenolic
compounds, known collectively as phytocannabinoids [72].
Most of these lipophilic cannabinoids are closely related and
differ only by a single chemical functional group. Cannabinoids
fall into 10 main groups, with constituents representing degra-
dation products, precursors, or byproducts (Fig. 2, adapted from
[73]). Two of the most abundant constituents are Δ9-THC and
CBD, the ratios of which vary by cannabis strain. Cannabis
sativa contains a higher ratio of Δ9-THC to CBD, producing
more stimulating, psychotropic effects. Cannabis indica strains
contains a higher ratio of CBD:Δ9-THC and are typically more
sedating [11,73].
Δ9-THC is a partial agonist at central nervous system (CNS)
Rs and CB
Rs in the immune system. Most behavioral,
cognitive, and psychotropic effects of cannabis result from the
effects of Δ9-THC at brain CB
Rs. The subjective high
produced by cannabis can be blocked by pretreatment with
the CB
R antagonist rimonabant [74]. Δ9-THC impairs
short-term working memory in several rodent models, which
R antagonist
[7578]. Inhibition of long-term potentiation at hippocampal
CA3 Schaffer Collateral/CA1 synapses may underlie this
Fig. 1 Biosynthesis, degradation, and signaling of endocannabinoids. (A)
Presynaptic cannabinoid type 1 receptor (CB
R) signaling. (B) Postsynaptic
endocannabinoid biosynthesis/signaling. NArPE = N-arachidonoyl
phosphatidylethanolamine; DAG = 1-acyl, 2-arachidonoyl diacylglycerol;
VGCC = voltage-gated calcium channels; PEA = palmitoylethanolamide;
ACPA = arachidonylcyclopropylamide; ACEA = arachidonyl-2'-
chloroethylamide; PMSF = phenylmethylsulfonyl fluoride
Cannabinoids and Epilepsy
effect on memory [35]. Δ9-THC or CB
R agonists can in-
crease or decrease food intake in different species [79]. Δ9-
THC also regulates neuronal excitability during seizures (see
Preclinical Evidence). Thus, Δ9-THC acts through the
endocannabinoid system toregulate mood, learning and mem-
ory, neuronal excitability, and energy balance. Δ9-THC exerts
potent anti-inflammatory functions via CB
Rs and CB
Rs on
microglia, the primary immune cells in the CNS. Δ9-THC or
R agonists limit neurotoxicity in in vitro and in vivo as-
says, including chemotoxic [8083], low Mg
[84], and is-
chemic [85,86]models.Δ9-THC has antioxidant effects in α-
amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid- and
N-methyl-D-aspartate-mediated cytotoxicity models via a
R-independent mechanism [87]. Cannabinoids reduce
neuronal and glial release of the proinflammatory cytokines
tumor necrosis factor-α, NO, interleukin (IL)-1 and IL-6
[8893], and increase release of anti-inflammatory cytokines
IL-4, IL-10, and IL-1 receptor antagonist (IL-1a) [94,95]via
CB1R- and CB2R-dependent mechanisms in neurons and glia
[94,95] (reviewed in [96]). Δ9-THC also transiently activates
and desensitizes the transient receptor potential (TRP) chan-
nels TRPA1, TRPV1, and TRPV2 [9799]. Given the syner-
gistic relation between seizures and inflammation [100102],
the cannabinoid system provides a novel strategy to target
both segments of this feedback cycle.
CBD resembles Δ9-THC structurally but the 2 molecules
differ significantly in pharmacology and function. CBD has
very low affinity at CB
R, unlike Δ9-THC
[103106]. The potential targets for CBD are reviewed in
detail in another article in this issue (Molecular Targets of
CBD in Neurological Disorders). CBD is an agonist at TRP
channels (TRPV1, TRPV2, TRPA1) [98,99,104], 5-
hydroxytryptamine1αreceptors [107], and glycine receptors
[108]. CBD is an antagonist at TRP melastatin type-8 chan-
nels [97], T-type voltage-gated calcium channels [109], and G
protein-coupled-receptor GPR55 (see below).
CBD exerts dynamic control over intracellular calcium
stores through multiple, activity-dependent pathways [110,
111]. CBD induces a bidirectional change in intracellular cal-
cium levels that depends on cellular excitability. Under normal
physiological Ca
conditions, CBD slightly increases intra-
cellular Ca
, whereas CBD reduces intracellular Ca
high-excitability conditions. These changes were blocked by
the pretreatment with an antagonist of the mitochondrial Na
exchanger, suggesting a mitochondrial site of action
[111]. CBD also produces biphasic changes in intracellular
calcium levels via antagonism of the mitochondrial voltage-
dependent anion channel 1 [112].
CBD antagonizes GPR55, which functions as a counterpart
to the canonical CB1R/CB2R signaling pathway [113].
GPR55 is present in the caudate, putamen, hippocampus, thal-
amus, pons, cerebellum, frontal cortex, and thalamus. GPR55
was initially characterized as a novel cannabinoid receptor,
coupled to Gα13 [114]. Activation of GPR55 in human em-
bryonic kidney cells triggers the release of intracellular Ca
from endoplasmic reticulum stores via a pathway dependent
on RhoA (Ras homolog gene family member A), phospholi-
pase C, and inositol 1,4.5-trisphosphate receptor [115]. The
endogenous membrane phospholipid L-α-
lysophosphatidylinositol is a GPR55 agonist [116]. Brief ap-
plication of L-α-lysophosphatidylinositol transiently in-
creases intracellular Ca
levels and vesicular release proba-
bility at excitatory hippocampal synapses. CBD opposes this
effect by reducing glutamate release, suggesting a potential
antiseizure mechanism [117]. CBD also reduces epileptiform
activity (burst amplitude and duration) in in vitro (4-
aminopyridine and Mg
) models through a CB1-indepen-
dent, concentration-dependent, and region-specific manner
in the hippocampus. Preclinical studies demonstrate an anti-
seizure effect of CBD (see Preclinical Evidence).
CBD also regulates several transporters, enzymes, and met-
abolic pathways that are common to Δ9-THC and
endocannabinoid signaling. CBD inhibits uptake of adenosine
by blocking the equilibrative nucleoside transporter [118,
119]. Increased levels of adenosine activate A2 receptors,
which regulate striatal CB
Rs [120]. At high micromolar
Fig. 2 Biosynthesis of phytocannabinoids [73]
levels, CBD also inhibits the uptake and enzymatic degrada-
tion of anandamide via FAAH, elevating anandamide extra-
cellular concentrations [121]. Thus, dynamic interactions like-
ly occur between the multiple plant cannabinoids such as
CBD and Δ9-THC (see Entourage Effect).
CBD limits inflammation and oxidative stress [122]. CBD
reduces oxidative toxicity in an in vitro glutamate excitotoxicity
assay [123], and raises adenosine to oppose lipopolysaccharide-
induced inflammation and tumor necrosis factor-αrelease [118,
124]. In mice with middle cerebral artery occlusion, CBD trig-
gered a CB
R-independent decrease in reperfusion injury, in-
flammation, and death. This neuroprotective action may result
from reduced myeloperoxidase activity, neutrophil migration,
and microglia high-mobility group box 1 expression [125,
126]. Additionally, CBD activates peroxisome proliferator-
activated receptor-γ, reduces NO and IL-βrelease, limits gliosis,
and restricts neuroinflammation in mice injected with amyloid β
[127129]. Finally, treatment of microglial cultures with
interferon-γraised mRNA levels of the CBD receptor GPR55
[130], which regulates the inflammatory responses to neuropath-
ic pain [131]. Taken together, these studies suggest that CBD
reduces neuroinflammation in several disease-specific
The Entourage Effect
The entourage effectwas a term originally coined by Ben-
Shabat et al. [132] to refer to the potentiating effects of
endocannabinoid metabolic byproducts on endocannabinoid
function at CB
Rs and CB
Rs. They observed that 2 esters of
the endocannabinoid 2-AGs2-linoleoyl-glycerol and 2-
palmitoyl-glycerolwere present in spleen, brain, and gut, to-
gether with 2-AG. While these esters do not bind to cannabi-
noid receptors or inhibit adenylyl cyclase via either CB
, each ester potentiated 2-AG-induced inhibition of motor
behavior, immobility on a ring, analgesia on a hot plate, and
hypothermia: behavioral tests commonly referred to as the tet-
radby which CB
-mediated effects can be detected [132].
Thus, the original concept of the entourage effect referred to a
specific group of endogenous compounds, structurally similar
to endocannabinoids, that potentiated the effects of endogenous
cannabinoid receptor agonists at CB
Rs and CB
Subsequently, the idea of theentourage effect has expanded
considerably both with regard to mechanisms of interactions,
as well as classes of chemical agents. The diversification of
entourage effects has been promoted by scientific and lay
authors, and often well beyond its original boundaries. Wag-
ner and Ulrich-Merzenich [133] proposed 4 potential mecha-
nisms of synergy for phytotherapeutics, using cannabis as an
exemplar: 1) multitarget effects; 2) pharmacokinetic effects
(e.g., improved bioavailability or solubility); 3) improved bac-
terial resistance; and 4) modulation of adverse events (AEs;
truly an antagonism, albeit a beneficial one) [133]. This ap-
proach thereby extended the tightly defined entourage effect
to include practically any plant mixture acting through any
molecular target to exert any effect.
The cannabis plant contains a complex mixture of both
cannabinoids (i.e., Δ9-THC and CBD) and terpenoids
(limonene, myrcene, α-pinene, linalool, β-caryophyllene,
caryophyllene oxide, nerolidol, and phytol) derived from a
common precursor (geranyl pyrophosphate). Several stud-
ies posited that the entourageof [whole] plants are bet-
ter drugs than the natural products isolated from them,
suggesting that the clinical effects of cannabis usage may
be due to complex interactions between several plant can-
nabinoids [134,135]. In support of this view, CBD may
potentiate the beneficial effects associated with Δ9-THC
(analgesia, antiemesis, and anti-inflammation) and reduce
the negative psychoactive effects of Δ9-THC (impaired
working memory, sedation, tachycardia, and paranoia)
[136138]. Users of cannabis with a high CBD:Δ9-THC
ratio have greater tolerability and lower rates of psychosis
than users of high Δ9-THC:CBD ratios (or Δ9-THC
alone) [139]. Additional reports claim potential synergis-
tic interactions of phytocannabinoids and phytoterpenoids
that may include therapeutic effects on pain, inflamma-
tion, depression, anxiety, addiction, epilepsy, cancer, fun-
gal, and bacterial infections [135,140]. However, proper
characterization of any synergisticeffects of multiple
plant cannabinoids requires statistically robust demonstra-
tions of effects greater than the sum of the parts. These
effects can be tested in vitro or in vivo using assays such
as the isobolographic approach [141,142]. Such a design
can show if any 2 compounds, extracts, or mixtures are
additive in the specific assay (e.g., models of seizure),
synergistic, or antagonistic, thereby avoiding speculation
about potential synergism or the confusion of additive
effects with synergism. Although experimental data sup-
port the efficacy of both CBD and Δ9-THC as individ-
ual agents in various animal models of epilepsy, we are
not aware of any studies demonstrating synergy of these
compounds in animal models nor any controlled trials
that establish a synergistic effect in patients with
Collectively, several studies demonstrate functional (but
not defined molecular) interactions between plant cannabi-
noids that extended the initial concept of the entourage effect
far beyond its original intent. While such interactions may
exist, further well-defined research is required to verify anec-
dotal claims regarding the increased antiseizure efficacy of
CBD with Δ9-THC (vs CBD alone) in patients with epilepsy.
While natural selection may have led to combinations of phy-
tochemicals in cannabis to resist infection or predation, there
is no reason to expect natureto combine chemicals in a
single plant to treat human epilepsy.
Cannabinoids and Epilepsy
Animal Models of Seizures and Epilepsy
Animal models provide powerful assays to assess the po-
tential antiseizure or antiepileptic effects of cannabinoids.
Each preclinical paradigm has unique advantages and dis-
advantages, and many represent unique seizure etiologies,
semiologies, or corresponding electroencephalography
(EEG) patterns. Table 1(adapted from [143145]) summa-
rizes animal models discussed in this review, grouped by
relevance to human epilepsies. Acute models (e.g., kainic
acid and pentylenetetrazol) allow high-throughput screen-
ing for upregulation of biomarkers, but cannot recapitulate
spontaneous recurrent seizures or reduced seizure thresh-
olds found in chronic epilepsy. Chronic models of seizure
activity elicit spontaneous, recurrent seizures that can be
recorded on video EEG. While technically challenging, the-
se models better represent epileptogenesis and drug screen-
ing for humans. However chronic models are specific to the
type of insult (traumatic brain injury, mouse genetic
models), and may not reflect broad anatomical or functional
changes in generalized epilepsy [145].
Preclinical Evidence of Cannabinoids in Epilepsy
Multiple animal models demonstrate the efficacy of cannabi-
noids in preventing seizures and reducing mortality in epilep-
sy. Animal models highlight dynamic changes in the
endocannabinoid system follow chronic seizures, with both
acute and chronic homeostatic regulatory components.
The Endocannabinoid System
Endocannabinoid release prevents seizure-induced neurotoxic-
ity. Kainic acid (KA) (30 mg/kg)-induced seizures increased
levels of the anandamide in wild-type mice (20 min postinjec-
tion) [146], and pilocarpine (375 mg/kg)-induced seizures in-
creased levels of 2-AG (15 min postseizure onset) [147]. Thus,
epileptiform activity triggers a neuroprotective, on-demand re-
lease of endocannabinoids (or increase endocannabinoid levels
in a downstream pathway unrelated to neuroprotection). Pre-
treatment with an anandamide reuptake inhibitor (UCM707;
3 mg/kg) reduced KA-induced seizure severity, but not in mice
with conditional CB1R deletion in principal forebrain excitato-
ry neurons [146]. Blockade of the endocannabinoid catabolic
enzyme FAAH (with AM374; 8 mg/kg) increased levels of
anandamide and protected against KA (10 mg/kg)-induced hip-
pocampal seizures and subsequent impairments in balance and
coordination [148]. Inhibition of both FAAH (with AM374)
and the anandamide reuptake transporter (with AM404) in rat
hippocampus prevented α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid-induced excitotoxic insults (cytoskele-
tal damage and synaptic decline) in vitro and behavioral and
memory impairment in vivo [149]. Blockage of FAAH and
DAGLα(with AM6701, 5 mg/kg) raised levels of anandamide
and 2-AG, protected against KA (10 mg/kg)-induced seizures,
and reduced seizure-induced cytotoxicity [150]. The
endocannabinoids, methanandamide, and 2-AG reduced neu-
ronal firing in a low Mg
in vitro model of status epilepticus, in
a dose-dependent manner (EC
145±4.15 nM
methanandamide, 1.68± 0.19 μM 2-AG) [151].
Animal models demonstrate that activation of CB
Rs reduces
seizure severity. Mice with conditional deletion of CB
Rs in
principal forebrain excitatory neurons (but not interneurons)
exhibited more severe KA-induced seizures (30 mg/kg) than
wild-type controls. Conditional deletion of the CB
creased gliosis and apoptosis following KA-induced seizures
and prevented activation of the protective immediate early
genes (c-Fos, Zif268, brain-derived neurotrophic factor)
[146]. CB
R expression in hippocampal glutamatergic (but
not GABAergic) inputs is necessary and sufficient to protect
against KA-induced seizures [152]. Further, viral-induced
overexpression of CB
Rs targeted to the hippocampus re-
duced KA-induced seizure severity, seizure-induced CA3 py-
ramidal cell death, and mortality [153], Together, these results
demonstrate that CB
Rs could limit seizure activity and pro-
tect neurons from subsequent cell death and reactive gliosis.
Seizures trigger homeostatic changes in hippocampal
Rs and the endocannabinoid system (reviewed in [154])
(Fig. 3). Levels of CB
R expression in the CA1-3 stratum
oriens and radiatum (presumed excitatory inputs) and dentate
gyrus steadily increased 1-week post-pilocarpine-induced sei-
zures (Fig. 3, dark green trace) [147,155158]. However,
sclerotic and nonsclerotic hippocampal tissue resected from
patients with epilepsy displayed a reduction in DAGLα(2-
AG biosynthetic enzyme), CB
R mRNA, and CB
R excitato-
ry terminal immunoreactivity (Fig. 3, light green trace) [159].
Furthermore, compared with healthy controls, patients with
temporal lobe epilepsy have reduced levels of anandamide
in cerebrospinal fluid samples [160]. These findings suggest
that seizure activity induces a homeostatic upregulation of
excitatory terminal CB
Rs, which may reduce excitatory neu-
rotransmitter release via DSE (see The Endocannabinoid
System). This compensatory process may be impaired in
patients with prolonged treatment-resistant epilepsy or hippo-
campal sclerosis, leading to neuronal hyperexcitability,
pharmacoresistance, and inconsistent effects of cannabis ex-
posure. However, further research is required to verify the
functional effects of this potential process in human patients,
and whether CB
R homeostasis indeed limits seizure severity
or occurrence.
In contrast to effects at excitatory terminals, seizures induce a
homeostatic reduction in CB
R expression in inhibitory
Tab le 1 Preclinical animal models of seizures (adapted from [143145])
Type of seizure model Method Mechanism Relevant human condition Common use
Acute MES Electrical stimulation Generalized tonicclonic
Drug screening (used as a first-line
screening method for AEDs)
R antagonist, Ca
(?), Na
channels (?)
Generalized seizure Drug screening (used as a first-line
screening method for AEDs),
seizure mechanism
Acute KA Ionotropic glutamate receptor (e.g.,
AMPAR, kainate receptor agonist)
Focal (temporal lobe) seizure Drug screening, mechanism of seizures/
epileptogenesis and cognitive impairments
Acute Flurothyl GABA
R antagonist Multiple acute seizures,
childhood epilepsy
Development of cognitive impairments
from early life seizures
Acute Other chemoconvulsant
(e.g., bicuculline, 3-MPA,
picrotoxin, etc.)
Various Generalized seizures (or focal,
if applied locally)
Drug screening
Acute Hypoxia/ischemia Anoxic depolarization, impaired Na
ATPa se , extracellular impairments K
[glutamte]/[aspartate], intracellular
Hypoxicischemic encephalopathy Age-specific (e.g., neonatal) drug screening,
mechanisms of seizures and cognitive
Acute Hyperthermia Activation of temperature-sensitive ion
channels, release of proinflammatory
Febrile seizures Drug screening, long-term consequences
of seizures
Chronic with high
propensity for induced
chemical kindling
AChR agonist Focal (temporal lobe) seizures Drug screening, mechanism of seizures/
epileptogenesis and cognitive impairments
Chronic with high
propensity for induced
Electrical (e.g., 6Hz
psychomotor, limbic)
Electric stimulation Focal (temporal lobe) seizures Drug screening, mechanism of seizures/
epileptogenesis and cognitive impairments
Chronic epilepsy (SRS) Stroke, TBI Disease-specific models Focal epilepsy Drug screening, mechanism of seizures/
epileptogenesis and cognitive impairments
Chronic epilepsy (SRS) SE Chronic treatment with KA or
Prolonged seizures Drug screening
Chronic epilepsy (SRS) Genetic (e.g., GAERs,
WAG/Ij mice,
photosensitive baboons)
Various Specific seizure models (e.g.,
absence seizures, genetic)
Drug screening
SRS = spontaneously recurring seizures; MES = maximal electroshock; PTZ = pentylenetetrazole; KA = kainic acid; 3-MPA = 3-mercaptopropionic acid; TBI = traumatic brain injury; SE = status
epilepticus; GAERs = genetic absence epilepsy rats from Strousberg; GABA
R=γ-aminobutyric acid type A receptor; AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor;
ATPase = adenosine triphosphatase; AChR = acetylcholine receptor; AEDs = antiepileptic drugs
Cannabinoids and Epilepsy
terminals (Fig. 3, dark red trace). Beginning 4 days following
pilocarpine-induced seizures in rats, CB
R expression progres-
sively decreased in hippocampal CCK+ inhibitory nerve termi-
nals [161], particularly in the CA1 stratum pyramidale and the
dentate gyrus inner molecular layer, unaccounted for by CA1
neuronal cell loss alone [155,156,162]. By reducing CB
expression on inhibitory terminals (and presumed DSI), this
homoeostatic process may limit network disinhibtion and restrain
elevated excitability during prolonged epileptiform activity. In
sclerotic hippocampal tissue removed from 1) 2 months post
pilocarpine-induced seizures in mice [163], and 2) human pa-
tients [164], levels of CB
Rs remained consistently elevated in
interneuron axonal terminals (Fig. 3, light red trace). This finding
suggests that patients with prolonged, pharmacoresistant epilepsy
may suffer from impaired CB
R homeostasis on inhibitory inter-
neuron terminals, leading to prolonged disinhibition and network
excitability. Postseizure changes in CB
Rs may be specific to
seizure type or developmental stage, as mice with a single epi-
sode of febrile seizures induce an overall increase in DSI and
R on CCK+ interneurons [165,166].
Modulators of the Endocannabinoid System
and Synthetic CB
R Agonists/Antagonists
Figure 4summarizes the effects of synthetic cannabinoids and
phytocannabinoids in 175 pre-clinical seizure models or dis-
crete conditions (adapted from [167]). These studies are
subclassified by drug typeand seizure model in corresponding
tables in the Appendix (see Supplementary Material).
Results from 13 studies from 3 species (rat, mouse, guinea
pig) demonstrate that modulation of the endocannabinoid sys-
tem (via inhibition of FAAH or anandamide reuptake) pro-
vides about 46.2 % (6/13) anticonvulsant, 23.1 % (3/13)
mixed effect, and 30.8 % (4/13) no significant effect in seizure
models. CB
R agonists produced an anticonvulsant effect in
68.1 % (47/69), proconvulsant effect in 2.9 % (2/69), mixed
effect in 7.2 % (5/69), and no significant effect in 21.7 % (15/
69) of seizure models in rats and mice. One study suggests that
R agonists may produce an anticonvulsant effect through
Rs at low doses, but a proconvulsive effect through
TRPV1 channels at high doses [168]. In addition, CB
nists (WIN55, 212, ACEA) often produce a additive effect
when combined with several commonly prescribed AEDs
(see Fig. 4B)[169177]. In 18 studies from mice, rats, and
guinea pigs, CB
R antagonists were pro convulsant in 38.9 %
(7/18), anti-convulsant in 5.6 % (1/18), and showed no signif-
icant effect in 55.6 % (10/18) of trials. Although CB
nists were anticonvulsant in 68.1 % of the studies, only 38.9 %
of CB
R antagonists were proconvulsive (most showed no
effect). Thus, while activation of the endocannabinoid system
may prevent long-term consequences of seizure sequelae, in-
hibition of the endogenous protective mechanisms may not
contribute significantly to seizures. Variations in the pro- vs
anticonvulsant effects in each system may reflect specific ef-
fects of the species, seizure models (acute vs chronic, focal vs
generalized), dose ranges, timing, or experimental design.
Phytocannabinoids: Δ9-THC and CBD
Evidence from 34 studies from 6 animal species demonstrate
that Δ9-THC is anticonvulsant in 61.8 % (21/34),
proconvulsant in 2.9 % (1/34), mixed in 2.9 % (1/34), and
shows no significant effect in 32.4 % (11/34) of seizure
models. Δ9-THC potentiated the effects of phenytoin and
phenobarbital in the maximal electroshock model of general-
ized seizures [178,179]. The National Toxicology Program
noted a pro convulsant effect of Δ9-THC in rats and mice
[180], although species-specific differences in CB
sion may underlie variable responses to Δ9-THC. CBD and
its homologue cannabidivarin (CBDV) were 80.5 % (33/41)
anticonvulsive and 19.5 % (8/41) ineffective, at reducing sei-
zures in mice and rats. Notably, no studies showed a
proconvulsive effect for CBD or CBDV. CBDV potentiated
the effects of phenobarbital, ethosuximide, and valproate in 2
seizure models [181]. These studies suggest that both Δ9-
THC and CBD provide significant protection from seizures
Fig. 3 Homeostatic changes to
hippocampal cannabinoid type 1
receptors (CB
Rs) in preclinical
animal seizure models [147,
154166]. GABA = γ-
aminobutryic acid
in preclinical animal trials, presenting potential targets for hu-
man studies.
Tole ra nc e a nd W ithdr aw al
Prolonged treatment with Δ9-THC or synthetic CB1 agonists
leads to a dose-dependent and region-specific desensitization,
downregulation, and internalization of CB
Rs [182203].
These changes produce tolerance to the acute behavioral ef-
fects of Δ9-THC in in vivo models, reducing cannabinoid-
induced hypomotility, hypothermia, antinocioception, and
memory impairment with repeated usage [182,183,185,
197,199,204,205]. In several seizure models, prolonged
Δ9-THC (but not CBD) exposure leads to tolerance to the
antiepileptic activity of cannabinoids [206210]. In humans,
chronic cannabinoid usage produces tolerance towards Δ9-
THC-mediated changes in autonomic behaviors, sleep and
sleep EEGs, and self-reported psychotropic high, although
these changes vary in frequent users [211216].
Withdrawal from rats chronically dosed with Δ9-THC trig-
gers rebound seizures and elevated anxiety-like responses in
several preclinical animal studies [217219]. Monkeys that
previously self-administered intravenous Δ9-THC demon-
strate abstinent symptoms of aggressiveness, hyperirritability,
and anorexia [220], as well as impaired operant behavior
[221]. Results from human studies demonstrated symptoms
of anxiety, aggression, dysphoria, irritability, anorexia, sleep
disturbances, and sweating during abstinence from chronic
Δ9-THC usage, rescued by Δ9-THC re-administration
[222]. Withdrawal from cannabis use can trigger rebound sei-
zures in several preclinical animal and human studies [203,
209,210,223226], although other studies show no
proconvulsant effect of cannabis withdrawal [178,227].
Unlike Δ9-THC, CBD (or nabiximols, CBD/Δ9-THC in a
1:1 ratio) does not seem to produce significant intoxication [228],
tolerance [229231], or withdrawal effects [232]. CBD and/or
nabiximols may counteract the Δ9-THC-dominant effects of
cannabis withdrawal [233235]. In summary, evidence suggests
that while both tolerance and some withdrawal symptoms may
occur with Δ9-THC, CBD may limit the effects of cannabis
tolerance and withdrawal, but more studies are needed.
Clinical Evidence of Cannabinoids in Epilepsy
Several clinical studies have examined the association be-
tween cannabis use and seizures. These include case studies,
surveys and epidemiological studies, and clinical trials.
Case Studies
Case reports describe proconvulsant and anticonvulsant effect
of cannabis, with the majority reporting either beneficial or
lack of effect on seizure control. Selected examples illustrate
the diverse spectrum of reported responses. Cannabis used 7
times within 3 weeks was associated withmultiple tonicclon-
ic seizures in a patient previously seizure free for 6 months on
phenytoin and phenobarbital. However, seizures were not
temporally correlated with immediate intoxication or with-
drawal [236]. Cannabis withdrawal increased complex partial
seizure frequency in a 29-year-old man with a history of alco-
holism and bipolar disorder (each of with are independently
associated with seizures) [226]. In another 2-part case study, a
43-year-old on carbamazepine experienced about 56nightly
violent seizures lasting 1 min each. When he consumed about
40 mg C. sativa at night, seizure frequency was reduced by
70 %, but withdrawal triggered a doubling of his baseline
seizure frequency. In the same study, a 60-year-old man with
a 40-year history of cannabis usage (68 cigarettes per day)
developed status epilepticus after cannabis withdrawal [225].
Additionally, synthetic designercannabinoid drugs (spice
or K2) induce new-onset seizures, tacharrythmia, and psy-
chosis, often with greater severity and toxicity than cannabis
[237245]. The toxicity of these synthetic agents may result
from their properties as full agonists of CB
R, while Δ9-THC
is a partial agonist.
The majority of other studies demonstrate an anticonvul-
sant effect of cannabis. In a 1949 trial, administration of a Δ9-
THC homolog (1,2-dimethyl heptyl) reduced the severe an-
ticonvulsant resistant (phenobarbital or phenytoin) grand mal
epilepsyin 2/5 children [246]. One patient whose seizures
were not controlled on low-dose phenobarbital or phenytoin
had fewer tonicclonic seizures while smoking 25cannabis
cigarettes per day [247]. Myoclonic and other seizures were
reportedly reduced in 3 adolescents on oral 0.070.14 mg/kg
Δ9-THC daily. Parents reported that their children were
more relaxedmore alert, more interested in her surround-
ings[248]. In another study, a 45-year-old man with cerebral
palsy and treatment-resistant focal epilepsy experienced a
marked reduction in focal and secondary generalized seizures
on daily marijuana [249]. Other recent cases also support the
observation that cannabis use can reduce seizures in some
patients [250,251]. These studies suggest that cannabis can
not only reduce seizure susceptibility, but also trigger rebound
seizures during withdrawal. Limitations of open-label, often
retrospective single case reports are compounded by the var-
iability in epilepsy syndrome, differences in cannabis dosage,
route, and composition.
Epidemiological Reports and Surveys
Recent epidemiological reports and surveys depict the incidence
of medical marijuana usage for seizure control. The predicted
prevalence of medical cannabis use in epileptic patients ranges
from about 4 % (77 =total patient population in US medical
cannabis program) to about 20 % (310= total patients at a tertiary
Cannabinoids and Epilepsy
epilepsy clinic in Germany) [252,253]. One percent of the med-
ical marijuana users in California (~2500= total patient popula-
tion) use cannabis to control seizures [254]. In a telephone survey
of 136 patients with epilepsy, 21.0 % were active users, 13.0 %
were frequent users, 8.1 % were heavy users, and 3.0 % met
Diagnostic and Statistical Manual of Mental Disorders-IV criteria
for marijuana dependence.
The majority of patient and caregiver surveys found either
beneficial effects or no significant effect of cannabis in patients
with epilepsy. In a small, 1976 survey of 300 patients with epi-
lepsy, cannabis usage had no effect on seizure frequency in 30 %
of patients, increased seizures in 1 patient, and decreased seizures
in another [255]. A 1989 12-year retrospective study reported
10 % of 47 patients with recreational drug-induced [tonicclon-
ic] seizureshad consumed cannabis prior to seizures, although
this was confounded by recent cocaine, amphetamine, or LSD
(lysergic acid diethylamide) usage. No seizures were reported
following cannabis use alone [256]. A single epidemiological
study provided limited evidence that cannabis may possess anti-
seizure properties in humans. In a study of i llicit drug use
and new-onset seizures in Harlem utilizing a casecontrol
methodology, cannabis used within 90 days before hospi-
talization was associated with a 2.8-fold decreased risk of
first seizures among men but not women [257]. In a tele-
phone survey of adult patients from a tertiary care epilep-
sy center, most active users reported beneficial effects on
seizures (68 % reduced severity, 54 % reduced incidence),
tive therapy for epilepsy. No patient reported a worsening
of seizures with cannabis use [258]. The majority (84 %)
of patients in a German tertiary care center reported that
cannabis had no effect on their seizure control [253].
No Significant Effe ct
Mixed Effect
Pro-Convulsive Effect
Anti-Convulsive Effect
of the Endo-
Canna binoid
Agonis ts
Cannabinoids and Preclinical Seizure Models
Modulators of
the Endo-
# of Species 32362
# of Discrete
13 69 18 34 41
Mixed Effect 3
Modulators of the
eCB System
CB1R Agonists
CB1R Antagonists
WIN 55, 212
Increased effect
Reduced effect
No significant effect
Mixed effect
Not tested
299 174, -7 172, -5 175 171, -2 177 171, -5 171 174 171 174, -7 177 174 172 177 177
173 170, -3 169, 173 170 170 170 170 170 173 319
299 299
292 181181
179, 181
Fig. 4 Summary of cannabinoids and preclinical seizure models. (A)
Composite data from 175 preclinical seizure models (e.g., maximal
electroshock, kainic acid) or discrete experimental designs (e.g., with
combined antiseizure medications). Pro-/antiseizure effects are
subclassified by given intervention: 1) modulators of the
endocannabinoid (eCB) system (e.g., fatty acid amide hydrolase
inhibitor URB597); 2) cannabinoid type 1 receptor (CB
R) agonists
(e.g., WIN55212-2); 3) CB
R antagonists (e.g., SR141716A); 4) Δ
tetrahydrocannabinol (Δ
-THC); and 5) cannabidiol (CBD)/
cannabidivarin (CBDV). (See Supplementary Material for complete
description of preclinical studies.) (B) Summary of preclinical data on
cannabinoid interactions with antiseizure medications. Sources
indicated in boxes. *Recent evidence from a phase I clinical trial
suggests that CBD/CBDV elevates serum concentrations of clobazam
and N-desmethylclobazam in human pediatric patients with treatment-
resistant epilepsy [292]. ACEA = arachidonyl-2'-chloroethylamide
A 2013 survey of 19 parents of children with treatment-
resistant epilepsy investigated the use of high CBD:Δ9-THC
ratio artisanal marijuana products. These parents were primarily
identified from social media and included 12 children with
Dravet syndrome (DS). Of the 12 children with DS, parents
reported that 5 (42 %) experienced a> 80 % reduction in seizure
frequency and 2 (11 %) reported complete seizure freedom. The
single child with LennoxGastaut syndrome (LGS) was reported
to have a>80 % reduction in seizure frequency. In addition to
seizure control, parents reported positive effects of increased
alertness (74 %), better mood (79 %), improved sleep (68 %),
and decreased self-stimulation (32 %), and rare AEs of drowsi-
ness (37 %) and fatigue (16 %) [259]. A more recent retrospec-
tive case study described 75 patients from Colorado with
treatment-resistant epilepsy who moved to Colorado for oral
cannabis extract treatment. Oral cannabis extract treatment con-
trolled seizures in 57 % of patients, reduced seizures by >50 % in
33 % of patients, and showed greater effectiveness in patients
with LGS (88.9 %) than in patients with DS (23.0 %). Reported
additional benefits included improved behavior/alertness (33 %),
language (10 %), and motor skills (10 %), as well as rare AEs of
increased seizures (13 %) and somnolence/fatigue (12 %). Inter-
estingly, the study also reported a significant, independent pla-
cebo effectof families moving to Colorado for treatment (see
Placebo Effect)[260]. Collectively, these surveys suggest a
predominantly antiseizure (or no significant) effect of cannabis
usage. However, it is essential to consider the limitations of sub-
jective self-reporting, potentially biased sampling of patient ad-
vocacy groups (over-reporting positive effects), and uncontrolled
differences in CBD:Δ9-THC content in various strains of can-
nabis in these studies.
Clinical Trials
A recent Cochrane review assessed 4 primary clinical trials to
examine the efficacy of medical marijuana in seizure control
(summarized in Table 2, adapted from [11], [13]). Two of
these studies demonstrated a partial antiseizure effect of
CBD [261,262], while 2 showed no significant effect [263,
264]. However, all 4 studies included significant limitations,
including low study sizes, insufficient blinding or randomiza-
tion, or incomplete data sets. The authors of the Cochrane
review and a recent meta-analysis from the American Acade-
my of Neurology both emphasized the need for follow-up
placebo-controlled, blinded, randomized clinical trials exam-
ining the role of CBD in seizure control [12,13].
Phase I Clinical Trial for CBD in Treatment-resistant
Preliminary preclinical and clinical evidence reveal the thera-
peutic potential of CBD to reduce seizures with high
tolerability and low toxicity. Accordingly, CBD represents a
highly desirable treatment alternative for patients with early-
onset, severe epilepsy such as DS and LGS. In addition to
pharmacoresistant seizures, these patients suffer from severe
neurodevelopmental delay, intellectual disability, autism, mo-
tor impairments, and significant morbidity and mortality [265,
266]. As patients with DS and LGS require effective and
better-tolerated therapies and represent relatively homoge-
neous populations, they stand out as candidates for an initial
trial of CBD safety and efficacy.
Study Design and Results
Investigator-initiated open-label studies at 10 epilepsy centers
using Epidiolex (GWPharma, Salisbury, UK; 99 % CBD)
collected data on 213 patients with treatment-resistant epilep-
sies. This predominantly pediatric population had a mean age
of 10.8 years (range 2.026.0 years). CBD was added to
existing AEDs; there was an average of 3 concomitant AEDs.
The average baseline was 60 per month for total seizures and
30 per month for convulsive seizures.
The primary goal of the study was to assess safety but
seizure diaries were obtained for convulsive, drop, and total
seizures to provide a potential signal regarding efficacy.
Twelve-week or longer continuous exposure data were obtain-
ed for 137 patients and were used in efficacy measures. The
most common epilepsy etiologies were DS and LGS syn-
dromes; others included Aicardi syndrome, Doose syndrome,
tuberous sclerosis complex, CDKL5, Dup15q syndrome, and
many others. At week 12, total convulsive and nonconvulsive
seizures showed a median percent reduction from baseline of
54 %, and total convulsive seizures showed a median percent
reduction from baseline of 51 %. In patients with DS (n=23),
CBD reduced convulsive seizure frequency by 53 %, and
16 % of DS reached complete convulsive seizure freedom
by week 12. Atonic seizure frequency among patients with
LGS (n=10) was reduced by a median of 52 % at week 12.
AEs> 10 % included somnolence (21 %), diarrhea (17 %),
fatigue (17 %), and decreased appetite (16 %). Nine patients
(4 %) were discontinued for AEs. The investigators concluded
that CBD reduced seizure frequency across multiple drug-
resistant epilepsy syndromes and seizure types and was gen-
erally well-tolerated in the open-label study. Randomized con-
trolled trials (RCTs) are now ongoing for DS and LGS.
Safety Issues
There is a strong tendency to equate cannabis as a natural
therapywith cannabis as a safe therapy. This a priori as-
sumptionthe naturalistic fallacyis countered by many in-
stances of toxic or deadly plants (e.g., amotoxins in mush-
rooms) and animals (e.g., tetrodotoxin in puffer fish). A more
muted naturalistic view is that if side effects occur with
Cannabinoids and Epilepsy
cannabis, they would be less severe than those from drugs
produced by the pharmaceutical industry. A recent Epilepsia
survey of 776 individuals found that 98 % of the general
public supported the use of medical marijuana for severe cases
of epilepsy, compared with only 48 % of epileptologists. Sim-
ilarly, the majority of the public and a minority of
epileptologists thought that there was sufficient safety (96 %
vs 34 %) and efficacy (95 % vs 28 %) data for medical mar-
ijuana use in severe epilepsy. This significant disparity in
opinion between professionals and the lay public, possibly
swayed by the appeal of natural remedies, emphasizes an in-
creased need for further research and public education regard-
ing medicinal cannabis and epilepsy [267].
As with efficacy, the most valid assessment of side effects is
with RCTs. RCT data on the safety of Δ9-THC and CBD in
adults comes from trials of cannabinoid-containing medications,
including nabixomols [Sativex (GWPharma) 1:1 Δ9-
THC:CBD], purified cannabis extracts [Cannador, Institute for
Clinical Research, IKF, Berlin, Germany, (2:1 Δ9-THC:CBD)],
synthetic Δ9-THC analogues Dronabinol and Nabilone. These
drugs have been approved by many international regulatory
agencies. In a meta-analysis of 1619 patients treated with
nabiximols for neurological indications (mainly pain, spasticity,
spasm, or tremor) for 6 months or less, 6.9 % of those on can-
nabinoid therapies were discontinued because of adverse effects
versus 2.25 % in the placebo groups [12]. Adverse effects occur-
ring in at least 2 studies included nausea, dizziness, increased
weakness, behavioral or mood changes, hallucinations, suicidal
ideation, fatigue, and feeling of intoxication. No deaths from
overdose were reported [12]. However, our knowledge on the
safety of these compounds in children is very limited.
The adverse health effects of recreational cannabis use were
recently reviewed [268]. Δ9-THC is presumed to be the major
cannabinoid resulting in adverse acute and chronic health effects
of cannabis. The 4-fold increase in Δ9-THC content of confis-
cated cannabis in the last 20 years is associated with increased
acute complications. In 2011, there were 129,000 emergency
department visits for cannabis alone and 327,000 additional visits
for cannabis in combination with other drugs. From 2004 to
2011, the rate of emergency department visits for cannabis tox-
icity doubled [268]. Short-term use can impair short-term mem-
ory, coordination, and judgment. In high doses, paranoia and
psychosis can occur [137,269]. Long-term use of recreational
cannabis in adolescents is associated with addiction (9 % overall
but 17 % among adolescents) and impaired cognitive and aca-
demic performance [270274]. Additionally, cannabis treatment
in animal and human studies altered brain development (espe-
cially with use in early childhood) and structure [272,275277],
creating long-lasting functional and structural brain abnormalities
[277279]. Early and/or heavy cannabis use is associated with
neurochemical abnormalities on magnetic resonance spectrosco-
py [272], impaired maintenance of neuronal cytoskeleton dy-
namics [277], decreased white matter development or integrity
[272,275,276], increased impulsivity [276], and abnormal acti-
vation patterns during cognitive tasks on functional magnetic
resonance imaging [272,280]. In patients with multiple sclerosis,
use of cannabis is associated with impaired cognition and acti-
vation patterns on functional magnetic resonance imaging [281].
Further research is required to determine the short- and long-term
effects of CBD alone, which may have lower toxicity than whole
plant cannabis or Δ9-THC.
Cannabidiol Formulations, Pharmacokinetics,
Pharmacodynamics, and DrugDrug Interactions
We are aware of 3 pharmaceutical products that are currently
in trials or in development: 1) Epidiolex (99 % CBD derived
from C. sativa plants, in a strawberry-flavored sesame oil), 2)
synthetic CBD from Insys Therapeutics (Chandler, AZ,
USA), and 3) Transdermal CBD gel from Zynerba Pharma-
ceuticals (Devon, PA, USA). Other CBD-containing products
are available commercially and obtained online [e.g., Realm
of Caring's Charlotte's Web (whole cannabis extract contain-
ing 50 mg/ml CBD)]. However, the quality control and con-
sistency of these products may vary considerably. Indeed, a
recent study by the US Food and Drug Administration tested
18 products, claimed to contain CBD, made by 6 companies.
Of these, 8 contained no CBD, 9 contained <1 % CBD, and 1
contained 2.6 % CBD (
Because lipophilic cannabinoids (including CBD) have low
water solubility, CBD is traditionally delivered orally in either
an oil-based capsule or sublingual spray, permitting less vari-
able pharmacokinetics in gastrointestinal absorption. A single
10-mg dose of nabiximols (equal parts CBD and Δ9-THC) in
humans produces a maximum serum concentration (C
3.0±3.1 μg/l (buccal) [2.5±1.8 μg/l (sublingual)] and maxi-
mum time (T
gual)] [282]. CBD is primarily protein-bound in the blood,
and preferentially deposits inbrainandadiposetissue[283].
The cannabinoids are primarily metabolized by the liver
cytochrome P-450 (CYP-450) enzymes. Both Δ9-THC and
CBD can inhibit CYP-450 metabolic activity, particularly the
CYP2C isozymes at low concentrations and CYP3A4 iso-
zymes at higher concentrations [284289]. CYP2C and
CYP3A4 are induced by carbamazepine, topiramate, and phe-
nytoin, and inhibited valproate and other drugs [290]. The
cannabinoids, particularly CBD, can inhibit other isozymes,
including 2D6 and 1A1 [285,291]. Therefore, use of Δ9-
THC or CBD could potentially contribute to bidirectional
drugdrug interactions with antiepileptic and other drugs. In
our open-label CBD study, patients treated with CBD had
elevated levels of the nordesmethyl metabolite of clobazam
[292], which may account for a portion of the apparent seda-
tion, as well as efficacy, of CBD.
Tab le 2 Clinical trials of cannabidiol (CBD) and epilepsy (adapted from [11,13])
Study Seizure type Population
Treat ment
(subjects per group)
Duration Outcome Toxicity Limitations
Mechoulam and
Carlini [261]
temporal lobe epilespy
9 CBD, 200 mg/day (4)
Placebo (5)
NS 3 months CBD: seizure free
(2), partial improvement
(1), no change (1);
placebo: no change (4)
None No baseline seizure frequency; no
definition of improvement; unclear
if AEDs were changed; not truly
randomized or blinded; unknown
if groups were matched
Cunha et al. [262] Treatment-resistant,
temporal lobe epilespy
15* CBD 200300 mg/day (8*)
Placebo (8*)
Yes 3 18 weeks CBD: near seizure freedom
(4), partial improvement
(3), no change (1); placebo:
no change (7), partial
improvement (1)
Somnolence Not clearly blinded (1 patient
transferred groups); doses were
adjusted in CBD group, not in
placebo; CBD group received
longer average treatment
Ames and
Cridland [263]
epilepsy, intellectual/
developmental disability
12 CBD 300 mg/day
for 1 week; 200 mg/day
for 3 weeks (6?)
Placebo (6?)
NS 4 weeks No difference between CBD
and placebo
Somnolence Brief letter to the editor, details
lacking on specifics; discontinued
owing to technical difficulties
in preparing the drug
Trembly and
Sherman [264]
Treatment-resistant epilepsy 1012
CBD 100 mg once
Yes 3 months baseline, 6 months
CBD or placebo, then
6 months crossover to
alternative treatment
No difference between CBD
and placebo (seizure frequency
or cognitive/behavioral tests)
None Differences in sample size reporting;
dada reported are incomplete
(conference abstract)
AEDs = antiepileptic drugs; NS = not stated
*1 patient switched groups after 1 month
Abstract and subsequent book chapters have different numbers
Only truly double-blind study
Cannabinoids and Epilepsy
Placebo Effect
The magnitude of the placebo response is related to the power
of belief. Given the social and mainstream media attention se-
lectively reporting dramatic benefits of artisanal cannabis prep-
arations for children with epilepsy, there are high expectations
on the part of many parents. The potent role of the placebo
response was suggested by a recent survey of parents whose
children with epilepsy who were cared for at Colorado Chil-
drens Hospital. A beneficial response (>50 % seizure reduc-
tion) was reported 3 times more often by parents who moved to
the state compared with those who were long-time residents
[260]. No differences in epilepsy syndrome, type of artisanal
preparation, or other factor could account for this difference.
While studies have reported a significant placebo response
in adult patients (such as those with ParkinsonsDisease
[293]), placebo response rates are particularly high among
children and adolescents in a subset of disorders, including
psychiatric (anxiety, major depression, and obsessive compul-
sive and attention deficit disorders), medical (asthma), and
painful (migraine, gastrointestinal) conditions [294,295]. As
the current RCTs of CBD primarily target children with severe
epilepsy, this may be an important issue. Among patients with
treatment-resistant focal epilepsy, a meta-analysis found that
the placebo response in children (19.9 %) was significantly
higher than in adults (9.9 %), while the response to the AED
was not statistically different in children (37.2 %) and adults
(30.4 %) [296]. In one predominantly pediatric LGS trial,
seizures were reduced in 63 % of placebo-treated patients
and 75 % of drug-treated patients [297]. Paradoxically, the
intense interest and strong beliefs in the efficacy of cannabis
for epilepsy may elevate placebo responses and make it more
difficult to demonstrate a true benefit in RCTs.
Legal/Ethical Concerns
The Drug Enforcement Agency (DEA) classifies cannabis and
products derived from cannabis plants as Schedule I drugs.
Schedule I drugs have a high potential for abuse and no cur-
rently accepted medical use; they are the most dangerous
drugs of all the drug schedules with potentially severe psycho-
logical or physical dependence (DEA website; http://www. It is thus paradoxical that opiates
and benzodiazepines, which have a much greater potential for
psychological and physical dependence than cannabis, are
classified as Schedule II drugs. With regard to the DEAs
claimthat cannabis-derived drugs have no currently accept-
ed medical use, therapies such as nabiximols (CBD and Δ9-
THC) and other products have been approved by regulatory
agencies in >20 countries. These approvals are based on RCTs
that establish efficacy and a favorable safety profile, including
a low potential for abuse [228,298].
The Schedule I categorization makes it challenging for inves-
tigators to study cannabis-derived cannabinoids in basic and clin-
ical science. There is often a long and costly process to secure
approvals and inspections to obtain cannabinoids, purchase a
large safe, the weight of which may require clearance from en-
gineers, and add security systems to the room and building in
which they are stored. The Schedule I designation often prevents
patients who live in developmental centers or residential homes
from participating in clinical trials. The threshold of effort for
basic and clinical investigators to study cannabinoids remains
as high as ever, while the availability of these substances for
parents to give is expanding rapidly. This has created a widening
gap between knowledge and exposure, an especially relevant
concern in children for whom safety data are largely lacking.
For over a millennium, pre-clinical and clinical evidence have
shown that cannabinoids such as CBD can be used to reduce
seizures effectively, particularly in patients with treatment-
resistant epilepsy. However, many questions still remain (see
Box 1) regarding the mechanism, safety, and efficacy of canna-
binoids in short- and long-term use. Future basic science re-
search and planned multicenter, placebo-controlled clinical tri-
als will provide insight into cannabinoid function and the po-
tential neuroprotective effects of the endocannabinoid system.
These findings will increase our mechanistic understanding of
seizures and may provide novel, targeted therapeutics for
Box 1 Unanswered questions and directions for future studies
1. How do the pro and anti-epileptic effects of cannabis change with
development? Are there age-specific differences in responsiveness,
side effects, and target receptor expression?
2. What are the long-term effects of cannabis/cannabidiol use?
3. Are certain types of seizures or genetic channelopathies more likely to
respond to cannabidiol than others?
4. What is the safety of cannabidiol in patients with special conditions
(pregnancy, recent or planned surgery, vagus nerve stimulation, etc.)?
5. How do synthetic cannabinoids (spiceor K2)dysregulatethe
central nervous system to induce seizures? What is their relative safety
Acknowledgments Drs. Orrin Devinsky and Ben Whalley have re-
ceived research support from GW Pharmaceuticals. We acknowledge
FACES (Finding a Cure for Epilepsy and Seizures) for generous help in
the preparation of this manuscript. R.W.T. is supported by grants from the
National Institute of Mental Health (5R37MH071739) and the National
Institute of Neurological Disorders and Stroke (5R01NS074785,
1. Fisher RS, et al. Epileptic seizures and epilepsy: definitions pro-
posedbytheInternationalLeague Against Epilepsy (ILAE) and
the International Bureau for Epilepsy (IBE). Epilepsia 2005;46:
2. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N
Engl J Med 2000;342:314-319.
3. Kwan P, Brodie MJ. Refractory epilepsy: a progressive, intractable
but preventable condition? Seizure 2002;11:77-84.
4. Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N
Engl J Med 2011; 365:919-926.
5. Nilsson L, et al. Risk factors for sudden unexpected death in ep-
ilepsy: a casecontrol study. Lancet 1999;353:888-893.
6. Walczak TS, et al. Incidence and risk factors in sudden unexpected
death in epilepsy: a prospective cohort study. Neurology 2001;56:
7. Devinsky O. Patients with refractory seizures. N Engl J Med
8. Jacoby A, Baker GA. Quality-of-life trajectories in epilepsy: a
review of the literature. Epilepsy Behav 2008;12:557-571.
9. Rogawski MA. The intrinsic severity hypothesis of
pharmacoresistance to antiepileptic drugs. Epilepsia
2013;54(Suppl. 2):33-40.
10. Perucca E. Is there a role for therapeutic drug monitoring of new
anticonvulsants? Clin Pharmacokinet 2000;38:191-204.
11. Devinsky O, et al. Cannabidiol: pharmacology and potential ther-
apeutic role in epilepsy and other neuropsychiatric disorders.
Epilepsia 2014;55:791-802.
12. Koppel BS, et al. Systematic review: efficacy and safety of med-
ical marijuana in selected neurologic disorders: report of the
Guideline Development Subcommittee of the American
Academy of Neurology. Neurology 2014;82:1556-63.
13. Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane
Database Syst Rev 2014; 3:CD009270.
14. Abel EL. Marihuana: the first twelve thousand years. Plenum
Press, New York, 1980.
15. Russo EB, et al. Phytochemical and genetic analyses of ancient
cannabis from Central Asia. J Exp Bot 2008;59:4171-4182.
16. Lozano I. The therapeutic use of Cannabis sativa L. in Arabic
medicine. J Cannabis Ther 2001;1:63-70.
17. Szaflarski JP, Bebin EM. Cannabis, cannabidiol, and epilepsy
from receptors to clinical response. Epilepsy Behav 2014;41:277-
18. O'Shaughnessy WB. On the preparations of the Indian hemp, or
Gunjah. Prov Med J Retrosp Med Sci 1843;5:363-369.
19. Reynolds JR. Epilepsy: its symptoms, treatment, and relation to
other chronic convulsive diseases. J. Churchill (Ed.) London,
20. Gowers W. Epilepsy and other chronic convulsive disorders.
Churchill (Ed.) London, 1881.
21. Gaoni Y, Mechoulam R. Isolation, structure, and partial synthesis
of an active constituent of hashish. J Am Chem Soc 1964;86:
22. Gaoni Y, Mechoulam R. The isolation and structure of delta-1-
tetrahydrocannabinol and other neutral cannabinoids from hash-
ish. J Am Chem Soc 1971;9:217-224.
23. Adams R, Pease DC, Clark JH. Isolation of cannabinol,
cannabidiol, and quebrachitrol from red oil of Minnesota wild
hemp. J Am Chem Soc 1940;62: 2194-2196.
24. Michoulam R, Shvo Y., Hashish, I. The structure of cannabidiol.
Tetrahedron 1963; 19:2073-2078.
25. Matsuda LA, et al. Structure of a cannabinoid receptor and func-
tional expression of the cloned cDNA. Nature 1990;346:561-564.
26. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization
of a peripheral receptor for cannabinoids. Nature 1993;365:61-65.
27. Llano I, et al. Synaptic- and agonist-inducedexcitatory currents of
Purkinje cells in rat cerebellar slices. J Physiol 1991;434:183-213.
28. Pitler TA, Alger BE. Postsynaptic spike firing reduces synaptic
responses in hippocampal pyramidal cells. J Neurosci
29. Kreitzer AC, Regehr WG. Retrograde inhibition of presynaptic
calcium influx by endogenous cannabinoids at excitatory synapses
onto Purkinje cells. Neuron 2001;29:717-727.
30. Kreitzer AC, Regehr WG. Cerebellar depolarization-induced sup-
pression of inhibition is mediated by endogenous cannabinoids. J
Neurosci 2001;21:RC174.
31. Wilson RI, Kunos G, Nicoll RA. Presynaptic specificity of
endocannabinoid signaling in the hippocampus. Neuron
32. Devane WA, et al. Isolation and structure of a brain constituent
that binds to the cannabinoid receptor. Science 1992;258:1946-
33. Mechoulam R, et al. Identification of an endogenous 2-monoglyc-
eride, present in canine gut, that binds to cannabinoid receptors.
Biochem Pharmacol 1995;50:83-90.
34. Sugiura T, et al. 2-Arachidonoylglycerol: a possible endogenous
cannabinoid receptor ligand in brain. Biochem Biophys Res
Commun 1995;215:89-97.
35. Alger BE. Retrograde signaling in the regulation of synaptic trans-
mission: focus on endocannabinoids. Prog Neurobiol 2002;68:
36. Brown SP, Brenowitz SD, Regehr WG. Brief presynaptic bursts
evoke synapse-specific retrograde inhibition mediated by endog-
enous cannabinoids. Nat Neurosci 2003;6:1048-1057.
37. Maejima T, Ohno-Shosaku T, Kano M. Endogenous cannabinoid
as a retrograde messenger from depolarized postsynaptic neurons
to presynaptic terminals. Neurosci Res 2001;40:205-210.
38. Melis M, et al. Prefrontal cortex stimulation induces 2-
arachidonoyl-glycerol-mediated suppression of excitation in do-
pamine neurons. J Neurosci 2004;24:10707-10715.
39. Katona I, Freund TF. Endocannabinoid signaling as a synaptic
circuit breaker in neurological disease. Nat Med 2008;14:923-930.
40. Di Marzo V, et al. Formation and inactivation of endogenous can-
nabinoid anandamide in central neurons. Nature 1994;372:686-
41. Di Marzo V, Deutsch DG. Biochemistry of the endogenous li-
gands of cannabinoid receptors. Neurobiol Dis 1998;5:386-404.
42. Di Marzo V, et al. Endocannabinoids: endogenous cannabinoid
receptor ligands with neuromodulatory action. Trends Neurosci
43. Sugiura T, et al. Biosynthesis and degradation of anandamide and
2-arachidonoylglycerol and their possible physiological signifi-
cance. Prostaglandins Leukot Essent Fatty Acids 2002;66:173-
44. Stella N, Schweitzer P, Piomelli D. A second endogenous canna-
binoid that modulates long-term potentiation. Nature 1997;388:
45. Pertwee RG. Cannabinoid receptor ligands: clinical and neuro-
pharmacological considerations, relevant to future drug discovery
and development. Expert Opin Investig Drugs 2000;9:1553-1571.
46. Pi-Sunyer F, et al. Effect of rimonabant, a cannabinoid-1 receptor
blocker, on weight and cardiometabolic risk factors in overweight
or obese patients - RIO-North America: A randomized controlled
trial. JAMA 2006;295:761-775.
47. Cahill K, Ussher M. Cannabinoid type 1 receptor antagonists
(rimonabant) for smoking cessation. Cochrane Database Syst
Rev 2007:CD005353.
48. Glass M,. Felder CC. Concurrent stimulation of cannabinoid CB1
and dopamine D2 receptors augments cAMP accumulation in
Cannabinoids and Epilepsy
striatal neurons: evidence for a Gs linkage to the CB1 receptor. J
Neurosci 1997;17:5327-5333.
49. Mackie K, Hille B. Cannabinoids inhibit N-type calcium channels
in neuroblastoma-glioma cells. Proc Natl Acad Sci U S A
50. Caulfield MP, Brown DA. Cannabinoid receptor agonists inhibit
Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-
sensitive mechanism. Br J Pharmacol 1992;106:231-232.
51. Twitchell W, Brown S, Mackie K. Cannabinoids inhibit N- and
P/Q-type calcium channels in cultured rat hippocampal neurons. J
Neurophysiol 1997;78:43-50.
52. Szabo GG, et al. Presynaptic calcium channel inhibition underlies
CB(1) cannabinoid receptor-mediated suppression of GABA re-
lease. J Neurosci 2014;34:7958-7963.
53. Deadwyler SA, et al. Cannabinoids modulate potassium current in
cultured hippocampal neurons. Receptors Channels 1993;1:121-
54. Deadwyler SA, et al. Cannabinoids modulate voltage sensitive
potassium A-current in hippocampal neurons via a cAMP-
dependent process. J Pharmacol Exp Ther 1995;273:734-743.
55. Hampson RE, et al. Role of cyclic AMP dependent protein kinase
in cannabinoid receptor modulation of potassium "A-current" in
cultured rat hippocampal neurons. Life Sci 1995;56:2081-2088.
56. Mu J, et al. Protein kinase-dependent phosphorylation and canna-
binoid receptor modulation of potassium A current (IA) in cul-
tured rat hippocampal neurons. Pflugers Arch 2000;439:541-546.
57. Henry DJ, Chavkin C. Activation of inwardly rectifying potassi-
um channels (GIRK1) by co-expressed rat brain cannabinoid re-
ceptors in Xenopus oocytes. Neurosci Lett 1995;186:91-94.
58. Mackie K, et al. Cannabinoids activate an inwardly rectifying
potassium conductance and inhibit Q-type calcium currents in
AtT20 cells transfected with rat brain cannabinoid receptor. J
Neurosci 1995;15:6552-6561.
59. McAllister SD, et al. Cannabinoid receptors can activate and in-
hibit G protein-coupled inwardly rectifying potassium channels in
a xenopus oocyte expression system. J Pharmacol Exp Ther
60. Photowala H, et al. G protein betagamma-subunits activated by
serotonin mediate presynaptic inhibition by regulating vesicle fu-
sion properties. Proc Natl Acad Sci U S A 2006;103:4281-4286.
61. Schlicker E, Kathmann M. Modulation of transmitter release via
presynaptic cannabinoid receptors. Trends Pharmacol Sci
62. Chevaleyre V, Takahashi KA, Castillo PE. Endocannabinoid-
mediated synaptic plasticity in the CNS. Annu Rev Neurosci
63. Piomelli D. The molecular logic of endocannabinoid signalling.
Nat Rev Neurosci 2003;4:873-884.
64. Katona I, et al. Presynaptically located CB1 cannabinoid receptors
regulate GABA release from axon terminals of specific hippocam-
pal interneurons. J Neurosci 1999; 19:4544-4558.
65. Marsicano G, Lutz B. Expression of the cannabinoid receptor CB1
in distinct neuronal subpopulations in the adult mouse forebrain.
Eur J Neurosci 1999;11: 4213-4225.
66. Dudok B, et al. Cell-specific STORM super-resolution imaging
reveals nanoscale organization of cannabinoid signaling. Nat
Neurosci 2015;18:75-86.
67. Kawamura Y, et al. The CB1 cannabinoid receptor is the major
cannabinoid receptor at excitatory presynaptic sites in the hippo-
campus and cerebellum. J Neurosci 2006;26:2991-3001.
68. Katona I, et al. Molecular composition of the endocannabinoid
system at glutamatergic synapses. J Neurosci 2006;26:5628-5637.
69. Lafourcade M, et al. Molecular components and functions of the
endocannabinoid system in mouse prefrontal cortex. PLoS One
70. Wittmann G, et al. Distribution of type 1 cannabinoid receptor
(CB1)-immunoreactive axons in the mouse hypothalamus. J
Comp Neurol 2007;503:270-279.
71. Robbe D, et al. Localization and mechanisms of action of canna-
binoid receptors at the glutamatergic synapses of the mouse nu-
cleus accumbens. J Neurosci 2001;21:109-116.
72. Elsohly MA, Slade D. Chemical constituents of marijuana: the
complex mixture of natural cannabinoids. Life Sci 2005;78:539-
73. Joy JE. Marijuana and medicine: assessing the science base.
National Academics Press, Washington, DC 1999.
74. Huestis MA, et al. Blockade of effects of smoked marijuana by the
CB1-selective cannabinoid receptor antagonist SR141716. Arch
Gen Psychiatry 2001;58:322-328.
75. Lichtman AH, Martin BR. Delta 9-tetrahydrocannabinol impairs
spatial memory through a cannabinoid receptor mechanism.
Psychopharmacology (Berl) 1996;126: 125-131.
76. Mallet PE, Beninger RJ. The cannabinoid CB1 receptor antagonist
SR141716A attenuates the memory impairment produced by
delta9-tetrahydrocannabinol or anandamide.
Psychopharmacology (Berl) 1998;140:11-19.
77. Varvel SA, et al. Differential effects of delta 9-THC on spatial
reference and working memory in mice. Psychopharmacology
(Berl) 2001;157:142-150.
78. Da S, Takahashi RN. SR 141716A prevents delta 9-
tetrahydrocannabinol-induced spatial learning deficit in a
Morris-type water maze in mice. Prog Neuropsychopharmacol
Biol Psychiatry 2002;26:321-325.
79. Pagotto U, et al. The emerging role of the endocannabinoid system
in endocrine regulation and energy balance. Endocr Rev 2006;27:
80. Abood ME, et al. Activation of the CB1 cannabinoid receptor
protects cultured mouse spinal neurons against excitotoxicity.
Neurosci Lett 2001;309:197-201.
81. van der Stelt M, et al. Neuroprotection by Delta9-tetrahydrocan-
nabinol, the main activecompound in marijuana, against ouabain-
induced in vivo excitotoxicity. J Neurosci 2001;21:6475-6479.
82. El-Remessy AB, et al. Neuroprotective effect of (-)Delta9-tetrahy-
drocannabinol and cannabidiol in N-methyl-D-aspartate-induced
retinal neurotoxicity: involvement of peroxynitrite. Am J Pathol
83. Mechoulam R, Panikashvili D, Shohami E. Cannabinoids and
brain injury: therapeutic implications. Trends Mol Med 2002;8:
84. Gilbert GL, et al. Delta9-tetrahydrocannabinol protects hippocam-
pal neurons from excitotoxicity. Brain Res 2007;1128:61-69.
85. Nagayama T, et al. Cannabinoids and neuroprotection in global
and focal cerebral ischemia and in neuronal cultures. J Neurosci
86. Zani A, et al. Delta9-tetrahydrocannabinol (THC) and AM 404
protect against cerebral ischaemia in gerbils through a mechanism
involving cannabinoid and opioid receptors. Br J Pharmacol
87. Hampson AJ, et al. Cannabidiol and (-)Delta9-tetrahydrocannab-
inol are neuroprotective antioxidants. Proc Natl Acad Sci U S A
88. Molina-Holgado F, Lledo A, Guaza C. Anandamide suppresses
nitric oxide and TNF-alpha responses to Theiler's virus or endo-
toxin in astrocytes. Neuroreport 1997;8:1929-1933.
89. Molina-Holgado F, et al. Role of CB1 and CB2 receptors in the
inhibitory effects of cannabinoids on lipopolysaccharide-induced
nitric oxide release in astrocyte cultures. J Neurosci Res 2002;67:
90. Shohami E, et al. Cytokine production in the brain following
closed head injury: dexanabinol (HU-211) is a novel TNF-alpha
inhibitor and an effective neuroprotectant. J Neuroimmunol
91. Puffenbarger RA, Boothe AC, Cabral GA. Cannabinoids inhibit
LPS-inducible cytokine mRNA expression in rat microglial cells.
Glia 2000;29:58-69.
92. Cabral GA, Harmon KN, Carlisle SJ. Cannabinoid-mediated inhi-
bition of inducible nitric oxide production by rat microglial cells:
evidence for CB1 receptor participation. Adv Exp Med Biol
93. Ehrhart J, et al. Stimulation of cannabinoid receptor 2 (CB2) sup-
presses microglial activation. J Neuroinflammation 2005;2:29.
94. Klein TW, et al. The cannabinoid system and cytokine network.
Proc Soc Exp Biol Med 2000;225:1-8.
95. Molina-Holgado F, et al. Endogenous interleukin-1 receptor an-
tagonist mediates anti-inflammatory and neuroprotective actions
of cannabinoids in neurons and glia. J Neurosci 2003;23:6470-
96. Benito C, et al. Cannabinoid CB2 receptors in human brain in-
flammation. Br J Pharmacol 2008;153:277-285.
97. De Petrocellis L, et al. Plant-derived cannabinoids modulate the
activity of transient receptor potential channels of ankyrin type-1
and melastatin type-8. J Pharmacol Exp Ther 2008;325:1007-
98. De Petrocellis L, et al. Effects of cannabinoids and cannabinoid-
enriched Cannabis extracts on TRP channels and
endocannabinoid metabolic enzymes. Br J Pharmacol 2011;163:
99. Qin N, et al. TRPV2 is activated by cannabidiol and mediates
CGRP release in cultured rat dorsal root ganglion neurons. J
Neurosci 2008;28:6231-6238.
100. Vezzani A, et al. The role of inflammation in epilepsy. Nat Rev
Neurol 2011;7:31-40.
101. Walker L, Sills GJ. Inflammation and epilepsy: thefoundations for
a new therapeutic approach in epilepsy? EpilepsyCurr 2012;12:8-
102. Devinsky O, et al. Glia and epilepsy: excitability and inflamma-
tion. Trends Neurosci 2013;36:174-184.
103. Thomas BF, et al. Comparative receptor binding analyses of can-
nabinoid agonists and antagonists. J Pharmacol Exp Ther
104. Bisogno T, et al. Molecular targets for cannabidiol and its synthetic
analogues: effect on vanilloid VR1 receptors and on the cellular
uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol
105. Pertwee RG. GPR55: a new member of the cannabinoid receptor
clan? Br J Pharmacol 2007;152:984-986.
106. Jones NA, et al. Cannabidiol displays antiepileptiform and antisei-
zure properties in vitro and in vivo. J Pharmacol Exp Ther
107. Russo EB, et al. Agonistic properties of cannabidiol at 5-HT1a
receptors. Neurochem Res 2005;30:1037-1043.
108. Ahrens J, et al. The nonpsychotropic cannabinoid cannabidiol
modulates and directly activates alpha-1 and alpha-1-Beta glycine
receptor function. Pharmacology 2009;83:217-222.
109. Ross HR, Napier I, Connor M. Inhibition of recombinant human
T-type calcium channels by Delta9-tetrahydrocannabinol and
cannabidiol. J Biol Chem 2008;283: 16124-16134.
110. Drysdale AJ, et al. Cannabidiol-induced intracellular Ca2+ eleva-
tions in hippocampal cells. Neuropharmacology 2006;50:621-
111. Ryan D, et al. Cannabidiol targets mitochondria to regulate intra-
cellular Ca2+ levels. J Neurosci 2009;29:2053-2063.
112. Rimmerman N, et al. The non-psychoactive plant cannabinoid,
cannabidiol affects cholesterol metabolism-related genes in
microglial cells. Cell Mol Neurobiol 2011; 31:921-930.
113. Ross RA. The enigmatic pharmacology of GPR55. Trends
Pharmacol Sci 2009;30: 156-163.
114. Ryberg E, et al. The orphan receptor GPR55 is a novel cannabi-
noid receptor. Br J Pharmacol 2007;152:1092-1101.
115. Lauckner JE, et al.GPR55is a cannabinoid receptor that increases
intracellular calciumand inhibits M current. Proc Natl Acad Sci U
S A 2008;105:2699-2704.
116. Oka S, et al. Identification of GPR55 as a lysophosphatidylinositol
receptor. Biochem Biophys Res Commun 2007;362:928-934.
117. Sylantyev S, et al. Cannabinoid- and lysophosphatidylinositol-
sensitive receptor GPR55 boosts neurotransmitter release at cen-
tral synapses. Proc Natl Acad Sci U S A 2013;110:5193-5198.
118. Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equili-
brative nucleoside transporter by cannabidiol: a mechanism of
cannabinoid immunosuppression. Proc Natl Acad Sci U S A
119. Pandolfo P, et al. Cannabinoids inhibit the synaptic uptake of
adenosine and dopamine in the rat and mouse striatum. Eur J
Pharmacol 2011;655:38-45.
120. Ferre S, et al. Adenosine-cannabinoid receptor interactions.
Implications for striatal function. Br J Pharmacol 2010;160:443-
121. De Petrocellis L, Di Marzo V. Non-CB1, non-CB2 receptors for
endocannabinoids, plant cannabinoids, and synthetic
cannabimimetics: focus on G-protein-coupled receptors and tran-
sient receptor potential channels. J Neuroimmune Pharmacol
122. Booz GW. Cannabidiol as an emergent therapeutic strategy for
lessening the impact of inflammation on oxidative stress. Free
Radic Biol Med 2011;51:1054-1061.
123. Hampson AJ, et al. Neuroprotective antioxidants from marijuana.
Ann N Y Acad Sci 2000;899:274-282.
124. Liou GI, et al. Mediation of cannabidiol anti-inflammation in the
retina by equilibrative nucleoside transporter and A2A adenosine
receptor. Invest Ophthalmol Vis Sci 2008;49:5526-5531.
125. Hayakawa K, et al. Delayed treatment with cannabidiol has a
cerebroprotective action via a cannabinoid receptor-independent
myeloperoxidase-inhibiting mechanism. J Neurochem 2007;102:
126. Hayakawa K, et al. Therapeutic time window of cannabidiol treat-
ment on delayed ischemic damage via high-mobility group box1-
inhibiting mechanism. Biol Pharm Bull 2009;32:1538-1544.
127. Iuvone T, et al. Neuroprotective effect of cannabidiol, a non-
psychoactive component from Cannabis sativa, on beta-
amyloid-induced toxicity in PC12 cells. J Neurochem 2004;89:
128. Esposito G, et al. Cannabidiol inhibits inducible nitric oxide syn-
thase protein expression and nitric oxide production in beta-
amyloid stimulated PC12 neurons through p38 MAP kinase and
NF-kappaB involvement. Neurosci Lett 2006;399:91-95.
129. Esposito G, et al. Cannabidiol in vivo blunts beta-amyloid induced
neuroinflammation by suppressing IL-1beta and iNOS expression.
Br J Pharmacol 2007;151:1272-1279.
130. Pietr M, et al. Differential changes in GPR55 during microglial
cell activation. FEBS Lett 2009;583:2071-2076.
131. Staton PC, et al. The putative cannabinoid receptor GPR55 plays a
role in mechanical hyperalgesia associated with inflammatory and
neuropathic pain. Pain 2008;139: 225-236.
132. Ben-Shabat S, et al. An entourage effect: inactive endogenous
fatty acid glycerol esters enhance 2-arachidonoyl-glycerol canna-
binoid activity. Eur J Pharmacol 1998;353: 23-31.
133. Wagner H, Ulrich-Merzenich G. Synergy research: approaching a
new generation of phytopharmaceuticals. Phytomedicine
Cannabinoids and Epilepsy
134. Mechoulam R, Ben-Shabat S. From gan-zi-gun-nu to anandamide
and 2-arachidonoylglycerol: the ongoing story of cannabis. Nat
Prod Rep 1999;16:131-143.
135. Russo EB. Taming THC: potential cannabis synergy and
phytocannabinoid-terpenoid entourage effects. Br J Pharmacol
136. Karniol IG, Carlini EA. Pharmacological interaction between
cannabidiol and delta 9-tetrahydrocannabinol.
Psychopharmacologia 1973;33:53-70.
137. Englund A, et al. Cannabidiol inhibits THC-elicited paranoid
symptoms and hippocampal-dependent memory impairment. J
Psychopharmacol 2013;27:19-27.
138. Russo E, Guy GW. A tale of two cannabinoids: the therapeutic
rationale for combining tetrahydrocannabinol and cannabidiol.
Med Hypotheses 2006;66:234-246.
139. Schubart CD, et al. Cannabis with high cannabidiol content is
associated with fewer psychotic experiences. Schizophr Res
140. Hemaiswarya S, Kruthiventi AK, Doble M. Synergism between
natural products and antibiotics against infectious diseases.
Phytomedicine 2008;15:639-652.
141. Tallarida RJ. Quantitative methods for assessing drug synergism.
Genes Cancer 2011; 2:1003-1008.
142. Hill AJ, et al. Phytocannabinoids as novel therapeutic agents in
CNS disorders. Pharmacol Ther 2012;133:79-97.
143. Raol YH, Brooks-Kayal AR. Experimental models of seizures and
epilepsies. Prog Mol Biol Transl Sci 2012;105:57-82.
144. Loscher W. Critical review of current animal models of seizures
and epilepsy used in the discovery and development of new anti-
epileptic drugs. Seizure 2011;20:359-368.
145. Simonato M, et al. The challenge and promise of anti-epileptic
therapy development in animal models. Lancet Neurol 2014;13:
146. Marsicano G, et al. CB1 cannabinoid receptors and on-demand
defense against excitotoxicity. Science 2003;302:84-88.
147. Wallace MJ, et al. The endogenous cannabinoid system regulates
seizure frequency and duration in a model of temporal lobe epi-
lepsy. J Pharmacol Exp Ther 2003;307: 129-137.
148. Karanian DA, et al. Endocannabinoid enhancement protects
against kainic acid-induced seizures and associated brain damage.
J Pharmacol Exp Ther 2007;322: 1059-1066.
149. Karanian DA, et al. Dual modulation of endocannabinoid trans-
port and fatty acid amide hydrolase protects against excitotoxicity.
J Neurosci 2005;25:7813-7820.
150. Naidoo V, et al. Equipotent inhibition of fatty acid amide hydro-
lase and monoacylglycerol lipasedual targets of the
endocannabinoid system to protect against seizure pathology.
Neurotherapeutics 2012;9:801-813.
151. Deshpande LS, et al. Endocannabinoids block status epilepticus in
cultured hippocampal neurons. Eur J Pharmacol 2007;558:52-59.
152. Monory K, et al. The endocannabinoid system controls key epi-
leptogenic circuits in the hippocampus. Neuron 2006;51:455-466.
153. Guggenhuber S, et al. AAV vector-mediated overexpression of
CB1 cannabinoid receptor in pyramidal neurons of the hippocam-
pus protects against seizure-induced excitoxicity. PLoS One
154. Alger BE. Seizing an opportunity for the endocannabinoid system.
Epilepsy Curr 2014; 14:272-276.
155. Falenski KW, et al. Status epilepticus causes a long-lasting redis-
tribution of hippocampal cannabinoid type 1 receptor expression
and function in the rat pilocarpine model of acquired epilepsy.
Neuroscience 2007;146:1232-1244.
156. Falenski KW, et al. Temporal characterization of changes in hip-
pocampal cannabinoid CB(1) receptor expression following
pilocarpine-induced status epilepticus. Brain Res 2009;1262:64-
157. Bhaskaran MD, Smith BN. Cannabinoid-mediated inhibition of
recurrent excitatory circuitry in the dentate gyrus in a mouse mod-
el of temporal lobe epilepsy. PLoS One 2010;5:e10683.
158. Sayers KW, et al. Statistical parametric mapping reveals regional
alterations in cannabinoid CB1 receptor distribution and G-protein
activation in the 3D reconstructed epileptic rat brain. Epilepsia
159. Ludanyi A, et al. Downregulation of the CB1 cannabinoid recep-
tor and related molecular elements of the endocannabinoid system
in epileptic human hippocampus. J Neurosci 2008;28:2976-2990.
160. Romigi A, et al. Cerebrospinal fluid levels of the endocannabinoid
anandamide are reduced in patients with untreated newly diag-
nosed temporal lobe epilepsy. Epilepsia 2010;51:768-772.
161. Wyeth MS, et al. Selective reduction of cholecystokinin-positive
basket cell innervation in a model of temporal lobe epilepsy. J
Neurosci 2010;30:8993-9006.
162. Sun C, et al. Loss of cholecystokinin-containing terminals in tem-
poral lobe epilepsy. Neurobiol Dis 2014;62:44-55.
163. Karlocai MR, et al. Redistribution of CB1 cannabinoid receptors
in the acute and chronic phases of pilocarpine-induced epilepsy.
PLoS One 2011;6:e27196.
164. Magloczky Z, et al. Dynamic changes of CB1-receptor expression
in hippocampi of epileptic mice and humans. Epilepsia
2010;51(Suppl. 3):115-120.
165. Chen K, et al. Long-term plasticity of endocannabinoid signaling
induced by developmental febrile seizures. Neuron 2003;39:599-
166. Chen K, et al. Prevention of plasticity of endocannabinoid signal-
ing inhibits persistent limbic hyperexcitability caused by develop-
mental seizures. J Neurosci 2007;27: 46-58.
167. Hill AJ, Hill TD, Whalley B. The development of cannabinoid
based therapies for epilepsy. In: Murillo-Rodriguez (Ed.)
Endocannabinoids: molecular, pharmacological, behavioral and
clinical features. bentham science publishers, Oak Park, IL,
2013, pp 164-204.
168. Manna SS, Umathe SN. Involvement of transient receptor poten-
tial vanilloid type 1 channels in the pro-convulsant effect of anan-
damide in pentylenetetrazole-induced seizures. Epilepsy Res
169. Luszczki JJ, et al. Arachidonyl-2'-chloroethylamide, a highly se-
lective cannabinoid CB1 receptor agonist, enhances the anticon-
vulsant action of valproate in the mouse maximal electroshock-
induced seizure model. Eur J Pharmacol 2006;547:65-74.
170. Luszczki JJ, et al. Effect of arachidonyl-2'-chloroethylamide, a
selective cannabinoid CB1 receptor agonist, on the protective ac-
tion of the various antiepileptic drugs in the mouse maximal
Neuropsychopharmacol Biol Psychiatry 2010;34:18-25.
171. Luszczki JJ, et al. Synthetic cannabinoid WIN 55,212-2 mesylate
enhances the protective action of four classical antiepileptic drugs
against maximal electroshock-induced seizures in mice.
Pharmacol Biochem Behav 2011;98:261-267.
172. Luszczki JJ, et al. Effects of WIN 55,212-2 mesylate (a synthetic
cannabinoid) on the protective action of clonazepam,
ethosuximide, phenobarbital and valproate against
pentylenetetrazole-induced clonic seizures in mice. Prog
Neuropsychopharmacol Biol Psychiatry 2011;35:1870-1876.
173. Andres-Mach M, et al. Effect of ACEAa selective cannabinoid
CB1 receptor agonist on the protective action of different antiep-
ileptic drugs in the mouse pentylenetetrazole-induced seizure
model. Prog Neuropsychopharmacol Biol Psychiatry 2012;39:
174. Luszczki JJ, et al. Effects of WIN 55,212-2 mesylate on the anti-
convulsant action of lamotrigine, oxcarbazepine, pregabalin and
topiramate against maximal electroshock-induced seizures in
mice. Eur J Pharmacol 2013;720:247-254.
175. Florek-Luszczki M, et al. Effects of WIN 55,212-2 (a non-
selective cannabinoid CB1 and CB 2 receptor agonist) on the
protective action of various classical antiepileptic drugs in the
mouse 6 Hz psychomotor seizure model. J Neural Transm
2014;121: 707-715.
176. Florek-Luszczki M, Zagaja M, Luszczki JJ. Influence of WIN 55,
212-2 on the anticonvulsant and acute neurotoxic potential of
clobazam and lacosamide in the maximal electroshock-induced
seizure model and chimney test in mice. Epilepsy Res 2014;108:
177. Florek-Luszczki M, et al. Effects of WIN 55,212-2 (a synthetic
cannabinoid CB1 and CB2 receptor agonist) on the anticonvulsant
activity of various novel antiepileptic drugs against 6Hz-induced
psychomotor seizures in mice. Pharmacol Biochem Behav 2015;
178. Chesher GB, Jackson DM. The effect of withdrawal from canna-
bis on pentylenetetrazol convulsive threshold in mice.
Psychopharmacologia 1974;40: 129-135.
179. Chesher GB, Jackson DM, Malor RM. Interaction of delta9-
tetrahydrocannabinol and cannabidiol with phenobarbitone in
protecting mice from electrically induced convulsions. J Pharm
Pharmacol 1975;27:608-609.
180. National Toxicology Program. NTP toxicology and carcinogene-
sis studies of 1-trans-delta(9)-tetrahydrocannabinol (CAS No.
1972-08-3) in F344 rats and B6C3F1 mice (gavage studies).
Natl Toxicol Program Tech Rep Ser 1996;446:1-317.
181. Hill AJ, et al. Cannabidivarin is anticonvulsant in mouse and rat.
Br J Pharmacol 2012;167:1629-1642.
182. Oviedo A, Glowa J, Herkenham M. Chronic cannabinoid admin-
istration alters cannabinoid receptor binding in rat brain: a quanti-
tative autoradiographic study. Brain Res 1993;616:293-302.
183. Rodriguez de Fonseca F, et al. Downregulation of rat brain canna-
binoid binding sites after chronic delta 9-tetrahydrocannabinol
treatment. Pharmacol Biochem Behav 1994;47:33-40.
184. Sim LJ, et al. Effects of chronic treatment with delta9-
tetrahydrocannabinol on cannabinoid-stimulated
[35S]GTPgammaS autoradiography in rat brain. J Neurosci
185. Fan F, et al. Cannabinoid receptor down-regulation without alter-
ation of the inhibitory effect of CP 55,940 on adenylyl cyclase in
the cerebellum of CP 55,940-tolerant mice. Brain Res 1996;706:
186. Romero J, et al. Effects of chronic exposure to delta9-
tetrahydrocannabinol on cannabinoid receptor binding and
mRNA levels in several rat brain regions. Brain Res Mol Brain
Res 1997;46:100-108.
187. Romero J, et al. Autoradiographic analysis of cannabinoid recep-
tor binding and cannabinoid agonist-stimulated [35S]GTP gamma
S binding in morphine-dependent mice. Drug Alcohol Depend
188. Romero J, et al. Cannabinoid receptor and WIN-55,212-2-stimu-
lated [35S]GTP gamma S binding and cannabinoid receptor
mRNA levels in the basal ganglia and the cerebellum of adult male
rats chronically exposed to delta 9-tetrahydrocannabinol. J Mol
Neurosci 1998;11:109-119.
189. Romero J, et al. Time-course of the cannabinoid receptor down-
regulation in the adult rat brain caused by repeated exposure to
delta9-tetrahydrocannabinol. Synapse 1998;30:298-308.
190. Zhuang S, et al. Effects of long-term exposure to delta9-THC on
expression of cannabinoid receptor (CB1) mRNA in different rat
brain regions. Brain Res Mol Brain Res 1998;62:141-149.
191. Hsieh C, et al. Internalization and recycling of the CB1 cannabi-
noid receptor. J Neurochem 1999;73:493-501.
192. Corchero J, et al. Time-dependent differences of repeated admin-
istration with Delta9-tetrahydrocannabinol in proenkephalin and
cannabinoid receptor gene expression and G-protein activation by
mu-opioidand CB1-cannabinoid receptors in the caudateputamen.
Brain Res Mol Brain Res 1999;67:148-157.
193. Breivogel CS, et al. Chronic delta9-tetrahydrocannabinol treat-
ment produces a time-dependent loss of cannabinoid receptors
and cannabinoid receptor-activated G proteins in rat brain. J
Neurochem 1999;73:2447-2459.
194. Breivogel CS, et al. The effects of delta9-tetrahydrocannabinol
physical dependence on brain cannabinoid receptors. Eur J
Pharmacol 2003;459:139-150.
195. McKinney DL, et al. Dose-related differences in the regional pat-
tern of cannabinoid receptor adaptation and in vivo tolerance de-
velopment to delta9-tetrahydrocannabinol. J Pharmacol Exp Ther
196. Sim-Selley LJ, Martin BR. Effect of chronic administration of R-
3-de]-1,4-benzoxaz inyl]-(1-naphthalenyl)methanone mesylate
(WIN55,212-2) or delta(9)-tetrahydrocannabinol on cannabinoid
receptor adaptation in mice. J Pharmacol Exp Ther 2002;303:36-
197. Sim-Selley LJ. Regulation of cannabinoid CB1 receptors in the
central nervous system by chronic cannabinoids. Crit Rev
Neurobiol 2003;15:91-119.
198. Sim-Selley LJ, et al. Prolonged recovery rate of CB1 receptor
adaptation after cessation of long-term cannabinoid administra-
tion. Mol Pharmacol 2006;70:986-996.
199. Martin BR, Sim-Selley LJ, Selley DE. Signaling pathways in-
volved in the development of cannabinoid tolerance. Trends
Pharmacol Sci 2004;25:325-330.
200. Villares J. Chronic use of marijuana decreases cannabinoid recep-
tor binding and mRNA expression in the human brain.
Neuroscience 2007;145:323-334.
201. Coutts AA, et al. Agonist-induced internalization and trafficking
of cannabinoid CB1 receptors in hippocampal neurons. J Neurosci
202. Lundberg DJ, Daniel AR, Thayer SA. Delta(9)-
Tetrahydrocannabinol-induced desensitization of cannabinoid-
mediated inhibition of synaptic transmission between hippocam-
pal neurons in culture. Neuropharmacology 2005;49:1170-1177.
203. Deshpande LS, Blair RE, DeLorenzo RJ. Prolonged cannabinoid
exposure alters GABA(A) receptor mediated synaptic function in
cultured hippocampal neurons. Exp Neurol 2011;229:264-273.
204. Dewey WL. Cannabinoid pharmacology. Pharmacol Rev
205. Abood ME, et al. Development of behavioral tolerance to delta 9-
THC without alteration of cannabinoid receptor binding or mRNA
levels in whole brain. Pharmacol Biochem Behav 1993;46:575-
206. Ten Ham M, Loskota WJ, Lomax P. Acute and chronic effects of
beta9-tetrahydrocannabinol on seizures in the gerbil. Eur J
Pharmacol 1975;31:148-152.
207. Corcoran ME, McCaughran JA, Jr., Wada JA, Antiepileptic and
prophylactic effects of tetrahydrocannabinols in amygdaloid kin-
dled rats. Epilepsia 1978;19: 47-55.
208. Colasanti BK, Lindamood C, 3rd, Craig CR. Effects of marihuana
cannabinoids on seizure activity in cobalt-epileptic rats.
Pharmacol Biochem Behav 1982;16: 573-578.
209. Karler R, Turkanis SA. Subacute cannabinoid treatment: anticon-
vulsant activity and withdrawal excitability in mice. Br J
Pharmacol 1980;68:479-484.
210. Blair RE, et al. Prolongedexposure to WIN55,212-2 causes down-
regulationof the CB1 receptor and the development of tolerance to
its anticonvulsant effects in the hippocampal neuronal culture
model of acquired epilepsy. Neuropharmacology 2009;57:208-
211. Jones RT, Benowitz N, Bachman J. Clinical studies of cannabis
tolerance and dependence. Ann N YAcad Sci 1976;282:221-239.
Cannabinoids and Epilepsy
212. Jones RT, Benowitz NL, Herning RI. Clinical relevance of canna-
bis tolerance and dependence. J Clin Pharmacol 1981;21(8-9
213. Kirk JM, de Wit H. Responses to oral delta9-tetrahydrocannabinol
in frequent and infrequent marijuana users. Pharmacol Biochem
Behav 1999;63:137-142.
214. Hart CL, et al. Comparison of smoked marijuana and oral
Delta(9)-tetrahydrocannabinol in humans. Psychopharmacology
(Berl) 2002;164:407-415.
215. Babor TF, et al. Marijuana consumption and tolerance to physio-
logical and subjective effects. Arch Gen Psychiatry 1975;32:1548-
216. Nowlan R, Cohen S. Tolerance to marijuana: heart rate and sub-
jective "high". Clin Pharmacol Ther 1977;22:550-556.
217. Aceto MD, et al. Cannabinoid precipitated withdrawal by the se-
lective cannabinoid receptor antagonist, SR 141716A. Eur J
Pharmacol 1995;282:R1-R2.
218. Tsou K, Patrick SL, Walker JM. Physical withdrawal in rats toler-
ant to delta 9-tetrahydrocannabinol precipitated by a cannabinoid
receptor antagonist. Eur J Pharmacol 1995;280:R13-R15.
219. Rodriguez de Fonseca F, et al. Activation of corticotropin-
releasing factor in the limbic system during cannabinoid with-
drawal. Science 1997;276:2050-2054.
220. Kaymakcalan S. Tolerance to and dependence on cannabis. Bull
Narc 1973;25:3947.
221. Beardsley PM, Balster RL, Harris LS. Dependence on tetrahydro-
cannabinol in rhesus monkeys. J Pharmacol Exp Ther 1986;239:
222. Budney AJ, Hughes JR. The cannabis withdrawal syndrome. Curr
Opin Psychiatry 2006;19:233-238.
223. Karler R, et al. Interaction between delta-9-tetrahydrocannabinol
and kindling by electrical and chemical stimuli in mice.
Neuropharmacology 1984;23:1315-1320.
224. Karler R, Calder LD, Turkanis SA. Prolonged CNS hyperexcit-
ability in mice after a single exposure to delta-9-tetrahydrocannab-
inol. Neuropharmacology 1986;25:441-446.
225. Hegde M, et al. Seizure exacerbation in two patients with focal
epilepsy following marijuana cessation. Epilepsy Behav 2012;25:
226. Ellison JM, Gelwan E, Ogletree J. Complex partial seizure symp-
toms affected by marijuana abuse. J Clin Psychiatry 1990;51:439-
227. Leite JR, Carlini EA. Failure to obtain "cannabis-directed behav-
ior" and abstinence syndrome in rats chronically treated with can-
nabis sativa extracts. Psychopharmacologia 1974;36:133-145.
228. Robson P. Abuse potential and psychoactive effects of delta-9-
tetrahydrocannabinol and cannabidiol oromucosal spray
(Sativex), a new cannabinoid medicine. Expert Opin Drug Saf
229. Wade DT, et al. Do cannabis-based medicinal extracts have gen-
eral or specific effects on symptoms in multiple sclerosis? A dou-
ble-blind, randomized, placebo-controlled study on 160 patients.
Mult Scler 2004;10:434-441.
230. Russo EB, Guy GW, Robson PJ. Cannabis, pain, and sleep: les-
sons from therapeutic clinical trials of Sativex, a cannabis-based
medicine. Chem Biodivers 2007; 4:1729-1743.
231. Rog DJ, Nurmikko TJ, Young CA. Oromucosal delta9-tetrahydro-
cannabinol/cannabidiol for neuropathic pain associated with mul-
tiple sclerosis: an uncontrolled, open-label, 2-year extension trial.
Clin Ther 2007;29: 2068-2079.
232. Perez J. Combined cannabinoid therapy via an oromucosal spray.
Drugs Today (Barc) 2006;42:495-503.
233. Crippa JA, et al. Cannabidiol for the treatment of cannabis with-
drawal syndrome: a case report. J Clin Pharm Ther 2013;38:162-
234. Allsop DJ, et al. Nabiximols as an agonist replacement therapy
during cannabis withdrawal: a randomized clinical trial. JAMA
Psychiatry 2014;71:281-291.
235. Allsop DJ, Lintzeris N, Copeland J, Dunlop A, McGregor IS.
Cannabinoid replacement therapy (CRT): Nabiximols (Sativex)
as a novel treatment for cannabis withdrawal. Clin Pharmacol
Ther 2015;97:571-574.
236. Keeler MH, Reifler CB. Grand mal convulsions subsequent to
marijuana use. Case report. Dis Nerv Syst 1967;28:474-475.
237. Lapoint J, et al. Severe toxicity following synthetic cannabinoid
ingestion. Clin Toxicol (Phila) 2011;49:760-764.
238. Jinwala FN, Gupta M. Synthetic cannabis and respiratory depres-
sion. J Child Adolesc Psychopharmacol 2012;22:459-462.
239. Hermanns-Clausen M, et al. Acute intoxication by synthetic can-
nabinoidsfour case reports. Drug Test Anal 2013;5:790-794.
240. Hermanns-Clausen M, et al. Acute toxicity due to the confirmed
consumption of synthetic cannabinoids: clinical and laboratory
findings. Addiction 2013;108: 534-544.
241. McQuade D, et al. First European case of convulsions related to
analytically confirmed use of the synthetic cannabinoid receptor
agonist AM-2201. Eur J Clin Pharmacol 2013; 69:373-376.
242. Pant S, et al. Spicy seizure. Am J Med Sci 2012;344:67-68.
243. Tofighi B, Lee JD. Internet highsseizures after consumption of
synthetic cannabinoids purchased online. J Addict Med 2012;6:
244. de Havenon A, et al. The secret "spice": an undetectable toxic
cause of seizure. Neurohospitalist 2011;1:182-186.
245. Castaneto MS, et al. Synthetic cannabinoids: epidemiology, phar-
macodynamics, and clinical implications. Drug Alcohol Depend
246. Davis JP, Ramsey HH. Anti-epileptic action of marijuana-active
substances. Fed Proc Am Soc Exp Biol 1949;8:284.
247. Consroe PF, Wood GC, Buchsbaum H. Anticonvulsant nature of
marihuana smoking. JAMA 1975;234:306-307.
248. Lorenz R. On the application of cannabis in paediatrics and
epileptology. Neuro Endocrinol Lett 2004;25:40-44.
249. Mortati K, Dworetzky B, Devinsky O. Marijuana: an effective
antiepileptic treatment in partial epilepsy? A case report and re-
view of the literature. Rev Neurol Dis 2007;4:103-106.
250. Gordon E, Devinsky O. Alcohol and marijuana: effects on epilep-
sy and use by patients with epilepsy. Epilepsia 2001;42:1266-
251. Maa E, Figi P. The case for medical marijuana in epilepsy.
Epilepsia 2014;55: 783-786.
252. Corral VJ. Differential effects of medical marijuana based on
strain and route of administration: a three-year observational
study. J Cannabis Ther 2001;1:43-59.
253. Hamerle M, et al. Cannabis and other illicit drug use in epilepsy
patients. Eur J Neurol, 2014;21:167-170.
254. Gieringer D. Madical use of cannabis: experience in California.
Haworth Press, Binghamton, NY, 2001.
255. Feeney D, Spiker M. Marijuana and epilepsy: activation of symp-
toms by delta-9-THC. In: C.S and S.RC (Eds.). The therapeutic
potential of marihuana. Plenum Press, New York, 1976.
256. Alldredge BK, Lowenstein DH, Simon RP. Seizures associated
with recreational drug abuse. Neurology 1989;39:1037-1039.
257. Brust JC, et al. Marijuana use and the risk of new onset seizures.
Trans Am Clin Climatol Assoc 1992;103:176-181.
258. Gross DW, et al. Marijuana use and epilepsy: prevalence in pa-
tients of a tertiary care epilepsy center. Neurology 2004;62:2095-
259. Porter BE, Jacobson C. Report of a parent survey of cannabidiol-
enriched cannabis use in pediatric treatment-resistant epilepsy.
Epilepsy Behav 2013;29:574-577.
260. Press CA, Knupp KG, Chapman KE. Parental reporting of re-
sponse to oral cannabis extracts for treatment of refractory epilep-
sy. Epilepsy Behav 2015;45: 4952.
261. Mechoulam R, Carlini EA. Toward drugs derived from cannabis.
Naturwissenschaften 1978;65:174-179.
262. Cunha JM, et al. Chronic administration of cannabidiol to healthy
volunteers and epileptic patients. Pharmacology 1980;21:175-
263. Ames FR, Cridland S. Anticonvulsant effect ofcannabidiol. S Afr
Med J 1986; 69:14.
264. Trembly B, Sherman M. Double-blind clinical study of
cannabidiol as a secondary anticonvulsant. In: Marijuana '90 in-
ternational conference on cannabis and cannabinoids, Kolympari,
Crete, 1990.
265. van Rijckevorsel K. Treatment of Lennox-Gastaut syndrome:
overview and recent findings. Neuropsychiatr Dis Treat 2008;4:
266. Dravet C. The core Dravet syndrome phenotype. Epilepsia
2011;52(Suppl. 2):3-9.
267. Mathern GW, Beninsig L, Nehlig A. Fewer specialists support
using medical marijuana and CBD in treating epilepsy patients
compared with other medical professionals and patients: result of
Epilepsia's survey. Epilepsia 2015;56:1-6.
268. Volkow ND, Compton WM, Weiss SR. Adverse health effects of
marijuana use. N Engl J Med 2014;371:879.
269. Morales-Munoz I, et al. Characterizing cannabis-induced psycho-
sis: a study with prepulse inhibition ofthe startle reflex. Psychiatry
Res 2014;220:535-540.
270. Lynskey M, Hall W. The effects of adolescent cannabis use on
educational attainment: a review. Addiction 2000;95:1621-1630.
271. Crean RD, Crane NA, Mason BJ. An evidence based review of
acute and long-term effects of cannabis use on executive cognitive
functions. J Addict Med 2011;5: 1-8.
272. Lisdahl KM, et al. Dare to delay? The impacts of adolescent alco-
hol and marijuana use onset on cognition, brain structure, and
function. Front Psychiatry 2013;4:53.
273. Crane NA, Schuster RM, Gonzalez R. Preliminary evidence for a
sex-specific relationship between amount of cannabis use and
neurocognitive performance in young adult cannabis users. J Int
Neuropsychol Soc 2013;19:1009-1015.
274. Jacobus J, et al. Cortical thickness and neurocognition in adoles-
cent marijuana and alcohol users following 28 days of monitored
abstinence. J Stud Alcohol Drugs 2014; 75:729-743.
275. Gilman JM, et al. Cannabis use is quantitatively associated with
nucleus accumbens and amygdala abnormalities in young adult
recreational users. J Neurosci 2014;34: 5529-5538.
276. Gruber SA, et al. Worth the wait: effects of age of onset of mari-
juana use on white matter and impulsivity. Psychopharmacology
(Berl) 2014;231:1455-1465.
277. Tortoriello G, et al. Miswiring the brain: Delta9-
tetrahydrocannabinol disrupts cortical development by inducing
an SCG10/stathmin-2 degradation pathway. EMBO J 2014;33:
278. Raver SM, Haughwout SP, Keller A. Adolescent cannabinoid ex-
posure permanently suppresses cortical oscillations in adult mice.
Neuropsychopharmacology 2013;38:2338-2347.
279. Raver SM, Keller A. Permanent suppression of cortical oscilla-
tions in mice after adolescent exposure to cannabinoids: receptor
mechanisms. Neuropharmacology 2014;86:161-173.
280. Houck JM, Bryan AD, Feldstein Ewing SW. Functional connec-
tivity and cannabis use in high-risk adolescents. Am J Drug
Alcohol Abuse 2013;39:414-423.
281. Pavisian B, et al. Effects of cannabis on cognition in patients with
MS: a psychometric and MRI study. Neurology 2014;82:1879-
282. Guy GW, Robson PJ. A phase I, open label, four-way crossover
study to compare the pharmacokinetic profiles of a single dose of
20 mg of a cannabis based medicine extract (CBME) administered
on 3 different areas of the buccal mucosa and to investigate the
pharmacokinetics of CBME per oral in healthy male and female
volunteers (GWPK0112). J Cannabis Ther 2003;3:79-120.
283. Hawksworth G, McArdle K. Metabolism and pharmacokinetics of
cannabinoids. Pharmaceutical Press, London, 2004.
284. Bornheim LM, et al. Characterization of cannabidiol-mediated
cytochrome P450 inactivation. Biochem Pharmacol 1993;45:
285. Yamaori S, et al. Cannabidiol, a major phytocannabinoid, as a
potent atypical inhibitor for CYP2D6. Drug Metab Dispos
286. Jiang R, et al. Identification of cytochrome P450 enzymes respon-
sible for metabolism of cannabidiol by human liver microsomes.
Life Sci 2011;89:165-170.
287. Yamaori S, et al. Potent inhibition of human cytochrome P450 3A
isoforms by cannabidiol: role of phenolic hydroxyl groups in the
resorcinol moiety. Life Sci 2011;88:730-736.
288. Jiang R, et al. Cannabidiol is a potent inhibitor of the catalytic
activity of cytochrome P450 2C19. Drug Metab Pharmacokinet
289. Stout SM, Cimino NM. Exogenous cannabinoids as substrates,
inhibitors, and inducers of human drug metabolizing enzymes: a
systematic review. Drug Metab Rev 2014;46:86-95.
290. Patsalos PN, Perucca E. Clinically important drug interactions in
epilepsy: interactions between antiepileptic drugs and other drugs.
Lancet Neurol 2003;2: 473-481.
291. Yamaori S, et al. Characterization of major phytocannabinoids,
cannabidiol and cannabinol, as isoform-selective and potent inhib-
itors of human CYP1 enzymes. Biochem Pharmacol 2010;79:
292. Friedman D, et al. The effect of Epidiolex (Cannabidiol) on serum
levels of concomminantanti-epileptic drugs in children and young
adults with treatment-resistant epilepsy in an expanded access
program. In: American Epilepsy Society, Seattle, WA, 2014.
293. Espay AJ, et al. Placebo effect of medication cost in Parkinson
disease: a randomized double-blind study. Neurology 2015;84:
294. Weimer K, et al. Placebo effects in children: a review. Pediatr Res
295. Kemeny ME, et al. Placebo response in asthma: a robust and
objective phenomenon. J Allergy Clin Immunol 2007;119:1375-
296. Rheims S, et al. Greater response to placebo in children than in
adults: a systematic review and meta-analysis in drug-resistant
partial epilepsy. PLoS Med 2008;5: e166.
297. Anon. Double-blind, placebo-controlled evaluation of cinromide
in patients with the Lennox-Gastaut Syndrome. The Group for the
Evaluation of Cinromide in the Lennox-Gastaut Syndrome.
Epilepsia 1989;30:422-429.
298. Rekand T. THC:CBD spray and MS spasticity symptoms: data
from latest studies. Eur Neurol 2014;71(Suppl. 1):4-9.
299. Naderi N, et al. Evaluation of interactions between cannabinoid
compounds and diazepam in electroshock-induced seizure model
in mice. J Neural Transm 2008;115:1501-1511.
300. Naderi N, et al. Modulation of anticonvulsant effects of cannabi-
noid compounds by GABA-A receptor agonist in acute
pentylenetetrazole model of seizure in rat. Neurochem Res
301. Vilela LR, et al. Effects of cannabinoids and endocannabinoid
hydrolysis inhibition on pentylenetetrazole-induced seizure and
electroencephalographic activity in rats. Epilepsy Res 2013;104:
Cannabinoids and Epilepsy
302. Shubina L, Aliev R, Kitchigina V. Attenuation of kainic acid-
induced status epilepticus by inhibition of endocannabinoid trans-
port and degradation in guinea pigs. Epilepsy Res 2015;111:33-
303. Wendt H, et al. Targeting the endocannabinoid system in the
amygdala kindling model of temporal lobe epilepsy in mice.
Epilepsia 2011;52:e62-e65.
304. Wallace MJ, et al. Assessment of the role of CB1 receptors in
cannabinoid anticonvulsant effects. Eur J Pharmacol 2001;428:
305. Payandemehr B, et al. Involvement of PPAR receptors in the an-
ticonvulsant effects of a cannabinoid agonist, WIN 55,212-2. Prog
Neuropsychopharmacol Biol Psychiatry 2015;57:140-145.
306. van Rijn CM, et al. WAG/Rij rats show a reduced expression of
CB(1) receptors in thalamic nuclei and respond to the CB(1) re-
ceptor agonist, R(+)WIN55,212-2, with a reduced incidence of
spike-wave discharges. Epilepsia 2010;51:1511-1521.
307. Citraro R, et al. CB1 agonists, locally applied to the cortico-
thalamic circuit of rats with genetic absence epilepsy, reduce epi-
leptic manifestations. Epilepsy Res 2013; 106:74-82.
308. Lambert DM, et al. Anticonvulsant activity of N-
palmitoylethanolamide, a putative endocannabinoid, in mice.
Epilepsia 2001;42:321-327.
309. Sheerin AH, et al. Selective antiepileptic effects of N-
palmitoylethanolamide, a putative endocannabinoid. Epilepsia
310. Wallace MJ, Martin BR, DeLorenzo RJ. Evidence for a physio-
logical role of endocannabinoids in the modulation of seizure
threshold and severity. Eur J Pharmacol 2002;452:295-301.
311. Shafaroodi H, et al. The interaction of cannabinoids and opioids
on pentylenetetrazole-induced seizure threshold in mice.
Neuropharmacology 2004;47:390-400.
312. Bahremand A, et al. The cannabinoid anticonvulsant effect on
pentylenetetrazole-induced seizure is potentiated by ultra-low
dose naltrexone in mice. Epilepsy Res 2008;81:44-51.
313. Bahremand A, et al. Involvement of nitrergic system in the anti-
convulsant effect of the cannabinoid CB(1) agonist ACEA in the
pentylenetetrazole-induced seizure in mice. Epilepsy Res
314. Rudenko V, et al. Inverse relationship of cannabimimetic (R+
)WIN 55, 212 on behavior and seizure threshold during the juve-
nile period. Pharmacol Biochem Behav 2012;100:474-484.
315. Di Maio R, Cannon JR, Timothy Greenamyre J. Post-status epi-
lepticus treatment with the cannabinoid agonist WIN 55,212-2
prevents chronic epileptic hippocampal damage in rats.
Neurobiol Dis 2014;73C:356-365.
316. Rizzo V, et al. Evidences of cannabinoids-induced modulation of
paroxysmal events in an experimental model of partial epilepsy in
the rat. Neurosci Lett 2009;462:135-139.
317. Kow RL, et al. Modulation of pilocarpine-induced seizures by
cannabinoid receptor 1. PLoS One 2014;9:e95922.
318. Kozan R, Ayyildiz M, Agar E. The effects of intracerebroventric-
ular AM-251, a CB1-receptor antagonist, and ACEA, a CB1-
receptor agonist, on penicillin-induced epileptiform activity in
rats. Epilepsia 2009;50:1760-1767.
319. Cakil D, et al. The effect of co-administration of the NMDA
blocker with agonist and antagonist of CB1-receptor on
penicillin-induced epileptiform activity in rats. Epilepsy Res
320. van Rijn CM, et al. Endocannabinoid system protects against
cryptogenic seizures. Pharmacol Rep 2011;63:165-168.
321. Vinogradova LV, Shatskova AB, van Rijn CM. Pro-epileptic ef-
fects of the cannabinoid receptor antagonist SR141716 in a model
of audiogenic epilepsy. Epilepsy Res 2011;96:250-256.
322. Gholizadeh S, et al. Ultra-low dose cannabinoid antagonist
AM251 enhances cannabinoid anticonvulsant effects in the
pentylenetetrazole-induced seizure in mice. Neuropharmacology
323. Dudek FE, et al. The effect of the cannabinoid-receptor antagonist,
SR141716, on the early stage of kainate-induced epileptogenesis
in the adult rat. Epilepsia 2010;51(Suppl. 3):126-130.
324. Echegoyen J, et al. Single application of a CB1 receptor antagonist
rapidly following head injury prevents long-term hyperexcitability
in a rat model. Epilepsy Res 2009;85:123-127.
325. Sofia RD, Kubena RK, Barry, H, 3rd. Comparison among four
vehicles and four routes for administering delta9-tetrahydrocan-
nabinol. J Pharm Sci 1974;63:939-941.
326. Chesher GB, Jackson DM. Anticonvulsant effects of cannabinoids
in mice: drug interactions within cannabinoids and cannabinoid
interactions with phenytoin. Psychopharmacologia 1974;37:255-
327. Johnson DD, et al. Epileptiform seizures in domestic fowl. V. The
anticonvulsant activity of delta9-tetrahydrocannabinol. Can J
Physiol Pharmacol 1975;53:1007-1013.
328. Wada JA, Osawa T, Corcoran ME. Effects of tetrahydrocannabi-
nols on kindled amygdaloid seizures and photogenic seizures in
Senegalese baboons, Papio papio. Epilepsia 1975;16:439-448.
329. Boggan WO, Steele RA, Freedman DX. 9 -Tetrahydrocannabinol
effect on audiogenic seizure susceptibility. Psychopharmacologia
330. Corcoran ME, McCaughran JA, Jr., Wada JA. Acute antiepileptic
effects of 9-tetrahydrocannabinol in rats with kindled seizures.
Exp Neurol 1973;40:471-483.
331. Wada JA, et al. Antiepileptic and prophylactic effects of tetrahy-
drocannabinols in amygdaloid kindled cats. Epilepsia 1975;16:
332. Turkanis SA, et al. An electrophysiological analysis of the anti-
convulsant action of cannabidiol on limbic seizures in conscious
rats. Epilepsia 1979;20:351-363.
333. Izquierdo I, Orsingher OA, Berardi AC. Effect of cannabidiol and
of other cannabis sativa compounds on hippocampal seizure dis-
charges. Psychopharmacologia 1973;28:95-102.
334. Karler R, Turkanis SA. Cannabis and epilepsy. Adv Biosci
335. Consroe P, et al. Effects of cannabidiol on behavioral seizures
caused by convulsant drugs or current in mice. Eur J Pharmacol
336. Shirazi-zand Z, et al. The role of potassium BK channels in anti-
convulsant effect of cannabidiol in pentylenetetrazole and maxi-
mal electroshock models of seizure in mice. Epilepsy Behav
337. Hill TD, et al. Cannabidivarin-rich cannabis extracts are anticon-
vulsant in mouse and rat via a CB1 receptor-independent mecha-
nism. Br J Pharmacol 2013;170:679-692.
338. Jones NA, et al. Cannabidiol exerts anti-convulsant effects in an-
imal models of temporal lobe and partial seizures. Seizure
... Cannabidiol (CBD) is a non-psychoactive cannabinoid known to have therapeutic effects in several neurological disorders, including epileptic syndromes [8][9][10][11][12]. In animal models, CBD has been shown to have anticonvulsant effects on spontaneous recurrent seizures and to attenuate the behavioral manifestations in several seizure models [13][14][15][16][17]. Cannabidiol reduced pentylenetetrazole (PTZ)-induced seizures in adult male mice [17], and had protective effects against seizures and neuronal death following pilocarpineinduced status epilepticus in adult male rats [13] and intrahippocampal kainic acid-induced seizures in juvenile male rats [14]. ...
... When seizures are induced by chemoconvulsants or electrical stimulation, pro-inflammatory cytokines are elevated, along with other inflammatory mediators, in brain areas associated with epileptic activity [21,22]. The beneficial effects of CBD appear to be related to neuroprotective mechanisms that inhibit excessive inflammatory responses and reduce proinflammatory cytokines, such as IL1-b, which in turn reduces seizure severity [12,[23][24][25][26]. ...