13652710, 2015, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpt.12235 by CAPES, Wiley Online Library on [09/11/2022].

See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 135–143 doi: 10.1111/jcpt.12235

Review Article
Phytocannabinoids and epilepsy

R. G. dos Santos* PhD, J. E. C. Hallak*† MD PhD, J. P. Leite* MD PhD, A. W. Zuardi*† MD PhD and J. A. S. Crippa*† MD PhD
*Department of Neuroscience and Behavior, Ribeir~ao Preto Medical School, University of S~ao Paulo, and †National Institute for Translational Medicine
(INCT-TM), CNPq, Ribeir~ao Preto, Brazil

Received 4 September 2014, Accepted 6 November 2014

Keywords: cannabidiol, cannabinoids, delta-9-tetrahydrocannabinol, epilepsy, seizure, treatment

nabivarin (THCV), cannabidivarin (CBDV), delta-8-tetrahydrocan-

SUMMARY
nabinol (delta-8-THC), cannabinol (CBN) and especially CBD have
What is known and objective: Antiepileptic drugs often produce anticonvulsant effects.13–17,23–29 Considering that currently avail-
serious adverse effects, and many patients do not respond to able anti-epileptic drugs are not efficient for many patients and
them properly. Phytocannabinoids produce anticonvulsant that these drugs often produce several side effects, there is a clear
effects in preclinical and preliminary human studies, and appear need to explore other compounds with higher efficacy and lower
to produce fewer adverse effects than available antiepileptic toxicity.23,24 Therefore, the present text presents a review of the
drugs. The present review summarizes studies on the anticon- studies on the anticonvulsant effects of phytocannabinoids.
vulsant properties of phytocannabinoids.
Methods: Literature search using the PubMed database to
METHODS
identify studies on phytocannabinoids and epilepsy.
Results and discussion: Preclinical studies suggest that phytoc- A literature search was performed in the PubMed database using
annabinoids, especially cannabidiol and cannabidivarin, have the words ‘cannabis’, ‘marijuana’, ‘cannabinoids’, ‘tetrahydrocan-
potent anticonvulsant effects which are mediated by the endoc- nabinol’, ‘THC’, ‘cannabidiol’, ‘CBD’, ‘cannabidivarin’, ‘CBDV’,
annabinoid system. Human studies are limited in number and ‘seizures’ and ‘epilepsy’, until October 2014. No date or language
quality, but suggest that cannabidiol has anticonvulsant effects limitation was used in the search. Only full peer-reviewed articles
in adult and infantile epilepsy and is well tolerated after were included in the review, abstracts and letters being excluded.
prolonged administration. Among selected articles, a selection was made based on the quality
What is new and conclusion: Phytocannabinoids produce anti- and relevance of the study.
convulsant effects through the endocannabinoid system, with
few adverse effects. Cannabidiol and cannabidivarin should be
RESULTS AND DISCUSSION
tested in randomized, controlled clinical trials, especially in
infantile epileptic syndromes.
Anticonvulsant effects of cannabis
Reports of the anti-epileptic potential of cannabis have thousands
WHAT IS KNOWN AND OBJECTIVE of years of age.1,4,5,8,16,26,28,30,31 Anecdotal reports suggest that
individuals using cannabis to treat their epilepsy may precipitate
The medicinal properties of cannabis have been known in China the re-emergence of convulsive seizures when they stop
and India for thousands of years, and by the XIX century, the cannabis use, while resuming cannabis consumption controls
therapeutic use of cannabis derivatives reached Europe and epilepsy.13,16,23,24,26,28–30,32–36
the United States.1–9 Nowadays, despite the fact that cannabis is As there is only anecdotal evidence supporting the anti-epileptic
the most consumed illegal recreational drug worldwide,10–12 there effects of cannabis, and considering that there are only a small
is increasing interest in its medicinal potentials.1,5,8,13–17 number of case reports describing this therapeutic potential, there
Cannabis contains over 100 compounds called phytocannabi- is insufficient information to make any conclusions regarding the
noids, which are unique to the plant.1,16,18 The main cannabinoids anticonvulsant effects of cannabis. Moreover, cannabis has several
are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). other substances, including other phytocannabinoids and non-
THC is responsible for producing most subjective effects of cannabinoid compounds, with unknown effects on epilepsy.
cannabis, whereas CBD lacks the psychoactivity of THC.19–22 Anecdotal evidence and case reports also suggest that, at least in
Epilepsy is a neurological condition characterized by recurrent some patients, cannabis may not affect epilepsy at all or may even
seizures.23,24 There is evidence that THC, delta-9-tetrahydrocan- produce seizure exacerbation.16,23,24,26,28–30,34,37
Even considering the absence of controlled studies, cannabis is
currently licensed in several states in the United States and in
Correspondence: Professor Dr J. A. S. Crippa, Departamento de
Neuroci^encias e Ci^encias do Comportamento, Faculdade de Medicina Canada for the treatment of epilepsy.23,24,33,35 This indicates that
de Ribeir~ao Preto, Universidade de S~ ao Paulo, Hospital das Clınicas, some physicians approve the use of cannabis on epileptic
Terceiro Andar, Av. Bandeirantes, 3900, Ribeir~ ao Preto, S~ao Paulo, syndromes and also suggests the potential efficacy of cannabis in
Brazil. Tel.: +55 16 3602 2201; fax: +55 16 3602 0713; e-mail: jcrippa@ at least some patients. Indeed, many epileptic patients use
fmrp.usp.br cannabis as a complementary or alternative anticonvulsant

© 2014 John Wiley & Sons Ltd 135

 13652710, 2015, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpt.12235 by CAPES, Wiley Online Library on [09/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Cannabinoids and epilepsy R. G. dos Santos et al.

medicine.26,29,35 However, given the quality of the available data, Although early studies reported anticonvulsant effects of THC,
no reliable conclusions can be drawn from the available studies. there was also evidence of proconvulsant effects.26,28,29,38–43 The
neurochemical basis for these opposite effects could depend on the
preferential action of THC on CB1 receptors located in glutama-
Anticonvulsant effects of THC
tergic or GABAergic neurons. Thus, THC could produce anticon-
THC is the main active compound in cannabis. THC acts as a vulsant effects by inhibiting the glutamatergic excitatory
partial agonist at cannabinoid CB1 receptors, found primarily in transmission and proconvulsant effects by inhibiting the release
the central nervous system (CNS), and CB2 receptors, found of GABA.26,30,44 These findings suggest that activation of CB1
primarily on cells of the immune system.5,19,21,22,26 receptors may not be sufficient to yield therapeutic benefits for
The anticonvulsant activity of THC was originally investigated epilepsy patients. Moreover, the development of tolerance and the
in the 1970s. In these studies, THC produced primarily anticon- subjective effects of THC limited the investigation of this com-
vulsant effects, but in other studies, there was no effect or even pound in clinical trials.
proconvulsant effects.26,28,29,38–43
THC (2
5–10 mg/kg) decreased the susceptibility of rat dorsal
Anticonvulsant effects of CBD
hippocampus to seizures discharges caused by afferent stimula-
tion.38 In a study in mice, the anticonvulsant potential of THC was Together with THC, CBD is one of the most important phytoc-
assessed utilizing the maximal electroshock seizure test (MES) and annabinoids. CBD pharmacology is not completely understood, as
the pentylenetetrazole (PTZ) seizure test.39 THC (1–80 mg/kg) it has multiple mechanisms of action and produces several
afforded no protection against PTZ-induced seizures, but was pharmacological effects. CBD effects in the endocannabinoid
effective against electroshock-induced seizures (160–200 mg/kg). system do not seem to depend directly on CB1/2 receptors. CBD
THC significantly potentiated the anticonvulsant effectiveness of possesses very low (micromolar range) affinity for CB1/2 receptors,
phenytoin against electroshock seizures, but no potentiation of but antagonizes CB1/2 agonists in the nanomolar range.14,25–28
phenobarbital effectiveness could be demonstrated in the PTZ- CBD also inhibits the uptake of anandamide at micromolar
induced seizure test. THC (20–75 mg/kg) also significantly concentrations and inhibits its enzymatic hydrolysis. CBD also
lengthened rather than shortened the hindlimb extensor phase of antagonizes the putative novel cannabinoid receptor GPR55 at
the electroshock seizures. nanomolar concentrations.14,25–28
The anticonvulsant effects of THC were assessed after acute and At micromolar concentrations, CBD activates 5-HT1A receptors,
chronic (6 days) administration utilizing a seizure sensitive strain inhibits the uptake of serotonin, activates TRPV1/2 and TRPA1
of gerbils.40 Although 20 mg/kg THC did not reduce seizure channels, inhibits the uptake of adenosine, noradrenaline,
patterns, 2 h after the first injection of the higher THC dose dopamine and GABA, stimulates the activity of the inhibitory
(50 mg/kg), no seizures were seen in any of the animals. glycine-receptor and antagonizes a1-adrenergic and l-opioid
Nevertheless, complete tolerance developed to the anticonvulsant receptors.14,25–28,45
effect of THC by the sixth day, which could limit the clinical use of Moreover, CBD reduces hydroperoxide-induced oxidative dam-
this compound, as anti-epileptic drugs are used in a daily basis for age, tissue cyclooxygenase (COX) activity, the production of nitric
prolonged periods of time. oxide (NO), T-cell responses, the release of bioactive tumour
In mice, several doses of THC (0
3125–107 mg/kg) were necrosis factor (TNF), the production of prostaglandin E2 (PGE2),
compared with diphenylhydantoin, phenobarbital and chlordiaz- cytokine interferon c (IFN-c) and tumour necrosis factor (TNF) and
epoxide using the MES test and in seizures induced by PTZ, also blocks voltage-gated Na+ channels.14,25–28,46
strychnine and nicotine.41 In the MES test, THC blocked convul- The multipharmacological profile of CBD corresponds well with
sions, increased their latency and prevented mortality. Seizures the wide range of therapeutic potentials reported for this
and mortality induced by PTZ or by strychnine were enhanced by compound, including its anti-epileptic activity. However, as many
THC, and none of the drugs prevented seizures in the nicotine test. of these effects are produced at the micromolar range, they are of
In another study,42 rats were exposed to the MES test and to the uncertain relevance for the pharmacological effects of CBD.
audiogenic seizure test (AS), and the median effective potency Although further research is needed to clarify the precise
(ED50) for THC anticonvulsant effect was calculated. In the MES mechanisms that underlie CBD therapeutic effects, including its
test, THC produced anti-epileptic effects with an ED50 of 35 mg/ anti-epileptic potentials, in the last decades, a growing number of
kg. In the AS test, THC produced anti-epileptic effects with an studies have reported that CBD may act as an sedative, anxiolytic,
ED50 of 21 mg/kg. antipsychotic, anti-inflammatory, antioxidative, neuroprotector,
In a study utilizing rats rendered chronically epileptic by anti-emetic, anticancer, antidepressant and mood stabilizer, and
bilateral implantation of cobalt into frontal cortices,43 10 mg/kg with therapeutic action on movement disorders, ischaemia and
THC was administered twice daily from day 7 through 10 after diabetes, and on cannabis withdrawal syndrome.1,8,13–15,17,18,25
cobalt implantation, at which time generalized seizure activity was Moreover, there are 18 clinical trials involving the administration
maximal. THC markedly reduced the incidence of seizures on the of CBD, including studies on with multiple sclerosis (six studies),
first and second days of administration. According to the authors, schizophrenia and bipolar mania (four studies), social anxiety (two
the effects of the first few injections of THC were dramatic: within studies), neuropathic and cancer pain (two studies), cancer
15–30 min after administration, generalized seizure activity was anorexia (one study), Huntington’s disease (one study), insomnia
completely abolished. Activity of the cobalt focus, on the other (one study) and epilepsy (one study).25
hand, was actually enhanced by THC (20 mg/kg). Moreover, on
the third and fourth days, tolerance developed to the effects of
CBD anticonvulsant effects: preclinical studies
THC, with a return of seizure frequency to values not significantly
different from those of controls. As previously commented, the The anti-epileptic effects of CBD were one of the first pharmaco-
development of tolerance could limit the clinical use of THC. logical actions described for this compound, still in the

© 2014 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 135–143
136
 13652710, 2015, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpt.12235 by CAPES, Wiley Online Library on [09/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Cannabinoids and epilepsy R. G. dos Santos et al.

Table 1. Anti-epileptic effects of CBD in animal models

Model Animals Resultsa Dose (mg/kg) References

Convulsant hippocampal discharges Rats Reduced susceptibility (+) 5 38

Leptazol-induced seizures Mice Seizure and mortality reduction (+) 200 47
Electroshock-induced seizure Mice Seizure reduction (+) ED50b = 120 48
Electroshock-induced seizure Rats Seizure reduction (+) ? 42
Electroshock-induced seizure transcorneal Mice Reduction of tonic seizures (+) ED50 = 267 49
Seizures induced by strychnine sulphate Mice No protection against seizures or death ( ) – 49
Picrotoxin-induced seizures Mice Reduction of tonic seizures (+) ED50 = 194
4 49
Seizures induced by 3-mercaptopropionic acid Mice Reduction of tonic seizures (+) ED50 = 122
5 49
Pentylenetetrazol-induced seizures Mice Reduction of tonic seizures (+) ED50 = 304
8 49
Seizures induced by isonicotinic acid hydrazide Mice Reduction of tonic seizures (+) ED50 = 266
1 49
Bicuculline-induced seizures Mice Reduction of tonic seizures (+) ED50 = 379
9 49
Epileptiform activity in hippocampal tissue In vitro (Rats) Protection (+) 1–100c 50
Pentylenetetrazol-induced seizures Rats Seizure and mortality reduction (+) 100 50
Pilocarpine-induced seizures Rats Seizure reduction (+) 1–100 51
Partial seizures induced by intraventricular penicillin Rats Seizure reduction (+) 10–100 51
Electroshock-induced seizure Mice Increased threshold (+) 20–200d 52
Pentylenetetrazol-induced seizures Mice Increased threshold (+) 200d 52

a
(+) anticonvulsant action, ( ) no anticonvulsant action.
b
median effective doses.
c
lM .
d
ng.
?, not known.

1970s.1,28,29,38,42,47,48 According to previous studies in rodents, aminopyridine (4-AP) models of epilepsy in the mammalian
CBD is an effective and relatively potent anticonvulsant.29,38,42,47,48 hippocampus, a key epileptogenic brain region.50 CBD (0
01–
Table 1 shows that preclinical evidence clearly attests the 100 lM) produced concentration-related and region-dependent
protective effect of CBD in respect to seizures induced by a attenuation of epileptiform activity in both seizure models. This
number of agents in laboratory animals. study also examined the effects of CBD in vivo using the PTZ test,
CBD decreased the susceptibility of rat dorsal hippocampus to reporting that 100 mg/kg CBD reduced the incidence of severe
seizures discharges caused by afferent stimulation and signifi- seizures and mortality in rodents. Moreover, this study assessed
cantly protected mice from the proconvulsant effects of CBD affinity for cannabinoid CB1 receptors, reporting that CBD
leptazol.38,47 acted with only low affinity at cannabinoid CB1 receptors. This last
In a study in rats using the MES and the AS tests, CBD result suggests that CBD anticonvulsant effects are produced by
enhanced the anticonvulsant effects of drugs clinically effective in CB1 receptor-independent mechanisms.
major seizures (phenytoin) and reduced the effects of drugs In another study in rodents, the anticonvulsant potential of CBD
effective in minor seizures (chlordiazepoxide, clonazepam, tri- was evaluated using the acute pilocarpine model of temporal lobe
methadione and ethosuximide).42 In the MES test, CBD produced seizures and the penicillin model of partial seizures.51 In the
anti-epileptic effects with a median effective dose (ED50) of 12 mg/ pilocarpine model, CBD (1–100 mg/kg) reduced the incidence of
kg. In the AS test, CBD produced anti-epileptic effects with an the most severe seizures, but did not reduce mortality. In the
ED50 of 17 mg/kg. CBD interactions with other anti-epileptic penicillin model, CBD produced anticonvulsant effects, reduced
drugs may result from pharmacokinetic or pharmacodynamic mortality and reduced the proportions of animals developing the
mechanisms. Nevertheless, CBD is a potent inhibitor of multiple most severe seizure types. CBD had very little effect on motor
cytochrome P450 enzymes including CYP1A2, CYP2B6, CYP2C9, function tests, suggesting a better safety profile when compared to
CYP2D6 and CYP3A4,25 which suggest that pharmacokinetic currently available anti-epileptic drugs, which may cause signif-
mechanisms are involved. icant motor side effects.
In a study in mice using a transcorneal electroshock current or A recent rodent study using the MES and the PTZ tests reported
convulsant drug administration to induce seizures,49 50–600 mg/ anticonvulsant effects of CBD (0
2–200 ng/mouse) in both seizure
kg CBD pretreatment prevented tonic convulsions caused by the models.52 This study also evaluated the possible interactions
electroshock current and by GABA-inhibitors, 3-mercaptoprop- between CBD and the potassium BK channel blocker paxilline,
ionic acid, picrotoxin, isonicotinic acid hydrazine, pentylenetetra- reporting that co-administration of CBD and paxilline attenuated
zol and bicuculline.49 Nevertheless, in a study utilizing rats the anticonvulsant effects of CBD in PTZ test. In the MES test, there
rendered chronically epileptic by bilateral implantation of cobalt was no interaction between both substances. These results suggest
into frontal cortices, 60 mg/kg CBD did not alter the frequency of a BK channel-mediated anticonvulsant action of CBD in the PTZ
appearance of seizures.43 test, where CBD could act by decreasing intracellular calcium
In an in vitro study, the electrophysiological effects of CBD on levels.
epileptiform activity were assessed by means of extracellular The effects of CBD and the structurally similar cannabinoid
multi-electrode array recordings using the Mg2+-free and 4- cannabigerol (CBG) on voltage-gated Na+ (NaV) channels were

© 2014 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 135–143
137
 13652710, 2015, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpt.12235 by CAPES, Wiley Online Library on [09/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Cannabinoids and epilepsy R. G. dos Santos et al.

investigated in rat hippocampal neurons, mouse cortical neurons, eight patients received 200–300 mg/day oral CBD for 8–18 weeks
human neuroblastoma cells and recombinant NaV channels.46 The and the other seven individuals received placebo. In this study,
effect of CBG on PTZ-induced seizures was assessed in the rat. four of eight CBD-treated patients evidenced significant improve-
CBD (10 lM) blocked NaV currents in mouse neurons, human cells ment in their condition, remaining virtually convulsion-free for the
and recombinant cell lines, affected spike parameters in rat duration of the study. The other three CBD-treated subjects
neurons and decreased membrane resistance. CBD effects were exhibited partial improvement in their clinical condition. More-
retained in the presence of a CB1 receptor antagonist, with the over, three CDB-treated patients showed improvements in elec-
exception of the decreased membrane resistance. CBG blocked troencephalographic (EEG) measures. In the placebo group, only
NaV to a similar degree to CBD in both human and mouse one patient improved. CBD was well tolerated by all participants.
recordings, but had no effect (50–200 mg/kg) on PTZ-induced A recent survey investigated the use of CBD-enriched cannabis
seizures. These results indicate that the anticonvulsant effects in children with treatment-resistant epilepsy.33 The researchers
of CBD are independent of NaV blockade and CB1 receptor presented a survey to parents who used CBD-enriched cannabis to
activation. treat their child’s seizures. Nineteen cases were reported in the
In resume, CBD produced anticonvulsant effects in several study: thirteen children had Dravet syndrome, four had Doose
preclinical studies, suggesting that this compound may have syndrome, one had Lennox–Gastaut syndrome, and one had
therapeutic effects in different epileptic syndromes. idiopathic epilepsy. The average number of anti-epileptic drugs
tried was 12 (range 4–17), and seizure frequency ranged from 2 per
week to 250 per day. The children experienced a variety of seizure
CBD anticonvulsant effects: human studies
types including focal, tonic–clonic, myoclonic, atonic and infantile
Although there is a growing number of preclinical studies and spasms. In most cases, the children experienced treatment-resistant
several case reports reporting the anti-epileptic action of CBD, only epilepsy for more than 3 years. The treatment period with CBD-
a small number of placebo-controlled clinical trials were pub- enriched cannabis ranged from 2 weeks to over 1 year. Sixteen
lished.1,13–15,17,23–25,28,29,53,54 Overall, trials reported reduction (84%) of the 19 parents reported a reduction in their child’s seizure
in seizures and few side effects after 4–12 months of 200–300 frequency. Of these, two (11%) reported complete seizure freedom,
mg/day CBD.1,13–15,17,23–25,28,29,53,54 eight (42%) reported a greater than 80% reduction in seizure
Human studies on the effectiveness of CBD in epilepsy are frequency, and six (32%) reported a 25–60% seizure reduction.
shown in Table 2. Other beneficial effects included increased alertness, better mood
The study by Cunha et al.53 seems to be the only double-blind, and improved sleep. Side effects were mild and included drows-
placebo-controlled clinical trial on the anti-epileptic effects of CBD iness and fatigue.
that was fully published in a peer-reviewed journal.1,13–15,17,23– The case of a girl with SCN1A-confirmed Dravet syndrome was
25,28,29,53,54
In other studies, few methodological details are given, recently reported.16,27,28 Adjunctive therapy with a high CBD
and the overall quality of the reports is low.14,17,23–25,29,53 concentration strain of cannabis reduced the girl’s seizure fre-
Cunha et al.53 evaluated fifteen patients (11 women; aged 14– quency from nearly 50 convulsive seizures per day to 2–3
49 years; average 24 years) suffering from secondary generalized nocturnal convulsions per month. According to the report, this
epilepsy with temporal lobe focus that was unresponsive to effect has persisted for 20 months.16
prescribed anti-epileptic drugs. Patients continued to take their Clinical studies with CBD focusing on children with intractable
regular anti-epileptic drugs throughout the study period. Patients epileptic syndromes such as Dravet and Lennox–Gastaut syn-
participated in a double-blind, placebo-controlled study, where dromes are currently underway (ClinicalTrials.gov Identifier:

Table 2. Human studies on the effectiveness of CBD in epilepsy

Study design Sample Results Dose Reference

Retrospective assessment with 19 children with 84% reported seizure reduction ? 33

questionnaires completed by treatment-resistant epilepsya
parents of children treated
with Cannabis extract rich in
CBD
Double-blind, 15 adults with 7 of 8 patients improved with 200–300 mg/day (add-on) 53
placebo-controlled trialb treatment-resistant epilepsy CBD 1 of 7 improved with 8–18 weeks
placebo
Open label trial 27 children or young adults Compared with baseline: 5–20 mg/kg/day GW Pharmaceuticals,
(up to 18 years) with 15% – no seizures 12 weeks 2014
treatment-resistant epilepsyc 22–90% reduction
41–70% reduction
48–50% reduction

a
12 children with Dravet syndrome, four with Doose syndrome, one with Lennox–Gastaut syndrome, one with mental retardation, and one with early-onset
idiopathic epilepsy.
b
single clinical trial fully published in a peer-reviewed journal.
c
predominantly with Dravet syndrome (n = 9).
?, not known.

© 2014 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 135–143
138
 13652710, 2015, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpt.12235 by CAPES, Wiley Online Library on [09/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Cannabinoids and epilepsy R. G. dos Santos et al.

NCT02091206, NCT02091375, NCT02224560, NCT02224573, Another study in rodents investigated the anticonvulsant
NCT02224690 and NCT02224703). profiles of cannabis extracts rich in CBDV in three animal models
of acute seizure and also assessed the binding of CBDV-rich
cannabis extracts and their components at CB1 receptors.57 CBDV-
Anticonvulsant effects of CBDV
rich cannabis extracts’ effects on motor function were investigated
A major advance in the last few years is the potential of CBDV, a using static beam and grip strength assays, and purified CBDV
CBD analogue derived from cannabigerovarin (CBGV), as an anti- and CBD were evaluated for potential pharmacological interac-
epileptic agent.45,55–57 Several preclinical studies reported that tions. On the rat PTZ test, 200–275 mg/kg CBDV-rich cannabis
CBDV has anticonvulsant properties that are apparently indepen- extracts had a significant anticonvulsant effect on seizure severity
dent of CB1 receptors, as CBDV binds to these receptors with only and significantly reduced seizure associated mortality. Both
very weak affinity.45,55–57 Moreover, CBDV inhibits the cellular ≥50 mg/kg purified CBDV and 100 mg/kg CBDV-rich cannabis
uptake of anandamide at micromolar concentrations, activates extracts significantly suppressed seizure severity, and mortality
TRPV1/2 and TRPA1 channels and inhibits the synthetic enzyme of was significantly reduced by both purified CBDV and CBDV-rich
the endocannabinoid 2-arachidonoylglycerol (2-AG) at nanomolar cannabis extracts (≥100 mg/kg). CBDV-rich cannabis extracts
concentrations and may also act via CB2 receptors.26,45,55–57 (≥87 mg/kg) exerted significant anticonvulsant effects in the mice
However, the pharmacological and clinical relevance of these AS test, and ≥100 mg/kg purified CBDV significantly reduced
effects is still uncertain. seizure incidence. CBDV-rich cannabis extracts suppressed pilo-
The anticonvulsant profile of CBDV was investigated in vitro carpine-induced convulsions in the rat (≥100 mg/kg). The anti-
using multi-electrode array recordings of epileptiform local field convulsant effects of ≥116 mg/kg purified CBDV and ≥27 mg/kg
potentials induced in rat hippocampal brain slices by 4-amino- CBD were linearly additive when co-administered. CBDV-rich
pyridine application or Mg2+-free conditions.55 CBDV (1–100 lM) cannabis extracts produced some motor effects on static beam
significantly decreased the amplitude and duration of local field performance, but no effects on grip strength. This study also
potentials. reported that CBDV binds to CB1 receptors with only very weak
CBDV effects were investigated in four rodent seizure models: affinity, suggesting that the anticonvulsant mechanisms of action
MES and AS tests in mice and PTZ- and pilocarpine-induced of CBDV are not mediated by CB1 receptors.
seizures in rats.55 CBDV effects on rat seizures were also assessed A recent study evaluated whether the epileptiform activity of
in combination with commonly used anti-epileptic drugs (valpro- CBDV was related to activation of transient receptor potential
ate, ethosuximide and phenobarbital). CBDV had significant (TRP) channels.45 Patch-clamp analysis in transfected HEK293
anticonvulsant effects on the MES (≥100 mg/kg), AS (≥50 mg/ cells demonstrated that CBDV (3–30 lM) dose-dependently acti-
kg) and PTZ tests (≥100 mg/kg). On the PTZ test, CBDV vated and rapidly desensitized TRPV1–2 and TRPA1, and these
significantly reduced mortality (100–200 mg/kg). CBDV effects were blocked by TRP antagonists. When tested on
(200 mg/kg) alone had no effect against pilocarpine-induced epileptiform neuronal spike activity in hippocampal brain slices
seizures, but produced significant anticonvulsant effects when exposed to a Mg2+-free solution using multi-electrode arrays,
co-administered with ethosuximide in the PTZ model and even CBDV reduced both epileptiform burst amplitude and duration.
greater effects when co-administered with valproate in the CBDV effects on burst amplitude were not reversed by a selective
pilocarpine model. CBDV did not affect the effects of phenobar- TRPV1 antagonist, suggesting that they are not uniquely medi-
bital in the pilocarpine model and had only very limited effects on ated by TRPV1.
the onset of seizures when co-administered with valproate before In resume, CBDV showed anticonvulsant properties in several
PTZ treatment. No negative interactions between CBDV and the preclinical models and produced few motor effects. Thus, CBDV
anti-epileptic drugs were observed. could be effective in a variety of epileptic syndromes and may be
The motor side effect profile of CBDV (50–200 mg/kg) was less toxic than currently available anti-epileptic drugs.
investigated using static beam test to assess motor coordination
and a grip strength test to assess drug-induced muscle relaxa- Anticonvulsant effects of CBN
tion and functional neurotoxicity.55 CBDV had no effect on
motor function, suggesting a better side effect profile compared Few studies investigated the anticonvulsant properties of CBN.
to current available anti-epileptic drugs, which often produce Similar to CBD and CBDV, micromolar concentrations of CBN
motor side effects. CBDV was administered orally to suppress inhibit cellular uptake of anandamide.26 In one study,42 rats were
PTZ seizures, as a prerequisite for human epilepsy treatment is exposed to the MES and AS tests and the ED50 for CBN
that a drug is effective after oral administration. CBDV anticonvulsant effect was calculated. In the MES test,
(400 mg/kg) significantly reduced the severity of PTZ-induced CBN produced anti-epileptic effects with an ED50 of 18 mg/kg.
seizures.55 CBN showed only minimal effectiveness in the AS test.
A study in rats evaluated CBDV effects on the PTZ test and
quantified expression levels of several epilepsy-related genes in Anticonvulsant effects of delta-8-THC
tissue from hippocampus, neocortex and prefrontal cortex.56
Delta-8-THC results from the isomerization of THC and has a
CBDV (400 mg/kg) significantly decreased seizure severity and
similar pharmacology, although it appears to be less active.5 In a
increased latency to the first seizure sign. PTZ treatment upreg-
study utilizing rats rendered chronically epileptic by bilateral
ulated mRNA expression coding for Fos, Egr1, Arc, Ccl4 and Bdnf
implantation of cobalt into frontal cortices, 10 mg/kg delta-8-THC
in all brain regions tested. Clear correlations between seizure
markedly reduced the incidence of seizures.43 Within 15–30 min
severity and mRNA expression were observed for these genes in
after delta-8-THC administration, generalized seizure activity was
the majority of brain regions, and mRNA expression of these genes
completely abolished. Nevertheless, tolerance developed after
was suppressed in the majority of brain regions after CBDV
chronic (6 days) delta-8-THC administration.
treatment.

© 2014 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 135–143
139
 13652710, 2015, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpt.12235 by CAPES, Wiley Online Library on [09/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Cannabinoids and epilepsy R. G. dos Santos et al.

compared to wild-type mice, suggesting that glutamatergic cortical

Anticonvulsant effects of delta-9-THCV
neurons are the main target of CB1-dependent protection against
Similar to CBDV, delta-9-THCV is derived from cannabigerovarin acute excitotoxic seizures. Moreover, this study reported that
(CBGV).26 Binding assays suggested a relatively high-affinity functional CB1 protein is abundantly present on glutamatergic
interaction of delta-9-THCV with CB1 receptors but a lack of hippocampal terminals in the inner molecular layer of the dentate
agonist action, leading to its description as a CB1 antagonist gyrus.
(although with evidence of agonist properties at higher doses).26,58 An in vitro study evaluated the effects of the endocannabinoids
Delta-9-THCV is also a potent CB2 receptor partial agonist.26 methanandamide (a stable analogue of anandamide) and 2-AG,
A study assessed the anticonvulsant potential of delta-9-THCV and of the anti-epileptic drugs phenobarbital and phenytoin, on
in an in vitro model of epileptiform activity induced by Mg2+-free refractory status epilepticus using the low-Mg2+ hippocampal
extracellular media.58 This study also investigated the effects of neuronal culture model.61 Phenobarbital and phenytoin were
delta-9-THCV in the PTZ test. Delta-9-THCV (20–50 lM) signifi- ineffective in completely blocking status epilepticus at the high
cantly reduced burst complex incidence and the amplitude and micromolar range. On the other hand, methanandamide (300 nM–
frequency of paroxysmal depolarizing shifts (PDSs), and slices 1 lM) and 2-AG (1–10 lM) inhibited status epilepticus in a very
pretreated with 10 lM delta-9-THCV exhibited significantly potent, dose-dependent manner, at nanomolar concentrations.
reduced burst complex incidence and PDS peak amplitude. Moreover, the effects of methanandamide and 2-AG were medi-
Delta-9-THCV (0
25 mg/kg) significantly reduced seizure inci- ated by agonism at the cannabinoid CB1 receptor, as they were
dence in the PTZ test. blocked by a CB1 receptor antagonist.
Another rodent study evaluated the long-term effects of status
epilepticus on CB1 receptor expression, binding and G protein
Anticonvulsant effects of CBG
activation in the rat pilocarpine model of acquired epilepsy, a model
CBG is the precursor of THC and CBD. Micromolar concentrations of partial complex or limbic epilepsy in humans.62 Status epilepticus
of CBG inhibit the uptake of anandamide, and this phytocanna- produced long-term redistribution of hippocampal CB1 receptors
binoid also activates TRPV1/2 channels and is an agonist at and regionally selective functional changes in CB1 receptor binding
a2-adrenoceptors and an antagonist at 5-HT1A receptors.26 and G protein activation. According to the authors, these results
The effects of CBG on NaV channels were investigated in mouse suggest that CB1 receptor redistribution may play an important role
cortical neurons and human neuroblastoma cells.46 The effect of in the permanent plasticity changes associated with brain injury
CBG on PTZ-induced seizures was assessed in the rat. CBG from status epilepticus and epileptogenesis.
blocked NaV in both human and mouse recordings, but had no In a study in mice, the pilocarpine-induced status epilepticus
effect (50–200 mg/kg) on PTZ-induced seizures. These results mouse model of temporal lobe epilepsy was used to study the
indicate that NaV blockade per se does not correlate with effect of endogenous cannabinoid agonists on recurrent excitatory
anticonvulsant effects. circuits of the dentate gyrus using electrophysiological recordings
in hippocampal slices.63 Anandamide (1–10 lM) and 2-AG (10 lM)
reduced the frequency of excitatory post-synaptic currents, an
The endocannabinoid system modulates cortical excitability
effect that was blocked by a CB1 receptor antagonist. 1 lM WIN55,
The endocannabinoid system represents a compelling target for 212-2, a CB1 receptor agonist, also reduced the frequency of
development of future anti-epileptic therapies, as it is intimately excitatory post-synaptic currents, an effect that was also blocked
involved in the regulation of cortical excitability, is altered in by a CB1 receptor antagonist. Moreover, there was an upregulation
epilepsy or by epileptic seizures, and its modulation can alter of CB1 receptors in the dentate gyrus of animals with temporal
seizure activity or change the development of epileptogenesis in lobe epilepsy. These findings suggest that activation of CB1
various in vitro and in vivo models.30,44 receptors present on nerve terminals can suppress recurrent
In a study in mice, the anticonvulsant effects of the endocann- excitation in the dentate gyrus.
abinoid anandamide and of its metabolically stable analogue O- A recent study investigated the role of cannabinoids in specific
1812 were assessed on seizure threshold and severity in the areas of the cortico-thalamic network involved in oscillations that
maximal electroshock model.59 Anandamide (50–300 mg/kg) and underlie seizures in a genetic animal model of absence epilepsy,
O-1812 (5 mg/kg) produced potent anticonvulsant effects, which the WAG/Rij rat.64 The study assessed the effects of focal injection
were mediated by cannabinoid CB1 receptor activation, as a CB1 of the endogenous cannabinoid anandamide, WIN55, 212-2, and of
receptor-specific antagonist blocked the anticonvulsant activity of a selective CB1 receptor antagonist/inverse agonist (rimonabant)
these compounds. Furthermore, administration of the CB1 receptor into thalamic nuclei and primary somatosensory cortex of the
antagonist alone produced a reduction of maximal seizure thresh- cortico-thalamic network. Anandamide (1–5 lg/0
5 lL) and
old, providing evidence for an endogenous cannabinoid tone WIN55, 212-2 (0
1–1 lg/0
5 lL) reduced absence seizures inde-
modulating the brain’s excitability. Interestingly, high concentra- pendently from the brain focal site of infusion, whereas rimona-
tions of anandamide are detected in the hippocampus, an area bant increased absence seizures only when focally administered to
with high cannabinoid CB1 receptor expression and which is the ventroposteromedial thalamic nucleus. These results support
known to be a major brain region involved in epileptogenesis and therapeutic potential for endocannabinoid system modulators in
seizure disorders.30,50,59–63 absence epilepsy and highlight that an attenuated endocannabin-
A study in rodents investigated the role of the endocannabinoid ergic tone might be present in the cortico-thalamic circuit under-
system in modulating the brain’s excitability using the kainic acid- lying absence epilepsy in WAG/Rij rats.
induced seizures model in mutant mice lacking CB1 receptor Finally, a recent study in rats used behavioural and video-
expression in the majority of cortical glutamatergic neurons, electroencephalographic (EEG) analysis to investigate the modula-
including hippocampus, neocortex and amygdala.60 Mutant mice tory potential of synthetic cannabinoids and anandamide hydrolysis
showed stronger seizures following kainic acid treatment as inhibitors [fatty acid amide hydrolase (FAAH) inhibitors] on

© 2014 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 135–143
140
 13652710, 2015, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpt.12235 by CAPES, Wiley Online Library on [09/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Cannabinoids and epilepsy R. G. dos Santos et al.

seizures induced by PTZ.65 WIN55, 212-2 (1 mg/kg) reduced agonist, inverse agonist) and binding affinities of phyto-, endo-
myoclonic seizure (‘minimal seizure’) threshold, whereas other and synthetic cannabinoids to cannabinoid receptors could also
doses (0
3 and 3 mg/kg) did not alter seizure threshold. WIN55, potentially cause differences in results. The potential action of
212-2 (1 mg/kg) also significantly increased EEG seizure duration. cannabinoids in other neurotransmitter systems should also be
The administration of arachidonyl-2-chloroethylamide (ACEA; 1– considered, especially with high doses.
4 mg/kg), a selective CB1 receptor agonist, significantly decreased Evidence from preclinical studies suggests a physiological role for
seizure threshold, whereas 2 mg/kg ACEA interfered with EEG the endocannabinoid system in the modulation of seizure threshold
seizure duration, significantly increasing epileptiform discharge and severity.30,44 Cannabinoid antagonists modify seizure threshold
duration. Rimonabant (0
3–3 mg/kg), a selective CB1 antagonist/ and severity.59,64 Anandamide has a protective action against
inverse agonist, did not alter myoclonic seizure threshold or electroshock seizures and reduces excitability in a hippocampal
epileptiform discharge duration and threshold. Contrary to the neuronal culture model.59,61 Moreover, anandamide and 2-AG
other cannabinoids, 3 mg/kg URB-597, a selective FAAH-inhibitor, reduce the frequency of excitatory post-synaptic currents,63 and
significantly increased seizure threshold, and 0
3–3 mg/kg URB- anandamide hydrolysis inhibitors (FAAH-inhibitors) have anticon-
597 reduced EEG epileptiform activity. WIN55, 212-2 and ACEA vulsant effects.59 Genetic deletion of CB1 receptors increases seizure
produced characteristic proconvulsant effects, whereas none of the severity,60 and CB1 receptors are upregulated in the dentate gyrus of
cannabinoids changed the threshold or epileptiform EEG latency for animals with temporal lobe epilepsy.63 Furthermore, status epilep-
tonic–clonic generalized (‘maximal’) seizures. ticus produces long-term redistribution of hippocampal CB1 recep-
tors and regionally selective functional changes in CB1 receptor
binding and G protein activation.62
Integrating the data on cannabinoids and epilepsy
These results corroborate the hypothesis that on-demand
There is contradictory information that support both anti- and synthesized endocannabinoids promote defence against acute
proconvulsant effects of smoked cannabis, and results from excitotoxicity, and the signalling pathways through which these
preclinical studies using isolated cannabinoid agonists are protective effects occur might involve opening K+ channels and
equally divergent.13,16,23,24,27–30,32–37 Conflicting results have also inhibition of inward Ca2+ currents, which are mediated by CB1
been observed with cannabinoid antagonists, with some studies receptors.30,44,59–63,65 The endocannabinoid system could also
showing anticonvulsant effects,58 others failing to report such produce neuroprotective effects by neurochemical mechanisms
effects,65 others reporting a reduction of maximal seizure that are independent of the CB1 receptor, such as inhibition of the
threshold after pharmacological blockade of CB1 receptors59 cellular uptake of anandamide and of its enzymatic hydroly-
and others reporting increased seizure severity after genetic sis.26,45,55–59,61,63
deletion of CB1 receptors.60 Although several phytocannabinoids discussed present anticon-
Nevertheless, regarding phytocannabinoids specifically, the vulsant potentials that deserve to be further investigated, CBD and
reviewed literature suggests that these compounds, especially CBDV appear to be the most promising phytocannabinoids
CBD and CBDV, are in general potent anticonvulsants that regarding epilepsy treatment, as the anticonvulsant properties of
produce few side effects. The contradictory reports regarding these compounds were reported in several in vitro and animal
cannabis could be explained by the different phytocannabinoids, studies, and also in a few small clinical trials.14,17,26–29,53 CBD and
with potentially conflicting pharmacology. Furthermore, the pref- CBDV have a multipharmacological profile, resulting in distinct
erential action of THC on CB1 receptors located in glutamatergic or mechanisms of action possibly responsible for their anticonvulsant
GABAergic could produce anti- or proconvulsant effects, respec- effects.13–17,23–29,45,55–58 CBD and CBDV anticonvulsant effects
tively.26,30,44 may result from numerous cannabinoid receptor-independent
Regarding THC and synthetic cannabinoids, although these mechanisms, as these phytocannabinoids have little affinity for
compounds seem to produce their anticonvulsant effects by CB1/2 receptors.13–17,23–29,45,55–58 Thus, CBD may potentially
activating CB1 receptors, several preclinical studies reported that modulate neuronal hyperexcitability via a number of different
CBD, CBDV, CBN, delta-9-THCV and CBG showed anticonvul- mechanisms, which include regulation of Ca2+ homeostasis,
sant properties that are apparently independent of CB1 recep- agonistic properties at 5-HT1A receptors and reduction in
tors.26,45,55–58 These compounds bind to CB1 receptors with only adenosine reuptake.14,25–29,50–52 Moreover, CBD and CBDV
very weak affinity, and their anticonvulsant effects seem to be inhibit the uptake of anandamide and of its enzymatic
mediated by activation of the endocannabinoids system through hydrolysis.26,45,55–59,61,63 Investigating the diverse mechanisms of
inhibition of the cellular uptake of anandamide and of its action responsible for CBD and CBDV anticonvulsant effects may
enzymatic hydrolysis.26,45,55–58 stimulate research with new anti-epileptic agents with a better
Moreover, the conflicting results could in part be mediated by therapeutic response and which produce few side effects than
several methodological aspects. Many of the reviewed studies current available anti-epileptic drugs.
used different animal models of seizures, which could interfere Considering that many patients report limited therapeutic
with results. Studies often used different rodent species, which efficacy with several currently available anti-epileptic drugs and
could potentially represent differences in the availability of that these drugs produce several side effects, it is necessary to
cannabinoid, GABAergic and glutamatergic receptors and endog- investigate drugs with better therapeutic efficacy and improved
enous neurotransmitters in different brain regions, potentially safety. Phytocannabinoids are potential candidates for these future
modifying results. Different rodent species may also present investigations.
different metabolism regarding cannabinoids and several anti-
epileptic drugs used in comparison studies, which could produce
WHAT IS NEW AND CONCLUSION
not only pharmacokinetic interactions, but also pharmacodynamic
modifications. Differences in administered doses, routes of admin- Phytocannabinoids, specially CBD and CBDV, have demonstrated
istration, mechanisms of action (i.e. agonist, antagonist, partial anticonvulsant effects in vitro and in vivo, and at least one double-

© 2014 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 135–143
141
 13652710, 2015, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpt.12235 by CAPES, Wiley Online Library on [09/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Cannabinoids and epilepsy R. G. dos Santos et al.

blind study suggest that CBD reduces seizure frequency and is effective in infantile intractable epileptic syndromes such as Dravet
well tolerated in adult epileptic patients. Moreover, CBD and and Lennox–Gastaut syndromes, and clinical studies with CBD
CBDV have demonstrated anticonvulsant properties in several focusing on the syndromes are currently underway.
preclinical models of seizures and produced few motor effects. Given the good safety profile of CBD and CBDV, there is a clear
Thus, CBD and CBDV could be effective in a variety of epileptic need to perform new randomized, controlled clinical trials with
syndromes and may be less toxic than currently available anti- these molecules.
epileptic drugs.
On the other hand, given the small number of clinical trials with
CONFLICT OF INTEREST
patients and the quality of the available data, no reliable
conclusions can be drawn from the available studies regarding Our research group has financial interests relating to issues
the possible therapeutic uses of phytocannabinoids in specific discussed in the manuscript (patent ownership: Fluorinated CBD
epileptic syndromes as standalone drugs or as adjunct treatments. compounds, compositions and uses thereof. Pub. No.: WO/2014/
However, anecdotal evidence strongly suggest that CBD may be 108899. International Application No.: PCT/IL2014/050023).

REFERENCES
1. Mechoulam R, Carlini EA. Toward drugs of action. Revista Brasileira de Psiquiatria, 26. Hill AJ, Williams CM, Whalley BJ, Stephens
derived from cannabis. Naturwissenschaften, 2008;30:271–280. GJ. Phytocannabinoids as novel therapeutic
1978;65:174–179. 15. Hazekamp A, Grotenhermen F. Review on agents in CNS disorders. Pharmacol Ther,
2. Schultes RE, Hofmann A. Plants of the gods: clinical studies with cannabis and cannabi- 2012;133:79–97.
their sacred, healing, and hallucinogenic powers. noids 2005–2009. Cannabinoids, 2010;5:1–21. 27. Cilio MR, Thiele EA, Devinsky O. The case
Rochester: Healing Arts Press, 1992. 16. Maa E, Figi P. The case for medical for assessing cannabidiol in epilepsy. Epi-
3. Furst PT. Alucinogenos y cultura. Mexico: marijuana in epilepsy. Epilepsia, 2014;55: lepsia, 2014;55:87–90.
Fondo de Cultura Econ omica, 1994. 783–786. 28. Devinsky O, Cilio MR, Cross H et al. Canna-
4. Robinson R. The great book of hemp: the 17. Robson PJ. Therapeutic potential of cannab- bidiol: pharmacology and potential therapeu-
complete guide to the environmental, commer- inoid medicines. Drug Test Anal, 2014;6:24– tic role in epilepsy and other neuropsychiatric
cial, and medicinal uses of the world’s most 30. disorders. Epilepsia, 2014;55:791–802.
extraordinary plant. Rochester: Park Street 18. Mechoulam R, Hanus L. Other cannabi- 29. Szaflarski JP, Martina Bebin E. Cannabis,
Press, 1995. noids. In: Castle D, Murray RM, D’Souza cannabidiol, and epilepsy – From receptors
5. Iversen L. The science of marijuana. Oxford: DC, eds. Marijuana and madness, 2nd edn. to clinical response. Epilepsy Behav,
Oxford University Press, 2000. Cambridge: Cambridge University Press, 2014;41:277–282.
6. Spinella M. The psychopharmacology of herbal 17–22, 2012. 30. Lutz B. On-demand activation of the
medicine: plant drugs that alter mind, brain and 19. Zuurman L, Roy C, Schoemaker RC et al. endocannabinoid system in the control of
behavior. London: The MIT Press, 2001. Effect of intrapulmonary tetrahydrocannab- neuronal excitability and epileptiform
7. Russo EB, Jiang HE, Li X et al. Phytochem- inol administration in humans. J Psycho- seizures. Biochem Pharmacol, 2004;68:1691–
ical and genetic analyses of ancient cannabis pharmacol, 2008;22:707–716. 1698.
from Central Asia. J Exp Bot, 2008;59:4171– 20. Morgan CJ, Freeman TP, Schafer GL, 31. Mechoulam R. Endocannabinoids and psy-
4182. Curran HV. Cannabidiol attenuates the chiatric disorders: the road ahead. Revista
8. Crippa JA, Zuardi AW, Hallak JE. Thera- appetitive effects of delta-9-tetrahydrocan- Brasileira de Psiquiatria, 2010;32:S5–S6.
peutical use of the cannabinoids in psychi- nabinol in humans smoking their chosen 32. Brust JC, Ng SK, Hauser AW, Susser M.
atry. Revista Brasileira de Psiquiatria, 2010;32: cannabis. Neuropsychopharmacology, 2010;35: Marijuana use and the risk of new onset
S56–S66. 1879–1885. seizures. Trans Am Clin Climatol Assoc,
9. Godlaski TM. Shiva, lord of bhang. Subst 21. Zuurman L, Roy C, Schoemaker RC et al. 1992;103:176–181.
Use Misuse, 2012;47:1067–1072. Inhibition of THC-induced effects on the 33. Porter BE, Jacobson C. Report of a parent
10. Degenhardt L, Ferrari AJ, Calabria B et al. central nervous system and heart rate by a survey of cannabidiol-enriched cannabis use
The global epidemiology and contribution novel CB1 receptor antagonist AVE1625. in pediatric treatment-resistant epilepsy.
of cannabis use and dependence to the J Psychopharmacol, 2010;24:363–371. Epilepsy Behav, 2013;29:574–577.
global burden of disease: results from the 22. Carbuto M, Sewell RA, Williams A et al.; 34. Hamerle M, Ghaeni L, Kowski A, Weiss-
GBD 2010 study. PLoS ONE, 2013;8: Yale THC Study Group. The safety of inger F, Holtkamp M. Cannabis and other
e76635. studies with intravenous D9-tetrahydrocan- illicit drug use in epilepsy patients. Eur J
11. Greydanus DE, Hawver EK, Greydanus nabinol in humans, with case histories. Neurol, 2014;21:167–170.
MM, Merrick J. Marijuana: current concepts. Psychopharmacology, 2012;219:885–896. 35. McConnell BV, Applegate M, Keniston A,
Front. Publ. Health, 2013;1:42. 23. Gloss D, Vickrey B Cannabinoids for epi- Kluger B, Maa EH. Use of complementary
12. Hall W, Degenhardt L. The adverse health lepsy. Cochrane Database Syst Rev, 2012;6: and alternative medicine in an urban county
effects of chronic cannabis use. Drug Test CD009270. hospital epilepsy clinic. Epilepsy Behav,
Anal, 2014;6:39–45. 24. Gloss D, Vickrey B Cannabinoids for epi- 2014;34:73–76.
13. Ben Amar M. Cannabinoids in medicine: a lepsy. Cochrane Database Syst Rev, 2014;3: 36. Hegde M, Santos-Sanchez C, Hess CP,
review of their therapeutic potential. J Eth- CD009270. Kabir AA, Garcia PA. Seizure exacerbation
nopharmacol, 2006;105:1–25. 25. Zhornitsky S, Potvin S. Cannabidiol in in two patients with focal epilepsy follow-
14. Zuardi AW. Cannabidiol: from an inactive humans – the quest for therapeutic targets. ing marijuana cessation. Epilepsy Behav,
cannabinoid to a drug with wide spectrum Pharmaceuticals, 2012;5:529–552. 2012;25:563–566.

© 2014 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 135–143
142
 13652710, 2015, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jcpt.12235 by CAPES, Wiley Online Library on [09/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Cannabinoids and epilepsy R. G. dos Santos et al.

37. Singh D, Huntwork M, Shetty V, Sequeira 47. Carlini EA, Leite JR, Tannhauser M, Berardi increases in epilepsy-related gene expres-
G, Akingbola O. Prolonged atrial fibrillation AC. Cannabidiol and Cannabis sativa sion. PeerJ, 2013;1:e214.
precipitated by new-onset seizures and extract protect mice and rats against 57. Hill TD, Cascio MG, Romano B et al. Cann-
marijuana abuse. Pediatrics, 2014;133:e443– convulsive agents. J Pharm Pharmacol, abidivarin-rich cannabis extracts are anti-
e446. 1973;25:664–665. convulsant in mouse and rat via a CB1
38. Izquierdo I, Orsingher OA, Berardi AC. 48. Turkanis SA, Cely W, Olsen DM, Karler R. receptor-independent mechanism. Br J Phar-
Effect of cannabidiol and of other Cannabis Anticonvulsant properties of cannabidiol. macol, 2013;170:679–692.
sativa compounds on hippocampal seizure Res Commun Chem Pathol Pharmacol, 58. Hill AJ, Weston SE, Jones NA et al. D9-
discharges. Psychopharmacologia, 1973;28:95– 1974;8:231–246. Tetrahydrocannabivarin suppresses in vitro
102. 49. Consroe P, Benedito MA, Leite JR, Carlini epileptiform and in vivo seizure activity in
39. Chesher GB, Jackson DM. Anticonvulsant EA, Mechoulam R. Effects of cannabidiol on adult rats. Epilepsia, 2010;51:1522–1532.
effects of cannabinoids in mice: drug inter- behavioral seizures caused by convulsant 59. Wallace MJ, Martin BR, DeLorenzo RJ.
actions within cannabinoids and cannabi- drugs or current in mice. Eur J Pharmacol, Evidence for a physiological role of endoc-
noid interactions with phenytoin. 1982;83:293–298. annabinoids in the modulation of seizure
Psychopharmacologia, 1974;37:255–264. 50. Jones NA, Hill AJ, Smith I, Bevan SA, threshold and severity. Eur J Pharmacol,
40. Ten Ham M, Loskota WJ, Lomax P. Acute Williams CM, Whalley BJ, Stephens GJ. 2002;452:295–301.
and chronic effects of D9-tetrahydrocannab- Cannabidiol displays antiepileptiform 60. Monory K, Massa F, Egertova M et al. The
inol on seizures in the gerbil. Eur J Pharma- and antiseizure properties in vitro and endocannabinoid system controls key epi-
col, 1975;31:148–152. in vivo. J Pharmacol Exp Ther, 2010;332:569– leptogenic circuits in the hippocampus.
41. Sofia RD, Solomon TA, Barry H 3rd. Anti- 577. Neuron, 2006;51:455–466.
convulsant activity of D9-tetrahydrocannab- 51. Jones NA, Glyn SE, Akiyama S et al. Cann- 61. Deshpande LS, Blair RE, Ziobro JM, Som-
inol compared with three other drugs. Eur J abidiol exerts anti-convulsant effects in ani- bati S, Martin BR, DeLorenzo RJ. Endoc-
Pharmacol, 1976;35:7–16. mal models of temporal lobe and partial annabinoids block status epilepticus in
42. Consroe P, Wolkin A. Cannabidiol – antiep- seizures. Seizure, 2012;21:344–352. cultured hippocampal neurons. Eur J Phar-
ileptic drug comparisons and interactions in 52. Shirazi-zand Z, Ahmad-Molaei L, Mota- macol, 2007;558:52–59.
experimentally induced seizures in rats. J medi F, Naderi N. The role of potassium 62. Falenski KW, Blair RE, Sim-Selley LJ, Martin
Pharmacol Exp Ther, 1977;201:26–32. BK channels in anticonvulsant effect of BR, DeLorenzo RJ. Status epilepticus causes
43. Colasanti BK, Lindamood C 3rd, Craig CR. cannabidiol in pentylenetetrazole and max- a long-lasting redistribution of hippocampal
Effects of marihuana cannabinoids on sei- imal electroshock models of seizure in mice. cannabinoid type 1 receptor expression and
zure activity in cobalt-epileptic rats. Phar- Epilepsy Behav, 2013;28:1–7. function in the rat pilocarpine model of
macol Biochem Behav, 1982;16:573–578. 53. Cunha JM, Carlini EA, Pereira AE et al. acquired epilepsy. Neuroscience, 2007;146:
44. Hofmann ME, Frazier CJ. Marijuana, en- Chronic administration of cannabidiol to 1232–1244.
docannabinoids, and epilepsy: potential and healthy volunteers and epileptic patients. 63. Bhaskaran MD, Smith BN. Cannabinoid-
challenges for improved therapeutic inter- Pharmacology, 1980;21:175–185. mediated inhibition of recurrent excitatory
vention. Exp Neurol, 2013;244:43–50. 54. Koppel BS, Brust JC, Fife T, Bronstein J, circuitry in the dentate gyrus in a mouse
45. Iannotti FA, Hill CL, Leo A et al. Nonpsy- Youssof S, Gronseth G, Gloss D. Systematic model of temporal lobe epilepsy. PLoS ONE,
chotropic plant cannabinoids, cannabidiva- review: efficacy and safety of medical 2010;5:e10683.
rin (CBDV) and cannabidiol (CBD), activate marijuana in selected neurologic disor- 64. Citraro R, Russo E, Ngomba RT et al. CB1
and desensitize transient receptor potential ders: report of the Guideline Develop- agonists, locally applied to the cortico-tha-
vanilloid 1 (TRPV1) channels in vitro: ment Subcommittee of the American lamic circuit of rats with genetic absence
potential for the treatment of neuronal Academy of Neurology. Neurology, 2014;82: epilepsy, reduce epileptic manifestations.
hyperexcitability. ACS Chem Neurosci, 1556–1563. Epilepsy Res, 2013;106:74–82.
2014;5:1131–1141. 55. Hill AJ, Mercier MS, Hill TD et al. 65. Vilela LR, Medeiros DC, Rezende GH, de
46. Hill AJ, Jones NA, Smith I, Hill CL, Wil- Cannabidivarin is anticonvulsant in Oliveira AC, Moraes MF, Moreira FA. Effects
liams CM, Stephens GJ, Whalley BJ. Volt- mouse and rat. Br J Pharmacol, 2012;167: of cannabinoids and endocannabinoid
age-gated sodium (NaV) channel blockade 1629–1642. hydrolysis inhibition on pentylenetetrazole-
by plant cannabinoids does not confer 56. Amada N, Yamasaki Y, Williams CM, induced seizure and electroencephalo-
anticonvulsant effects per se. Neurosci Lett, Whalley BJ. Cannabidivarin (CBDV) sup- graphic activity in rats. Epilepsy Res,
2014;566:269–274. presses pentylenetetrazole (PTZ)-induced 2013;104:195–202.

© 2014 John Wiley & Sons Ltd Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 135–143
143