Plant-Derived and Endogenous

Cannabinoids in Epilepsy
By Alberto Verrotti, Miriam Castagnino, Mauro Maccarrone and Filomena Fezza
Abstract:
Cannabis is one of the oldest psychotropic drugs and its anticonvulsant properties
have been known since the last century. The aim of this review was to analyze
the efficacy of cannabis in the treatment of epilepsy in adults and children. In
addition, a description of the involvement of the endocannabinoid system in
epilepsy is given in order to provide a biochemical background to the effects of
endogenous cannabinoids in our body. General tolerability and adverse events
associated with cannabis treatment are also investigated. Several anecdotal
reports and clinical trials suggest that in the human population cannabis has
anticonvulsant properties and could be effective in treating partial epilepsies and
generalized tonic-clonic seizures, still known as grand mal. They are based,
among other factors, on the observation that in individuals who smoke marijuana
to treat epilepsy, cessation of cannabis use precipitates the re-emergence of
convulsive seizures, whereas resuming consumption of this psychotropic drug
controls epilepsy in a reproducible manner. In conclusion, there is some anecdotal
evidence for the potential efficacy of cannabis in treating epilepsy. Though there
has been an increased effort by patients with epilepsy, their caregivers, growers,
and legislators to legalize various forms of cannabis, there is still concern about its
efficacy, relative potency, availability of medication-grade preparations, dosing,
and potential short- and long-term side effects, including those on prenatal and
childhood development.


What are Cannabinoids?
Cannabinoids are a class of diverse chemical compounds that acts on cannabinoid
receptors in cells. Ligands for the cannabinoid receptors include the
endocannabinoids (produced naturally by animals), synthetic cannabinoids
(manufactured artificially), and the phytocannabinoids (found in cannabis and some
other plants). The phytocannabinoid tetrahydrocannabinol (THC), is the primary
psychoactive compound in cannabis, Cannabidiol (CBD) is another major constituent
of the plant.
Epilepsy:
Is a neurological disorder marked by sudden
recurrent episodes of sensory disturbance,
loss of consciousness, or convulsions,
associated with abnormal electrical activity
in the brain.
1. Introduction and Historical Issues:
Cannabiss anticonvulsive
properties have been known for
the last century, its one of the
oldest psychotropic drugs.
The most relevant species of
cannabis are Cannabis sativa,
Cannabis indica, and Cannabis
ruderalis.
OShaughnessy, is a British
physician and surgeon that
discovered, appetite-stimulant,
the analgesic, muscle relaxant,
antiemetic, and anticonvulsant
properties of cannabis back in 1839
In 1854, cannabis was sold freely in
pharmacies in the U.S. and in
Western countries.
After the prohibition of alcohol was
lifted, the U.S. banned cannabis,
because it was considered to be
responsible for insanity, moral and
intellectual deterioration,
violence, and various crimes.
Research has increased
significantly in the last 15 years
particularly in the therapeutic
applications of cannabis and its
derivatives.
 Cannabis ruderalis

Cannabis sativa

Cannabis indica
2. The Endocannabinoid System:
Cannabis contains in excess of 460
known chemicals, of which more than
60 are grouped under CBs.
In mammals most CBs carry out their
function mainly through specific
receptors: type 1 and type 2
cannabinoid receptors (CB1R and CB2R).
Endocannabinoids (eCBs), their receptor
targets (including CBRs), and metabolic
enzymes responsible for eCBs synthesis
and degradation are termed: the
endocannabinoid system (ECS).
CB1R is mostly found in the central
nervous system (CNS), with high levels
in the hippocampus, and CB2R is
located mainly in the periphery.
CB1R is also expressed by non-neuronal
cells and CB2R by neurons upon brain
insult.
The main eCBs are two 3-fatty acids
containing lipid molecules, anandamide
(N-arachidonoylethanolamine, AEA) and
2-arachidonoylglycerol (2-AG).
The actions of eCBs are regulated by
their concentration, by a balance of
synthesis and degradation.
Fig. 2 Main signaling pathways
triggered by (endo)cannabinoids
Table 1: Major biosynthetic and Table 2: Major biosynthetic
hydrolytic enzymes of antiepileptic and hydrolytic enzymes of
agents 2-AG
3. Literature Search Strategy:
They performed a systematic search in Medline and PubMed up to 31 August
2015. Randomized controlled trials were identified by searching Medline
(PubMed), EMBASE, and Cochrane CENTRAL for the words Cannabis,
Cannabinoids, Endocannabinoids, and randomized controlled trial
with different search strategies, setting the limits humans and English.
The keywords used were cannabis, marijuana, marihuana, randomized,
double-blind, simple blind, human. The reference lists of all the relevant
articles was also analyzed to include all reports and reviews related to the
subject.
The search included studies and data available in English and French. For
each clinical study, the number of patients assessed, the type of study and
comparisons made, the products and the dosages used, and their efficacy and
adverse effects were identified.
4. (Endo)Cannabinoids in Epilepsy:
Epilepsy affects about 1% of the Several anecdotal reports suggest
worlds population. It is estimated that cannabis has anticonvulsant
that 2030% of epilepsies are properties and would be effective in
resistant to conventional drugs. treating partial epilepsies and
generalized tonic-clonic seizures.
There have been reports of
alterations of distinct components of
ECS both in animal models and in
humans suffering from epilepsy.
ECS-targeting compounds have been
shown to be effective against
epilepsy (Table 3).
ECS activation seems to prevent
seizures, whereas pharmacologically
blocking the ECS exerts a pro-
convulsive action (Table 3).
Cannabidiol (CBD) appears to be the
most promising CB in animal studies.
It has a powerful anticonvulsant
activity and minimal neurotoxicity.

In 1975 CBD and four of its
derivatives were shown to:
Protect mice against maximal
electroshock convulsions.
Potentiate pentobarbital sleeping-
time.
Reduce spontaneous motor activity.
CBD was found to be an effective
anticonvulsant with specific activity
comparable to antiepileptic drugs.
It was suggested for the treatment of
children with resistant epilepsy.
CBD has interesting therapeutic
potential, but additional research into
its anticonvulsant properties, either
alone or in combined with standard
drugs, is necessary.
4.1 Cannabis as a Treatment for Epilepsy:
Efficacy and Safety

Several studies suggest that However, current data are

cannabis would be effective in
treating partial epilepsies and
generalized tonic-clonic seizures,
still known as grand mal due to
its anticonvulsant properties.
Individuals who smoke marijuana
to treat their epilepsy, cessation of
cannabis use correlates with the
re-emergence of convulsive
seizures, while resuming
consumptioncontrols epilepsy
(Table 4).
insufficient to provide support for
the efficacy of CBs for reducing
seizure frequency.
A daily dose of 200300 mg of CBD
(520 mg/kg/day) is considered
safe.
The treatments lasted only for a
short period of time, therefore we
have no information about long
term effects.
Furthermore, drugdrug
interactions should be considered.
4.2 Adverse Effects and Toxicity:

Synthetic CBs: Marijuana:

Agitation Convulsions have only rarely been
associated with marijuana
Anxiety
exposures.
Emesis (vomiting)
Hallucinations
Psychosis
Tachycardia
Unresponsiveness.
4.3 Cannabinoid Use in Children:

Data for the safety and tolerability of 16 (87%) reported reduction in

high-CBD cannabis used on children
are not available.
Severe epilepsies in children are
characterized by: frequent seizures,
impaired quality of life, and
neurodevelopmental delays.
In the case where conventional
treatments fail, parents try to find
alternative treatments.
A Facebook survey was conducted
with 19 children using CBD enriched
cannabis as a treatment for epilepsy.
seizure frequency. Of these, 2 (11%)
reported being seizure free, while 8
(42%) reported at least an 80%
decrease in seizure frequency, and 6
(32%) reported a decrease of 25 to
60%.
Beneficial effects: better mood,
increased alertness, and improved
sleep.
Side effects: drowsiness and fatigue.
Currently a CBD based drug
(Epidiolex) is in clinical trial.
5. Conclusion