Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
1
2
Dr. Margaret
Gedde, Gedde
Whole Health LLC
and Realm of
Caring Foundation
and Dr. Edward H.
Maa, University of
Colorado School of
Medicine
(Submitted to be
published to
American Epilepsy
Society)
December 2013
Epilepsy Behav.
29(3):574-7. doi:
10.1016/j.yebeh.20
13.08.037.
Dr. Catherine
Jacobson, Ph.D.
Post-Doctoral
Scholar in
Neurology,
Stanford University
& UCSF; Dr.
Brenda E. Porter,
M.D., Ph.D.
Sanford University
Abstract
Whole Cannabis Extract of High Concentration Cannabidiol May Calm Seizures in
Highly Refractory Pediatric Epilepsies.
Survey of families with severely epileptic children. Of 11 families who treated their
children with high-CBD oil, eight reported that their children’s seizures had fallen by 98
to 100 percent. Of the 11, 8 reported 98-100% reduction, 1 reported 75% reduction, and 2
reported 20-45% reduction in weekly seizures at the end of three months. At three months,
5 of the 11 patients (50%) were seizure-free. Two children had Dravet Syndrome
(Dravet), four had Doose Syndrome (Doose), one had Lennox-Gastaut Syndrome (LGS),
one with metachromatic leukodystrophy, 1 with cortical dysplasia and two with idiopathic
epilepsy. The average number of antiepileptic drugs (AEDs) tried before using
cannabidiol-enriched cannabis was 10.
https://docs.com/YJM3
Report of a parent survey of cannabidiol-enriched cannabis use in pediatric
treatment-resistant epilepsy.
This survey explored the use of cannabidiol-enriched cannabis in children with treatmentresistant epilepsy. Thirteen children had Dravet syndrome, four had Doose syndrome, and
one each had LGS and idiopathic epilepsy. 16 (84%) of the 19 parents reported a
reduction in their child's seizure frequency while taking cannabidiol-enriched cannabis. Of
these, two (11%) reported complete seizure freedom, eight (42%) reported a greater than
80% reduction in seizure frequency, and six (32%) reported a 25-60% seizure reduction.
Other beneficial effects included increased alertness, better mood, and improved sleep.
Side effects included drowsiness and fatigue. The average number of antiepileptic drugs
(AEDs) tried before using cannabidiol-enriched cannabis was 12.
http://www.ncbi.nlm.nih.gov/pubmed/24237632
Comments
8 reported 98100% reduction,
1 reported 75%
reduction, and 2
reported 20-45%
reduction in
weekly seizures
at the end of
three months.
16 (84%) of the
19 parents
reported a
reduction in their
child's seizure
frequency while
taking
cannabidiolenriched
cannabis.
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
3
November 11,
2013
Excerpts from Dear
Colleague letter
from:
Francis Filloux,
M.D.
Chief, Division of
Pediatric
Neurology
The Glenn and Ben
Schmitt/Edgar
Chair of Pediatric
Neurology
Professor of
Pediatrics,
Neurology
University of Utah
School of Medicine
e-mail:
francis.filloux@hsc
.utah.edu
Abstract
I am writing to express my strong support for Utah families seeking to make a
specialized cannabis-oil product available to their children here in Utah. I am the
Division Director of Pediatric Neurology at the University of Utah and a member of
the Child Neurology Society.
Cannibidiol (CBD) is one of the cannabinoids or naturally occurring chemical
elements found in the natural product Cannabis, or Marijuana. There is extensive
"pre-clinical" data that indicates that CBD as a chemical is effective in reducing
epileptic activity, electrophysiologic disturbances analogous to epilepsy or in
blocking molecular pathways that are involved in the generation of seizures or
epilepsy. Thus, there is extensive and reproducible data demonstrating that, from
an experimental point of view, CBD holds great promise as an antiepileptic agent.
In addition to this, there have been recently publicized cases of children with severe
epilepsy who have experienced extraordinary seizure control and improvement in
their quality of life from natural substances that contain high content of CBD.
These substances are purposefully manufactured with high content of CBD (a nonpsychoactive component of cannabis) and very low or nearly undetectable levels of
tetrahydrocannabinol (THC) which is the "psychoactive" ingredient of cannabis or
marijuana
As a pediatric neurologist who cares for many children with severe epilepsy, l
believe any product that is actually legally available in the United States and is
legally taken by some of our citizens should be available to United States citizens
whether they be residents of Colorado or of Utah…
In this discussion, the following key points should be considered:
•
•
•
•
•
•
CBD oil is very high in CBD but has THC content that is as low as or lower
than other natural substances such as hemp-bas ed creams that currently can be
legally purchased in Uta h
CBD oil is not a psychoactive substance; it does not "produce a high" and
is not "mind-altering" in its effect.
CBD may be extremely effective in some cases: The anecdotal experience of
many patients and families is that CBD oil results in remarkable seizure control
with improvement in quality of life. (This is despite the fact that all these
children have previously been on numerous anti-seizure medications with
minimal benefit).
CBD appears to be safe: So far, experience with CBD oil and related products
containing CBD indicates that side effects are very limited or non-existent.
This alone is a very unusual property for a substance that may produce
remarkable seizure control.
CBD is not available currently in the US as a pharmaceutical product.
Thus, our patients in Utah currently can not access this potentially extremely
helpful treatment with CBD without physically moving to a state where they
can be legally treated with CBD oil or where they can participate in one of
two limited medium sized IND trials (which are only available currently at
UCSF [California] or NYU [New York])
Pediatric neurologists and physicians routinely recommend substances to
their patients that are not FDA-approved medications. There is no logical
reason that CBD oil should not be similarly available.
In summary, I would like to express my strong belief that CBD-based oils should be
available as soon as possibl e to Utah children with severe epilepsy.The substance is
not psychoactive or hallucinogenic, it contains less THC than do other materials that
can be legall y purchased in Utah, and it has absolutely no abuse potential. In Utah
Comments
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
4
April 18, 2013
Testimony of
Elizabeth Anne
Thiele, MD, PhD
Director, Pediatric
Epilepsy Program
Massachusetts
General Hospital
Department of
Public Health
public hearings on
proposed
regulations at
105 CMR 725.000
Abstract
My name is Dr. Elizabeth Anne Thiele, and I am the Director of the Pediatric Epilepsy
Service at Massachusetts General Hospital and a Professor in Neurology at Harvard
Medical School.
I received my medical degree and PhD from Johns Hopkins University School of
Medicine in Baltimore, Maryland and completed an internship and residency in pediatrics
at the Johns Hopkins Hospital. I also completed a second residency in child neurology and
a postdoctoral research fellowship in neurology at Children’s Hospital in Boston.
Based on a review of the literature and first-hand experience treating pediatric epilepsy
patients, it is my opinion that medical marijuana—and, particularly, the non-psychoactive
ingredient in medical marijuana, cannabidiol (CBD)—may have substantial medical
benefit for pediatric epilepsy patients, as well as significantly fewer adverse side effects
than many of the other anti-epileptic therapies available today.
Numerous studies performed in the past 40 years have demonstrated the anticonvulsant
effects of CBD both in animal models and in human adults. In a double blind, placebocontrolled study showing that CBD reduces seizure activity, the most commonly reported
side effect was somnolence, and no patients reported any psychotropic effects. Indeed,
studies suggest that CBD has no negative impact on psychomotor or psychological
functions. Although the impact of CBD on seizures has not yet been studied in the
pediatric population, several of my colleagues and I plan to commence a clinical trial in
the near future to demonstrate the safety, efficacy and tolerability of CBD in children with
intractable epilepsy.
My colleagues and I have witnessed the dramatic effect of CBD on many of our pediatric
patients. For example, I have a pediatric patient with severe intractable epilepsy who had
been experiencing up to 100 seizures every day, despite trials of 18 antiepileptic drugs.
After CBD was introduced into his treatment regimen, his seizures decreased
dramatically. He now has between 0 and 5 seizures a day. He is also more alert, and
turns out to have a wicked good sense of humor.
I have heard numerous similar reports from my colleagues practicing in California,
Colorado and abroad, where medical marijuana and/or pharmaceutical CBD are available.
These anecdotal reports are support by a recently completed survey conducted by
researchers at Stanford of parents of children with severe childhood epilepsies who are
treating their child’s seizures with high CBD to THC ratio marijuana plants. 70% of
parents reported a decrease in seizure frequency of >50% after starting this treatment, and
only 15% saw no change in their children’s seizure frequency. Additionally, these parents
reported very few negative side effects from marijuana use. In fact, the most commonly
reported side effects were better sleep, increased alertness and better mood. 11 of the 20
parents (55%) also were able to wean their children from an average of two anti-epileptic
drugs. Thus, not only does this survey suggest that CBD dramatically reduces seizure
activity in pediatric patients with intractable epilepsy, it also demonstrates an
improvement in the patients’ quality of life.
I recognize that use of medical marijuana to treat pediatric patients is a controversial
topic, and that it may not be appropriate in all circumstances. But, unquestionably, there
are numerous pediatric patients with intractable epilepsy residing in Massachusetts for
whom the use of high CBD to THC ratio marijuana plants may be the best available
treatment at this time.
Comments
For example, I
have a pediatric
patient with
severe
intractable
epilepsy who had
been
experiencing up
to 100 seizures
every day,
despite trials of
18 antiepileptic
drugs. After
CBD was
introduced into
his treatment
regimen, his
seizures
decreased
dramatically. He
now has between
0 and 5 seizures
a day. He is also
more alert, and
turns out to have
a wicked good
sense of humor.
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
Abstract
5
Br J Pharmacol.
2013
Oct;170(3):679-92.
doi:
10.1111/bph.12321
.
Cannabidivarinrich cannabis
extracts are
anticonvulsant in
mouse and rat via
a CB1 receptorindependent
mechanism.
Hill TD, et al.
BACKGROUND AND PURPOSE:
Epilepsy is the most prevalent neurological disease and is characterized by recurrent
seizures. Here, we investigate (i) the anticonvulsant profiles of cannabis-derived botanical
drug substances (BDSs) rich in cannabidivarin (CBDV) and containing cannabidiol
(CBD) in acute in vivo seizure models and (ii) the binding of CBDV BDSs and their
components at cannabinoid CB1 receptors.
EXPERIMENTAL APPROACH:
The anticonvulsant profiles of two CBDV BDSs (50-422 mg·kg(-1) ) were evaluated in
three animal models of acute seizure. Purified CBDV and CBD were also evaluated in an
isobolographic study to evaluate potential pharmacological interactions. CBDV BDS
effects on motor function were also investigated using static beam and grip strength
assays. Binding of CBDV BDSs to cannabinoid CB1 receptors was evaluated using
displacement binding assays.
KEY RESULTS:
CBDV BDSs exerted significant anticonvulsant effects in the pentylenetetrazole
(≥100 mg·kg(-1) ) and audiogenic seizure models (≥87 mg·kg(-1) ), and suppressed
pilocarpine-induced convulsions (≥100 mg·kg(-1) ). The isobolographic study revealed
that the anticonvulsant effects of purified CBDV and CBD were linearly additive when
co-administered. Some motor effects of CBDV BDSs were observed on static beam
performance; no effects on grip strength were found. The Δ(9) -tetrahydrocannabinol and
Δ(9) -tetrahydrocannabivarin content of CBDV BDS accounted for its greater affinity for
CB1 cannabinoid receptors than purified CBDV.
CONCLUSIONS AND IMPLICATIONS:
CBDV BDSs exerted significant anticonvulsant effects in three models of seizure that
were not mediated by the CB1 cannabinoid receptor and were of comparable efficacy with
purified CBDV. These findings strongly support the further clinical development of
CBDV BDSs for the treatment of epilepsy.
6
Drug Test Anal.
2013 Sep 4. doi:
10.1002/dta.1529.
Cannabis was extensively used as a medicine throughout the developed world in the
nineteenth century but went into decline early in the twentieth century ahead of its
emergence as the most widely used illicit recreational drug later that century. Recent
advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid
system (ECS) have re-ignited interest in cannabis-based medicines. The ECS has emerged
as an important physiological system and plausible target for new medicines. Its receptors
and endogenous ligands play a vital modulatory role in diverse functions including
immune response, food intake, cognition, emotion, perception, behavioural reinforcement,
motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption,
and various aspects of hormonal control. In disease it may act as part of the physiological
response or as a component of the underlying pathology. In the forefront of clinical
research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their
contrasting pharmacology will be briefly outlined. The therapeutic potential and possible
risks of drugs that inhibit the ECS will also be considered. This paper will then go on to
review clinical research exploring the potential of cannabinoid medicines in the following
indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable
nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS,
psychosis, epilepsy, addiction, and metabolic disorders. Copyright © 2013 John Wiley &
Sons, Ltd.
Therapeutic
potential of
cannabinoid
medicines.
Robson PJ.
Comments
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
7
Experimental
Neurology
2013 | 244 |
Complete | 43-50
Marijuana,
endocannabinoids
, and epilepsy:
Potential and
challenges for
improved
therapeutic
intervention
Mackenzie E.
Hofmann Charles
J. Frazier
Abstract
Phytocannabinoids isolated from the cannabis plant have broad potential in medicine that
has been well recognized for many centuries. It is presumed that these lipid soluble
signaling molecules exert their effects in both the central and peripheral nervous system in
large part through direct interaction with metabotropic cannabinoid receptors. These same
receptors are also targeted by a variety of endogenous cannabinoids including 2arachidonoyl glycerol and anandamide. Significant effort over the last decade has
produced an enormous advance in our understanding of both the cellular and the synaptic
physiology of endogenous lipid signaling systems. This increase in knowledge has left us
better prepared to carefully evaluate the potential for both natural and synthetic
cannabinoids in the treatment of a variety of neurological disorders. In the case of
epilepsy, long standing interest in therapeutic approaches that target endogenous
cannabinoid signaling systems are, for the most part, not well justified by available
clinical data from human epileptics. Nevertheless, basic science experiments have clearly
indicated a key role for endogenous cannabinoid signaling systems in moment to moment
regulation of neuronal excitability. Further it has become clear that these systems can both
alter and be altered by epileptiform activity in a wide range of in vitro and in vivo models
of epilepsy. Collectively these observations suggest clear potential for effective
therapeutic modulation of endogenous cannabinoid signaling systems in the treatment of
human epilepsy, and in fact, further highlight key obstacles that would need to be
addressed to reach that goal.
Słowa kluczowe
Catherine Jacobsen refers to this study when she states, “CBD differs from
currently available anti-seizure medications in two important ways. First, its
target is novel - most likely involving the endogenous cannabinoid system,
though the precise mechanism of CBD's anti-seizure effects are not known.”
8
Pertwee, R.G. et al. (2010) International Union of Basic and Clinical
Pharmacology. LXXIX. Cannabinoid receptors and their ligands:
beyond CB1 and CB2. Pharmacal Rev 62(4):588-631.
9
Br J Clin
Pharmacol. 2013
Feb;75(2):323-33.
Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous
disorders exerted through molecular mechanisms that are yet to be completely identified.
CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, antioxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential
medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and
Cannabidiol for
neurodegenerativ nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD,
based on the combination of its anti-inflammatory and anti-oxidant properties, is of
e disorders:
particular interest and is presently under intense preclinical research in numerous
important new
neurodegenerative disorders. In fact, CBD combined with Δ(9)-tetrahydrocannabinol is
clinical
already under clinical evaluation in patients with Huntington's disease to determine its
applications for
potential as a disease-modifying therapy. The neuroprotective properties of CBD do not
this
phytocannabinoid appear to be exerted by the activation of key targets within the endocannabinoid system for
plant-derived cannabinoids like Δ(9)-tetrahydrocannabinol, i.e. CB(1) and CB(2) receptors,
?
Fernández-Ruiz J, as CBD has negligible activity at these cannabinoid receptors, although certain activity at
et al.
the CB(2) receptor has been documented in specific pathological conditions (i.e. damage of
immature brain). Within the endocannabinoid system, CBD has been shown to have an
inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme),
thereby enhancing the action of these endogenous molecules on cannabinoid receptors,
which is also noted in certain pathological conditions. CBD acts not only through the
endocannabinoid system, but also causes direct or indirect activation of metabotropic
receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family
and also ion channels.
Comments
Cannabidiol (CBD) and Epilepsy Research
10
Date, Publication,
Authors
Abstract
Comments
Slim Evidence for
Cannabinoids for
Epilepsy
BACKGROUND: Marijuana appears to have anti-epileptic effects in animals. It is not
currently known if it is effective in patients with epilepsy. Some states in the United
States of America have explicitly approved its use for epilepsy. OBJECTIVES: To assess
the efficacy of marijuana, or one of marijuana's constituents in the treatment of people
with epilepsy. SEARCH METHODS: We searched the Cochrane Epilepsy Group
Specialized Register (May 15, 2012), the Cochrane Central Register of Controlled Trials
(CENTRAL issue 4 of 12, The Cochrane Library 2012),MEDLINE (PubMed, searched
on May 15, 2012), ISI Web of Knowledge
(May 15, 2012), CINAHL (EBSCOhost, May 15, 2012), and ClinicalTrials.gov (May 15,
2012). In addition, we included studies we personally knew about that were not found by
the searches, as well as references in the identified studies. SELECTION CRITERIA:
Randomized controlled trials (RCTs), whether blinded or not. DATA COLLECTION
AND ANALYSIS: Two authors independently selected trials for inclusion and extracted
data. The primary outcome investigated was seizure freedom at one year or more, or three
times the longest interseizure interval. Secondary outcomes included: responder rate at six
months or more, objective quality of life data, and adverse events. MAIN RESULTS: We
found four randomized reports which included a total of 48 patients, each of which used
cannabidiol as the treatment agent. One report was an abstract, and another was a letter to
the editor. Anti-epileptic drugs were continued in all. Details of randomisation were not
included in any study. There was no investigation of whether control and treatment groups
were the same or different. All the reports were low quality. The four reports only
answered the secondary outcome about adverse effects. None of the patients in the
treatment groups suffered adverse effects. AUTHORS' CONCLUSIONS: No reliable
conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment
for epilepsy. The dose of 200 to 300 mg daily of cannabidiol was safely administered to
small numbers of patients, for generally short periods of time, and so the safety of long
term cannabidiol treatment cannot be reliably assessed.
The references
for this article
are either
positive for CBD
or make no
mention of CBD.
John W. Miller,
MD, PhD
Commentary
Cannabinoids for
Epilepsy.
Gloss D, Vickrey
B. Cochrane
Database of
Systematic
Reviews. 2012;
Issue 6. Art.
References
1. Gross DW, Hamm J, Ashworth NL, Quigley D. Marijuana use and
epilepsy: Prevalence in patients of a tertiary care epilepsy center.
Neurology 2004;62:2095–2097. (Study below-indicates that patients with epilepsy
think medical marijuana helps)
2. Keeler MH, Reifler CB. Grand mal convulsions subsequent to marijuana
use: Case report. Dis Nerv Syst 1967;28:474–475. (One individual case report, can't
find any details)
3. Radwan MM, Elsohly MA, Slade D, Ahmed SA, Khan IA, Ross SA.
Biologically active cannabinoids from high-potency Cannabis sativa.
J Nat Prod 2009;72:906–911. (Describing nine active cannabinoids)
4. Karler R, Turkanis SA. The cannabinoids as potential antiepileptics. J
Clin Pharmacol 1981;21(suppl 8–9): S437–S448. (Study below-indicate CBP has
unique antiepileptic properties)
5. Wada JA, Wake A, Sato M, Corcoran ME. Antiepileptic and prophylactic
effects of tetrahydrocannabinoids in amygdaloid kindled cats.
Epilepsia 1975;16:503–510. (No reference of CBD)
6. Feigenbaum JJ, Bergmann F, Richmond SA, Mechoulam R, Nadler
V, Kloog Y, Sokolovsky M. Nonpsychotropic cannabinoid acts as a
functional N-methyl-D-aspartate receptor blocker. Proc Natl Acad Sci
U S A 1989;86:9584–9587. (Study on synthetic cannabinoid 7-hydroxy-delta 6tetrahydrocannabinol, not CBD)
7. Martin P, Consroe P. Cannabinoid induced behavioral convulsions in
rabbits. Science 1976;194:965–967. (Study below-special breed of rabbit susceptible to
THC induced seizures)
8. Brust JCM, Ng SK, Hauser AW, Susser M. Marijuana use and the risk of
new onset seizures. Trans Am Clin Climatol Assoc 1992;103:176–181. (Study below-this
study suggests marijuana is anticonvulsant)
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
11
12
Consroe, P., et
al. (1991)
Controlled
clinical trial of
cannabidiol in
huntington's
disease. Pharm
Biochem &
Behav 40: 701708.
Philos Trans R Soc
Lond B Biol Sci.
2012 Dec
5;367(1607):335363.
Targeting the
endocannabinoid
system with
cannabinoid
receptor agonists:
pharmacological
strategies and
therapeutic
possibilities.
Pertwee RG.
Abstract
Catherine Jacobsen refers to this study when she states “CBD is the secondmost prevalent cannabinoid found in the cannabis plant. It is not psychoactive
and has been shown to be well-tolerated and safe for
use in adults.”
Consroe, P., et al. (1991) Controlled clinical trial of cannabidiol in huntington's
disease. Pharm
Biochem & Behav 40: 701-708.
Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by
endogenously released 'endocannabinoids' or exogenously administered compounds in a
manner that reduces the symptoms or opposes the underlying causes of several disorders
in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2)
receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can
be prescribed for the amelioration of chemotherapy-induced nausea and vomiting
(Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of
cancer pain and/or management of neuropathic pain and spasticity in adults with multiple
sclerosis (Sativex). This review mentions several possible additional therapeutic targets
for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety,
depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke,
cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and
hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies
for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These
are strategies that involve (i) targeting cannabinoid receptors located outside the bloodbrain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii)
targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2)
receptors, and/or (v) adjunctive 'multi-targeting'.
Comments
Cannabidiol (CBD) and Epilepsy Research
13
Date, Publication,
Authors
Abstract
Comments
Cochrane Database
Syst Rev. 2012 Jun
13
BACKGROUND:
Marijuana appears to have anti-epileptic effects in animals. It is not currently known if it
is effective in patients with epilepsy. Some states in the United States of America have
explicitly approved its use for epilepsy.
OBJECTIVES:
To assess the efficacy of marijuana, or one of marijuana's constituents in the treatment of
people with epilepsy.
SEARCH METHODS:
We searched the Cochrane Epilepsy Group Specialized Register (May 15, 2012), the
Cochrane Central Register of Controlled Trials (CENTRAL issue 4 of 12, The Cochrane
Library 2012),MEDLINE (PubMed, searched on May 15, 2012), ISI Web of Knowledge
(May 15, 2012), CINAHL (EBSCOhost, May 15, 2012), and ClinicalTrials.gov (May 15,
2012). In addition, we included studies we personally knew about that were not found by
the searches, as well as references in the identified studies.
SELECTION CRITERIA:
Randomized controlled trials (RCTs), whether blinded or not.
DATA COLLECTION AND ANALYSIS:
Two authors independently selected trials for inclusion and extracted data. The primary
outcome investigated was seizure freedom at one year or more, or three times the longest
interseizure interval. Secondary outcomes included: responder rate at six months or more,
objective quality of life data, and adverse events.
MAIN RESULTS:
We found four randomized reports which included a total of 48 patients, each of which
used cannabidiol as the treatment agent. One report was an abstract, and another was a
letter to the editor. Anti-epileptic drugs were continued in all. Details of randomisation
were not included in any study. There was no investigation of whether control and
treatment groups were the same or different. All the reports were low quality.The four
reports only answered the secondary outcome about adverse effects. None of the patients
in the treatment groups suffered adverse effects.
AUTHORS' CONCLUSIONS:
No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as
a treatment for epilepsy. The dose of 200 to 300 mg daily of cannabidiol was safely
administered to small numbers of patients, for generally short periods of time, and so the
safety of long term cannabidiol treatment cannot be reliably assessed.
In the 3+ years
of researching
Jackson's health
the Cochrane
database has
proven to
reliably support
nothing
including IVIG
and steroids for
epilepsy. Also
similar to IVIG
and steroids, the
research quality
and conclusions
are highly
suspect and
easily
contradicted.
Cannabinoids for
epilepsy.
Gloss D, Vickrey
B.
14
Epilepsy Behav.
2012 Dec;
25(4):563-6.
Seizure
exacerbation in
two patients with
focal epilepsy
following
marijuana
cessation.
Hegde M, et al.
While animal models of epilepsy suggest that exogenous cannabinoids may have
anticonvulsant properties, scant evidence exists for these compounds' efficacy in humans.
Here, we report on two patients whose focal epilepsy was nearly controlled through
regular outpatient marijuana use. Both stopped marijuana upon admission to our epilepsy
monitoring unit (EMU) and developed a dramatic increase in seizure frequency
documented by video-EEG telemetry. These seizures occurred in the absence of other
provocative procedures, including changes to anticonvulsant medications. We review
these cases and discuss mechanisms for the potentially anticonvulsant properties of
cannabis, based on a review of the literature.
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
15
Seizure. 2012
Jun;21(5):344-52.
Cannabidiol
exerts anticonvulsant effects
in animal models
of temporal lobe
and partial
seizures.
Jones NA, et al.
16
Pharmaceuticals
(Basel). 2012 May
21;5(5):529-52.
.
Cannabidiol in
humans-the quest
for therapeutic
targets.
Zhornitsky S,
Potvin S.
Abstract
Cannabis sativa has been associated with contradictory effects upon seizure states despite
its medicinal use by numerous people with epilepsy. We have recently shown that the
phytocannabinoid cannabidiol (CBD) reduces seizure severity and lethality in the wellestablished in vivo model of pentylenetetrazole-induced generalised seizures, suggesting
that earlier, small-scale clinical trials examining CBD effects in people with epilepsy
warrant renewed attention. Here, we report the effects of pure CBD (1, 10 and 100mg/kg)
in two other established rodent seizure models, the acute pilocarpine model of temporal
lobe seizure and the penicillin model of partial seizure. Seizure activity was video
recorded and scored offline using model-specific seizure severity scales. In the pilocarpine
model CBD (all doses) significantly reduced the percentage of animals experiencing the
most severe seizures. In the penicillin model, CBD (≥ 10 mg/kg) significantly decreased
the percentage mortality as a result of seizures; CBD (all doses) also decreased the
percentage of animals experiencing the most severe tonic-clonic seizures. These results
extend the anti-convulsant profile of CBD; when combined with a reported absence of
psychoactive effects, this evidence strongly supports CBD as a therapeutic candidate for a
diverse range of human epilepsies.
Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, is attracting
growing attention in medicine for its anxiolytic, antipsychotic, antiemetic and antiinflammatory properties. However, up to this point, a comprehensive literature review of
the effects of CBD in humans is lacking. The aim of the present systematic review is to
examine the randomized and crossover studies that administered CBD to healthy controls
and to clinical patients. A systematic search was performed in the electronic databases
PubMed and EMBASE using the key word "cannabidiol". Both monotherapy and
combination studies (e.g., CBD + ∆9-THC) were included. A total of 34 studies were
identified: 16 of these were experimental studies, conducted in healthy subjects, and 18
were conducted in clinical populations, including multiple sclerosis (six studies),
schizophrenia and bipolar mania (four studies), social anxiety disorder (two studies),
neuropathic and cancer pain (two studies), cancer anorexia (one study), Huntington's
disease (one study), insomnia (one study), and epilepsy (one study). Experimental studies
indicate that a high-dose of inhaled/intravenous CBD is required to inhibit the effects of a
lower dose of ∆9-THC. Moreover, some experimental and clinical studies suggest that
oral/oromucosal CBD may prolong and/or intensify ∆9-THC-induced effects, whereas
others suggest that it may inhibit ∆9-THC-induced effects. Finally, preliminary clinical
trials suggest that high-dose oral CBD (150-600 mg/d) may exert a therapeutic effect for
social anxiety disorder, insomnia and epilepsy, but also that it may cause mental sedation.
Potential pharmacokinetic and pharmacodynamic explanations for these results are
discussed.
Comments
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
17
Pharmacol Ther.
2012 Jan;
133(1):79-97.
Phytocannabinoid
s as novel
therapeutic agents
in CNS disorders.
Hill AJ, et al.
18
J Pharmacol Exp
Ther. 2010 Feb;
332(2):569-77.
Cannabidiol
displays
antiepileptiform
and antiseizure
properties in vitro
and in vivo.
Jones NA, et al.
Abstract
The Cannabis sativa herb contains over 100 phytocannabinoid (pCB) compounds and has
been used for thousands of years for both recreational and medicinal purposes. In the past
two decades, characterisation of the body's endogenous cannabinoid (CB)
(endocannabinoid, eCB) system (ECS) has highlighted activation of central CB(1)
receptors by the major pCB, Δ(9)-tetrahydrocannabinol (Δ(9)-THC) as the primary
mediator of the psychoactive, hyperphagic and some of the potentially therapeutic
properties of ingested cannabis. Whilst Δ(9)-THC is the most prevalent and widely
studied pCB, it is also the predominant psychotropic component of cannabis, a property
that likely limits its widespread therapeutic use as an isolated agent. In this regard,
research focus has recently widened to include other pCBs including cannabidiol (CBD),
cannabigerol (CBG), Δ(9)tetrahydrocannabivarin (Δ(9)-THCV) and cannabidivarin
(CBDV), some of which show potential as therapeutic agents in preclinical models of
CNS disease. Moreover, it is becoming evident that these non-Δ(9)-THC pCBs act at a
wide range of pharmacological targets, not solely limited to CB receptors. Disorders that
could be targeted include epilepsy, neurodegenerative diseases, affective disorders and the
central modulation of feeding behaviour. Here, we review pCB effects in preclinical
models of CNS disease and, where available, clinical trial data that support therapeutic
effects. Such developments may soon yield the first non-Δ(9)-THC pCB-based medicines.
Catherine Jacobsen refers to this study (and the next two) when she states,
“Four patients became seizure-free for the duration of the four and a half
month study. Three patients experienced a reduction in their seizure
burden, and one patient did not respond to CBD. The most often cited side
effect was mild drowsiness. CBD has been shown to reduce the seizure
burden in animal models of epilepsy, as well as to reduce epileptiform
activity in brain slice models.”
Plant-derived cannabinoids (phytocannabinoids) are compounds with emerging
therapeutic potential. Early studies suggested that cannabidiol (CBD) has anticonvulsant
properties in animal models and reduced seizure frequency in limited human trials. Here,
we examine the antiepileptiform and antiseizure potential of CBD using in vitro
electrophysiology and an in vivo animal seizure model, respectively. CBD (0.01-100
muM) effects were assessed in vitro using the Mg(2+)-free and 4-aminopyridine (4-AP)
models of epileptiform activity in hippocampal brain slices via multielectrode array
recordings. In the Mg(2+)-free model, CBD decreased epileptiform local field potential
(LFP) burst amplitude [in CA1 and dentate gyrus (DG) regions] and burst duration (in all
regions) and increased burst frequency (in all regions). In the 4-AP model, CBD
decreased LFP burst amplitude (in CA1 only at 100 muM CBD), burst duration (in CA3
and DG), and burst frequency (in all regions). CBD (1, 10, and 100 mg/kg) effects were
also examined in vivo using the pentylenetetrazole model of generalized seizures. CBD
(100 mg/kg) exerted clear anticonvulsant effects with significant decreases in incidence of
severe seizures and mortality compared with vehicle-treated animals. Finally, CBD acted
with only low affinity at cannabinoid CB(1) receptors and displayed no agonist activity in
[(35)S]guanosine 5'-O-(3-thio)triphosphate assays in cortical membranes. These findings
suggest that CBD acts, potentially in a CB(1) receptor-independent manner, to inhibit
epileptiform activity in vitro and seizure severity in vivo. Thus, we demonstrate the
potential of CBD as a novel antiepileptic drug in the unmet clinical need associated with
generalized seizures.
Jones, N.A., et al. (2010) Cannabidiol displays anti-epileptiform and antiseizure properties in vitro
and in vivo. J Pharmacal Exp Ther 332: 569-577.
Comments
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
19
Eur J Pharmacol.
1982 Sep 24;83(34):293-8.
Effects of
cannabidiol on
behavioral
seizures caused by
convulsant drugs
or current in
mice.
Consroe P, et al.
Abstract
Catherine Jacobsen refers to this study when she comments about side effects.
See #18 above.
In mice, running, clonic and tonic convulsions and lethality were assessed following
transcorneal (electroshock) current or convulsant drugs, each administered alone and after
cannabidiol (CBD) pretreatment. CBD prevented tonic convulsions caused by a
convulsant current (CC) 99.99, and by the convulsant dose (CD) 99.99 values of gammaaminobutyric acid (GABA) inhibitors, 3-mercaptoproprionic acid (3MPA), picrotoxin
(PIC), isonicotinic acid hydrazine (INH), pentylenetetrazol (PTZ) and bicuculline (BIC).
Rankorder potencies, based on the antitonic ED50 of CBD, were: 3MPA greater than PIC
= current = PTZ = BIC. Further, CBD prevented 3MPA-induced lethality, but failed to
prevent the occurrence of the other behavioral endpoints of the above treatments. CBD
also failed to prevent convulsions and lethality caused by the CD 99.99 of strychnine, a
glycine antagonist. The differential effects of CBD suggest that the cannabinoid acts to
inhibit seizure spread in the CNS by an action on GABA, but not glycine, mechanisms.
Consroe, P., Benedito, M.A., Leite, J.R., Carlini, E.A. & R. Mechoulam. Effects of cannabidiol on
behavioral seizures caused by convulsant drugs or current in mice. Eur J Pharmacol. 1982; 83(3-4):
293-8.
20
J Clin Pharmacol.
1981 Aug-Sep;
21(8-9 Suppl):
437S-448S.
The cannabinoids
as potential
antiepileptics.
Karler R, Turkanis
SA.
21
Catherine Jacobsen refers to this study when she comments about side effects.
See #18 above.
Comparative studies of the anticonvulsant properties of the cannabinoids and prototype
antiepileptic drugs in numerous animal seizure models demonstrate that (1) as an
anticonvulsant, cannabidiol (CBD), in contrast to delta 9-tetrahydrocannabinol (THC), is
relatively selective in terms of both central nervous system (CNS), depressant and
excitatory properties; (2) the potency of cannabidiol, unlike that of phenytoin and
phenobarbital, varies greatly with the species; (3) the large potency difference between the
cannabinoids and the antiepileptics in the mouse appears to be due to dispositional
differences, because brain concentrations of all the drugs are very similar; (4) tolerance to
the anticonvulsant properties of cannabidiol is not a prominent feature; in three seizure
models, tolerance developed in one, but "reverse tolerance" developed in the other two;
and (5) the results of a study of the electrophysiologic mechanisms of action indicate that
cannabidiol produces some unique effects and that its spectrum of antiepileptic activity
may be different from that of the prototype drugs. The anticonvulsant nature of
cannabidiol suggests that it has a therapeutic potential in at least three of the four major
types of epilepsy: grand mal, cortical focal, and complex partial seizures.
Karler, R., et al. (1981) The Cannabinoids as Potential Antiepileptics. J Clin
Pharmacol21: 437S448S.
Catherine Jacobsen states, “CBD is currently in Schedule I of the
Controlled Substances Act (GSA) in the United States. However, there is
precedent for both NIH funding of and FDA approval for clinical trials in
adults using CBD” referring to the following three trials:
NIH Project 10: OA027781 Cannabidiol as treatment intervention for opiate
relapse.
Clinical TriaiiO: NCT01311778 Study to test the safety and efficacy of
cannabidiol as a treatment intervention for opioid relapse.
Clinical Trial 10: NCT 00530764 A study of Sativex® for pain relief in patients
with advanced
malignancy.
Comments
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
Abstract
Comments
Mice were used as subjects in this study. Immune cells that target and harm the
brain were treated with either CBD or THC. In both cases, the immune cells
produced fewer inflammatory molecules, particularly one strongly associated with
multiple sclerosis. (This summary is from an article in ScienceDaily; the article is
based on materials provided by American Friends of Tel Aviv University. )
22
Ewa Kozela, Ana Juknat, Nathali Kaushansky, Neta Rimmerman, Avraham BenNun, Zvi Vogel. Cannabinoids Decrease the Th17 Inflammatory Autoimmune
Phenotype. Journal of Neuroimmune Pharmacology, 2013; DOI:
10.1007/s11481-013-9493-1
http://www.sciencedaily.com/releases/2013/10/131007132253.htm
Research results from University of Reading (UK)’s Department of Pharmacy and School of
Psychology, in collaboration with GW Pharma and Otsuka Pharmaceuticals. In the study,
“cannabidivarin (CBDV), a natural compound in cannabis, has the potential to prevent more seizures
with few side effects caused by many existing anti-epilepsy drugs.”
23
http://www.reading.ac.uk/pcls/news/pcls-120912.aspx
The International Association for Cannabinoid Medicines has compiled spreadsheet providing
information from 360 clinical studies and case reports on the use of cannibas. Each entry includes
information such as topic, authors, year, type of treatment, and summary of results.
24
http://www.cannabis-med.org/studies/study.php
Pharmacol
Biochem Behav.
2009
Aug;93(2):91-6.
Cannabidiol
reverses the
reduction in social
interaction
produced by low
dose Delta(9)tetrahydrocannab
inol in rats.
Malone DT, et al.
While Delta(9)-tetrahydrocannabinol (THC) is the main psychoactive constituent of the
cannabis plant, a non-psychoactive constituent is cannabidiol (CBD). CBD has been
implicated as a potential treatment of a number of disorders including schizophrenia and
epilepsy and has been included with THC in a 1:1 combination for the treatment of
conditions such as neuropathic pain. This study investigated the effect of THC and CBD,
alone or in combination, on some objective behaviours of rats in the open field. Pairs of
rats were injected with CBD or vehicle followed by THC or vehicle and behaviour in the
open field was assessed for 10 min. In vehicle pretreated rats THC (1 mg/kg) significantly
reduced social interaction between rat pairs. Treatment with CBD had no significant effect
alone, but pretreatment with CBD (20 mg/kg) reversed the THC-induced decreases in
social interaction. A higher dose of THC (10 mg/kg) produced no significant effect on
social interaction. However, the combination of high dose CBD and high dose THC
significantly reduced social interaction between rat pairs, as well as producing a
significant decrease in locomotor activity. This data suggests that CBD can reverse social
withdrawal induced by low dose THC, but the combination of high dose THC and CBD
impairs social interaction, possibly by decreasing locomotor activity.
Summary of
studies
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
Rev Neurol Dis.
2007 Spring;
4(2):103-6.
Marijuana: an
effective
antiepileptic
treatment in
partial epilepsy?
A case report and
review of the
literature.
Abstract
Although more data are needed, animal studies and clinical experience suggest that
marijuana or its active constituents may have a place in the treatment of partial epilepsy.
Here we present the case of a 45-year-old man with cerebral palsy and epilepsy who
showed marked improvement with the use of marijuana. This case supports other
anecdotal data suggesting that marijuana use may be a beneficial adjunctive treatment in
some patients with epilepsy. Although challenging because of current federal regulations,
further studies are needed to examine the role of marijuana in the treatment of this
disorder.
Mortati K,
Dworetzky B,
Devinsky O.
The
Endocannabinoid
System Controls
Key Epileptogenic
Circuits in the
Hippocampus
Krisztina Monory,
et, al.,
Neuron. 2006
August 17; 51(4):
455–466.
Balanced control of neuronal activity is central in maintaining function and viability of
neuronal circuits. The endocannabinoid system tightly controls neuronal excitability.
Here, we show that endocannabinoids directly target hippocampal glutamatergic neurons
to provide protection against acute epileptiform seizures in mice. Functional CB1
cannabinoid receptors are present on glutamatergic terminals of the hippocampal
formation, colocalizing with vesicular glutamate transporter 1 (VGluT1). Conditional
deletion of the CB1 gene either in cortical glutamatergic neurons or in forebrain
GABAergic neurons, as well as virally induced deletion of the CB1 gene in the
hippocampus, demonstrate that the presence of CB1 receptors in glutamatergic
hippocampal neurons is both necessary and sufficient to provide substantial endogenous
protection against kainic acid (KA)-induced seizures. The direct endocannabinoidmediated control of hippocampal glutamatergic neurotransmission may constitute a
promising therapeutic target for the treatment of disorders associated with excessive
excitatory neuronal activity.
Comments
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
18 August 2005
A tale of two
cannabinoids:
The therapeutic
rationale for
combining
tetrahydrocannabin
ol and cannabidiol
Ethan Russo,
Geoffrey W. Guy
GW Pharmaceuticals,
University of
Washington School of
Medicine,
University of
Montana Department
of Pharmaceutical
Sciences
Neuro Endocrinol
Lett.
2004 Feb-Apr;
25(1-2):40-4.
On the
application of
cannabis in
paediatrics and
epileptology.
Abstract
Comments
This study examines the current knowledge of physiological and clinical effects of
tetrahydrocannabinol (THC) and cannabidiol (CBD) and presents a rationale for their
combination in pharmaceutical preparations.
Cannabinoid and vanilloid receptor effects as well as non-receptor mechanisms are
explored, such as the capability of THC and CBD to act as anti-inflammatory substances
independent of cyclo-oxygenase (COX) inhibition. CBD is demonstrated to antagonise
some undesirable effects of THC including intoxication, sedation and tachycardia, while
contributing analgesic, anti-emetic, and anti-carcinogenic properties in its own right. In
modern clinical trials, this has permitted the administration of higher doses of THC,
providing evidence for clinical efficacy and safety for cannabis based extracts in treatment
of spasticity, central pain and lower urinary tract symptoms in multiple sclerosis, as well
as sleep disturbances, peripheral neuropathic pain, brachial plexus avulsion symptoms,
rheumatoid arthritis and intractable cancer pain.
Prospects for future application of whole cannabis extracts in neuroprotection, drug
dependency, and neoplastic disorders are further examined. The hypothesis that the
combination of THC and CBD increases clinical efficacy while reducing adverse events is
supported.
An initial report on the therapeutic application of delta 9-THC (THC) (Dronabinol,
Marinol) in 8 children resp. adolescents suffering from the following conditions, is given:
neurodegenerative disease, mitochondriopathy, posthypoxic state, epilepsy, posttraumatic
reaction. THC effected reduced spasticity, improved dystonia, increased initiative (with
low dose), increased interest in the surroundings, and anticonvulsive action. The doses
ranged from 0.04 to 0.12 mg/kg body weight a day. The medication was given as an oily
solution orally in 7 patients, via percutaneous gastroenterostomy tube in one patient. At
higher doses disinhibition and increased restlessness were observed. In several cases
treatment was discontinued and in none of them discontinuing resulted in any problems.
The possibility that THC-induced effects on ion channels and transmitters may explain its
therapeutic activity seen in epileptic patients is discussed.
Lorenz R.
Neurology. 2004
Jun 8;62(11):20957.
Marijuana use
and epilepsy:
prevalence in
patients of a
tertiary care
epilepsy center.
Gross DW, Hamm
J, Ashworth NL,
Quigley D.
The authors sought to determine the prevalence of marijuana use in patients with epilepsy
by performing a telephone survey in a tertiary care epilepsy center. Twenty-one percent of
subjects had used marijuana in the past year with the majority of active users reporting
beneficial effects on seizures. Twenty-four percent of all subjects believed marijuana was
an effective therapy for epilepsy. Despite limited evidence of efficacy, many patients with
epilepsy believe marijuana is an effective therapy for epilepsy and are actively using it.
Author of 2012
Cochrane
database review
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
Neuropsychopharm
acology (2004)
29, 417–426
Effects of
Cannabidiol
(CBD) on
Regional Cerebral
Blood
Flow
Jose´ Alexandre de
Souza Crippa*, et
al.
1Department of
Neuropsychiatry
and Medical
Psychology,
Faculty of
Medicine of
Ribeira˜o Preto,
University of Sa˜o
Paulo, Brazil;
Abstract
Comments
Animal and human studies have suggested that cannabidiol (CBD) may possess anxiolytic
properties, but how these effects are mediated centrally is unknown. The aim of the
present study was to investigate this using functional neuroimaging. Regional cerebral
blood flow (rCBF) was measured at rest using 99mTc-ECD SPECT in 10 healthy male
volunteers, randomly divided into two groups of five subjects.
Each subject was studied on two occasions, 1 week apart. In the first session, subjects
were given an oral dose of CBD (400 mg) or placebo, in a double-blind procedure.
SPECT images were acquired 90 min after drug ingestion. The Visual Analogue Mood
Scale was applied to assess subjective states. In the second session, the same procedure
was performed using the drug that had not been administered in the previous session.
Within-subject between-condition rCBF comparisons were performed using statistical
parametric mapping (SPM).
CBD significantly decreased subjective anxiety and increased mental sedation, while
placebo did not induce significant changes. Assessment of brain regions where anxiolytic
effects of CBD were predicted a priori revealed two voxel clusters of significantly
decreased ECD uptake in the CBD relative to the placebo condition (po0.001, uncorrected
for multiple comparisons). These included a medial temporal cluster encompassing the
left amygdala–hippocampal complex, extending into the hypothalamus, and a second
cluster in the left posterior cingulate gyrus. There was also a cluster of greater activity
with CBD than placebo in the left parahippocampal gyrus
(po0.001). These results suggest that CBD has anxiolytic properties, and that these effects
are mediated by an action on limbic and paralimbic brain areas.
Department of
Psychological
Medicine, Section
of Neuroimaging,
Institute of
Psychiatry,
University
of London, UK
Cannabinoids as
antioxidants and
neuroprotectants
United States
Patent
6,630,507
Hampson , et al.
October 7, 2003
Cannabinoids have been found to have antioxidant properties, unrelated to NMDA
receptor antagonism. This new found property makes cannabinoids useful in the treatment
and prophylaxis of wide variety of oxidation associated diseases, such as ischemic, agerelated, inflammatory and autoimmune diseases. The cannabinoids are found to have
particular application as neuroprotectants, for example in limiting neurological damage
following ischemic insults, such as stroke and trauma, or in the treatment of
neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and HIV
dementia. Nonpsychoactive cannabinoids, such as cannabidoil, are particularly
advantageous to use because they avoid toxicity that is encountered with psychoactive
cannabinoids at high doses useful in the method of the present invention. A particular
disclosed class of cannabinoids useful as neuroprotective antioxidants is formula (I)
wherein the R group is independently selected from the group consisting of H, CH.sub.3,
and COCH.sub.3.
In 2003, the U.S.
government
patented
cannabinoids,
including those
in marijuana
based on these
chemicals'
prevention of
trauma- and agerelated brain
damage
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
Abstract
Cannabidiol: An
Overview of Some
Pharmacological
Aspects
Cannabidiol (CBD) was first isolated from the cannabis plant in the late 1930s and early
1940s, and its structure was elucidated in 1963. For an introduction to the chemistry of
CBD, see Mechoulam and Hanus. No pharmacological work was reported on CBD until
the early 1970s, except the determination that it had no cannabis-like activity in vivo.
Over the next few years, some work was reported, particularly on its anticonvulsive
effects. Later, antianxiety effects were noted, and some of its actions on the immune
system were explored. More recently, its effects on nausea, as an antioxidant in biological
systems and as an antirheumatoid arthritis drug, were reported. The present review
summarizes these advances. Zuardi et al, have recently critically discussed the effects of
CBD on some of these states. To avoid duplication, we emphasize in this review the
antinausea and immune system effects, including rheumatoid arthritis, that are not
evaluated by Zuardi et al.
Journal of Clinical
Pharmacology,
2002;42:11S-19S
Raphael Mechoulam,
Linda A. Parker, and
Ruth Gallily
CBD: ANTICONVULSIVE EFFECTS
In the early 1970s, several groups found that CBD was active in reducing or blocking
convulsions produced in experimental animals by a variety of procedures. The CBD
effects were comparable to those of diphenylhydantion (DPH) and other drugs, which are
clinically effective in major seizures. CBD was also found to enhance the anticonvulsant
potency of DPH and phenobarbital. Karler and Turkanis compared the effects of CBD and
THC in the maximal electroshock test in mice, which measures anticonvulsant activity.
The ED50 of CBD (118 mg/kg) was close to that of Δ9-THC (101 mg/kg). In frogs (Rana
pipiens), both cannabinoids were about 1000 times more active, but only in the summer.
In the winter, the frogs were not responsive to either cannabinoid, even at massive doses.
However, in another assay—the pentylenetetrazol minimal-seizure threshold test in
mice—differences between the activities of CBD and THC were noted. It was assumed
that THC and CBD act by different mechanisms, with CBD more closely resembling the
well established antiepileptics at that time (e.g., phenobarbital and DPH) than does Δ9THC. Indeed, when conformational energy maps were computed and compared for DPH
and CBD, it was noted that the spatial relationship between the two rings in the two drugs
was similar and close to the respective structures in the crystal. This was supported by 1H
and 13C NMR measurements.
It was also found that both compounds fulfill the stereochemical requirements suggested
for anticonvulsant drug action. The early preclinical anticonvulsant work is well reviewed.
Consroe, in a more recent review, has suggested that CBD is largely inactive in animal
models of absence seizures produced by electroshock or chemoshock models. However, it
is active against cortical focal seizures produced by topical application of convulsant
metals or limbic seizures produced by electrical stimulation or kindling, as well as in
generalized maximal (tonic-clonic) seizures produced by electroshock or GABAinhibiting drugs.
Both CBD enantiomers are anticonvulsive. It is quite possible that they act by different
mechanisms. While the natural (–) CBD does not bind to the central cannabinoid receptor,
CB1, the synthetic (+) CBD has recently been shown to bind to CB1. The mechanism of
(–) CBD anticonvulsive activity is unknown; however, it is reasonable to assume that (+)
CBD, like THC, acts by activation of CB1. Recently, Wallace et al compared the
anticonvulsant effects of THC with those of CBD. The effects of THC could be blocked
with a cannabinoid receptor antagonist, while those of CBD could not. The authors thus
confirmed that the effects of CBD are not CB1 receptor mediated. These conclusions
support the early observation by Karler and Turkanis. CBD has very low toxicity. LD50
on IV administration
to the rhesus monkey was 212 mg/kg. The oral LD50 could not be established, but it was
pointed out that “the results obtained with prolonged oral CBD treatment should be
viewed with the knowledge that the oral route requires 20-50 times larger cannabinoid
dose than the i.v. route to initiate severe intoxication.” CBD did not elicit signs of CNS
inhibition or stimulation and did not cause autonomic aberrations. Clinical measurements,
eye examinations, and EKG recordings were normal. There were no significant alterations
in growth rates.
Comments
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
Cannabinoids on
the brain.
Andrew J Irving,
Mark G Rae,
Angela A Coutts
TheScientificWorl
dJOURNAL
(Impact Factor:
1.73). 04/2002;
2:632-48.
Epilepsia. 2001
Oct;42(10):126672.
Alcohol and
marijuana: effects
on epilepsy and
use by patients
with epilepsy.
Gordon E,
Devinsky O.
Proc Natl Acad Sci
U S A. 1989
Dec;86(23):9584-7.
Nonpsychotropic
cannabinoid acts
as a functional Nmethyl-Daspartate receptor
blocker.
Feigenbaum JJ, et
al.
Abstract
Cannabis has a long history of consumption both for recreational and medicinal uses.
Recently there have been significant advances in our understanding of how cannabis and
related compounds (cannabinoids) affect the brain and this review addresses the current
state of knowledge of these effects. Cannabinoids act primarily via two types of receptor,
CB1 and CB2, with CB1 receptors mediating most of the central actions of cannabinoids.
The presence of a new type of brain cannabinoid receptor is also indicated. Important
advances have been made in our understanding of cannabinoid receptor signaling
pathways, their modulation of synaptic transmission and plasticity, the cellular targets of
cannabinoids in different central nervous system (CNS) regions and, in particular, the role
of the endogenous brain cannabinoid (endocannabinoid) system. Cannabinoids have
widespread actions in the brain: in the hippocampus they influence learning and memory;
in the basal ganglia they modulate locomotor activity and reward pathways; in the
hypothalamus they have a role in the control of appetite. Cannabinoids may also be
protective against neurodegeneration and brain damage and exhibit anticonvulsant
activity. Some of the analgesic effects of cannabinoids also appear to involve sites within
the brain. These advances in our understanding of the actions of cannabinoids and the
brain endocannabinoid system have led to important new insights into neuronal function
which are likely to result in the development of new therapeutic strategies for the
treatment of a number of key CNS disorders.
We review the safety of alcohol or marijuana use by patients with epilepsy. Alcohol
intake in small amounts (one to two drinks per day) usually does not increase seizure
frequency or significantly affect serum levels of antiepileptic drugs (AEDs).
Animal and human research on the effects of marijuana on seizure activity are
inconclusive. There are currently insufficient data to determine whether occasional or
chronic marijuana use influences seizure frequency. Some evidence suggests that
marijuana and its active cannabinoids have antiepileptic effects, but these may be specific
to partial or tonic-clonic seizures. In some animal models, marijuana or its constituents
can lower the seizure threshold. Preliminary, uncontrolled clinical studies suggest that
cannabidiol may have antiepileptic effects in humans. Marijuana use can transiently
impair short-term memory, and like alcohol use, may increase noncompliance with AEDs.
Marijuana use or withdrawal could potentially trigger seizures in susceptible patients.
Binding studies using the enantiomers of the synthetic cannabinoid 7-hydroxy-delta 6tetrahydrocannabinol 1,1-dimethylheptyl homolog in preparations of rat brain cortical
membranes reveal that the (+)-(3S,4S) enantiomer HU-211 blocks N-methyl-D-aspartate
(NMDA) receptors in a stereospecific manner and that the interaction occurs at binding
sites distinct from those of other noncompetitive NMDA antagonists or of glutamate and
glycine. Moreover, HU-211 induces stereotype and locomotor hyperactivity in mice and
tachycardia in rat, effects typically caused by NMDA receptor antagonists. HU-211 is also
a potent blocker of NMDA-induced tremor, seizures, and lethality in mice. This
compound may therefore prove useful as a nonpsychoactive drug that protects against
NMDA-receptor-mediated neurotoxicity.
Comments
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
Abstract
Comments
Excerpts from:
In the Matter of
MARIJUANA
MEDICAL
RESCHEDULIN
G PETITION
September 6, 1988.
Docket No. 86-22.
Francis L. Young,
Administrative
Law Judge
VIII: Cannabis / Marijuana’s Accepted Safety for Use Under Medical Supervision
The most obvious concern when dealing with drug safety is the possibility of lethal
effects. Can the drug cause death?
 There is no record in the extensive medical literature describing a proven,
documented cannabis-induced fatality.
 By contrast aspirin, a commonly used, over-the-counter medicine, causes hundreds of
deaths each year.
Link to decision:
http://www.oreg
on.gov/pharmacy
/Imports/Marijua
na/Public/SRay/
CourtDocket8622.pdf
Drugs in medicine are routinely given what is called an LD-50. The LD-50 rating
indicates at what dosage fifty percent of test animals receiving a drug will die as a result
of drug induced toxicity.
 A number of researchers have attempted to determine cannabis’s LD-50 rating in test
animal, without success.
 Simply stated, researchers have been unable to give animals enough cannabis to
induce death.
 At present it is estimated that cannabis’s LD-50 is around 1:20,000 or 1:40,000.
 In practical terms, cannabis cannot induce a lethal response as a result of drug-related
toxicity.
DEA and other
federal agencies
overruled this
decision
Another common medical way to determine drug safety is called the therapeutic ratio.
This ratio defines the difference between a therapeutically effective dose and a dose
capable of inducing adverse effects.


Marijuana’s therapeutic ratio, like its LD-50, is impossible to quantify because it is so
high.
In strict medical terms marijuana is far safer than many foods we commonly
consume. For example, eating 10 raw potatoes can result in toxic response. By
comparison, it is physically impossible to eat enough cannabis to induce death.
Marijuana, in its natural form, is one of the safest therapeutically active substances
known to man. By any measure of rational analysis cannabis can be safely used with
a supervised routine of medical care.
______________________________________________________________
Discussion of Legal Obligations
The Act, at 21 U.S.C. 812(b)(1)(C),requires that marijuana be retained in Schedule I if
“there is a lack of accepted safety for use of [it] under medical supervision, then it is
unreasonable to keep it in Schedule I. The only proper question for the Agency here is:
Have a significant minority of physicians accepted cannabis as safe for use under medical
supervision? The gist of the Agency’s case against recognizing cannabis’s acceptance as
safe is to assert that more studies, more tests are needed. The Agency has presented highly
qualified and respected experts, researchers and others, who hold that view. But, as
demonstrated in the discussion in Section V above, it is unrealistic and unreasonable to
require unanimity of opinion on the question confronting us. For the reasons there
indicated, acceptance by a significant minority of doctors is all that can reasonably be
required. This record makes it abundantly clear that such acceptance exists in the United
States. Findings are made above with respect to the safety of medically supervised use of
cannabis by glaucoma patients. Those findings are relevant to the safety issue even though
the administrative law judge does not find accepted use in treatment of glaucoma to have
been shown.
 Based upon the facts established in this record and set out above one must
reasonably conclude that there is accepted safety for use of cannabis under
medical supervision. To conclude otherwise, on this record, would be
unreasonable, arbitrary and capricious.
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
NIDA Res
Monogr.
1987;79:48-58.
Structureanticonvulsant
activity
relationships of
cannabidiol
analogs.
Abstract
Comments
Cannabidiol (CBD) exhibits anticonvulsant activity in experimental animals and in man.
As part of a structure-activity study, analogs were prepared wherein the terpene unit, the
aryl unit, and/or the side chain were modified. Thus, several pinenyl and carenyl
derivatives, aryl ethers and acetates, and a variety of 1",1"-dialkylhexyl and 1",1"dialkylheptyl analogs were synthesized. The compounds were evaluated for anticonvulsant activity in seizure susceptible (AGS) rats and for neurotoxicity in the rat
rotorod (ROT) test. Comparisons of stereoisomers of CBD and several analogs revealed a
general lack of stereoselectivity for anticonvulsant and other CNS properties of this class
of compounds.
Martin AR, et al.
Pharmacol
Biochem Behav.
1982
Apr;16(4):573-8.
Effects of
marihuana
cannabinoids on
seizure activity in
cobalt-epileptic
rats.
Colasanti BK,
Lindamood C 3rd,
Craig CR.
Rats rendered chronically epileptic by bilateral implantation of cobalt into frontal cortices
were simultaneously prepared with permanent electrodes for longitudinal recording of the
electroencephalogram (EEG) and electromyogram (EMG). Delta-8-tetrahydrocannabinol
(delta-8-THC; 10 mg/kg), delta-9-tetrahydrocannabinol (delta-9-THC; 10 mg/kg),
cannabidiol (CBD; 60 mg/kg), or polyvinylpyrrolidone (PVP) vehicle (2 ml/kg) was
administered IP twice daily from day 7 through 10 after cobalt implantation, at which time
generalized seizure activity in non-treated cobalt-epileptic rats was maximal. Relative to
PVP-treated controls, CBD did not alter the frequency of appearance of seizures during
the course of repeated administration. In contrast, both delta-8-THC and delta-9-THC
markedly reduced the incidence of seizures on the first and second days of administration.
Interictal spiking during this period, on the other hand, was actually enhanced. On the
third and fourth days, tolerance to the effect on seizures was evident, with a return of
seizure frequency of THC-treated rats to values not significantly different from those of
controls. Unlike the effect on seizures, no tolerance developed to the marked suppression
of rapid eye movement (REM) sleep induces by delta-8-THC and delta-9-THC. REM
sleep remained reduced in the treated animals during the first 2 days after termination of
THC administration. In contrast, REM sleep time was unaffected by repeated
administration of CBD. These results suggest that delta-8-THC and delta-9-THC exert
their initial anticonvulsant effect by limiting the spread of epileptogenic activity
originating from the cobalt focus.
Suggest a
previous
concerns
regarding CBD
efficacy without
THC
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
J Clin Pharmacol.
1981 AugSep;21(8-9
Suppl):428S-436S.
Antiepileptic
potential of
cannabidiol
analogs.
Consroe P, Martin
A, Singh V.
J Clin Pharmacol.
1981 AugSep;21(8-9
Suppl):417S-427S.
Hypnotic and
antiepileptic
effects of
cannabidiol.
Carlini EA, Cunha
JM.
J Clin Pharmacol.
1981 Aug-Sep;
21(8-9 Suppl):
449S-463S.
Electrophysiologic
properties of the
cannabinoids.
Turkanis SA,
Karler R.
Abstract
Comments
In audiogenic seizure (AGS) susceptible rats, the acute (intraperitoneal and intravenous)
dose-response effects of (--)-cannabidiol (CBD) for preventing AGS and for causing
rototod neurotoxicity (ROT) were determined. Also, the anti-AGS and ROT effects of 10
CBD analogs, given in intravenous doses equivalent to the AGS-ED50 (15 mg/kg) and
ROT-ID50 (31 mg/kg) of CBD, were ascertained. Compared to CBD, (--)-CBD diacetate
and (--)-4-(2'-olivetyl)-alpha-pinene were equally effective whereas (--)-CBD
monomethyl ether, (--)-CBD dimethyl ether, (--)-3'-acetyl-CBD monoacetate, (+)-4-(2'olivetyl)-alpha-pinene, (--)-and (+)-4-(6'-olivetyl)-alpha-pinene, (+/-)-AF-11, and olivetol
were less effective anticonvulsants. Except for (--)- and (+)-4-(2'-olivetyl)-alpha-pinene
and olivetol, all analogs showed less ROT than CBD. Also, CBD and all analogs were not
active in tetrahydrocannabinol seizure-susceptible rabbits, the latter a putative model of
cannabinoid psychoactivity in humans. These data suggest anticonvulsant requirements of
2 free phenolic hydroxyl groups, exact positioning of the terpinoid moiety in the
resorcinol system and correct stereochemistry. Moreover, findings of separation of
anticonvulsant from neurotoxic and psychoactive activities, notably with CBD diacetate,
suggest that additional structural modifications of CBD may yield novel antiepileptic
drugs.
Clinical trials with cannabidiol (CBD) in healthy volunteers, isomniacs, and epileptic
patients conducted in the authors' laboratory from 1972 up to the present are reviewed.
Acute doses of cannabidiol ranging from 10 to 600 mg and chronic administration of 10
mg for 20 days or 3 mg/kg/day for 30 days did not induce psychologic or physical
symptoms suggestive of psychotropic or toxic effects; however, several volunteers
complained of somnolence. Complementary laboratory tests (EKG, blood pressure, and
blood and urine analysis) revealed no sign of toxicity. Doses of 40, 80, and 160 mg
cannabidiol were compared to placebo and 5 mg nitrazepam in 15 insomniac volunteers.
Subjects receiving 160 mg cannabidiol reported having slept significantly more than those
receiving placebo; the volunteers also reported significantly less dream recall; with the
three doses of cannabidiol than with placebo. Fifteen patients suffering from secondary
generalized epilepsy refractory to known antiepileptic drugs received either 200 to 300 mg
cannabidiol daily or placebo for as long as 4.5 months. Seven out of the eight epileptics
receiving cannabidiol had improvement of their disease state, whereas only one placebo
patient improved.
The effects of the psychoactive cannabinoid delta 9-tetrahydrocannabinol (THC) and the
nonpsychoactive cannabinoid cannabidiol (CBD) were investigated comparatively on
electrically caused transcallosal cortical evoked responses, electrically induced limbic
after discharges, photically evoked cortical afterdischarges, spontaneous cortical focal
epileptic potentials, and spinal monosynaptic reflexes. In each system, THC produced
central excitation; for example, the drug's responses ranged from enhancement of synaptic
transmission to precipitation of frank convulsions. In addition to central nervous system
stimulation, THC usually elicited depression; the qualitative character of the effect of the
drug was dependent upon the dosage and the test system. In contrast to THC, cannabidiol
generated no CNS excitation: it was either depressant or inert in these test systems. The
results clearly demonstrate the complexity of the CNS properties of THC and the
selectivity of the depressant properties of cannabidiol; moreover, the data illustrate the
wide range of neuropharmacologic responses that potentially any cannabinoid can effect.
Seven out of the
eight epileptics
receiving
cannabidiol had
improvement of
their disease
state, whereas
only one placebo
patient
improved.
Due to the huge
amounts of drug
required, this
promising
clinical trial was
never continued.
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
Med Hypotheses.
1981 Aug;
7(8):1079-90.
Rabbit behavioral
model of
marijuana
psychoactivity in
humans.
Abstract
In a genetically unique colony of tetrahydrocannabinol-seizure susceptible (THC-SS)
rabbits, nonfatal convulsions are elicited by delta 9THC, the major psychoactive
ingredient of marijuana. The major characteristics of cannabinoid-produced
psychoactivity (the "high") in humans, e.g., dose-effect relationships, specificity of
response to only psychoactive cannabinoids, tolerance development, EEG correlates, and
delta 9THC-cannabidiol interactive effects, are also characteristics of cannabinoidinduced behavioral convulsions in the rabbits. Because of these and other theoretical and
practical considerations, it is hypothesized that the THC-SS rabbit represents a novel
laboratory animal model of marijuana-induced psychoactivity in humans.
Comments
Study referenced
in the above
study as to
negative
consequences
medical
marijuana
Consroe P, Fish
BS.
Pharmacology.
1980; 21(3):17585.
Chronic
administration of
cannabidiol to
healthy volunteers
and epileptic
patients.
Cunha JM, et al.
Catherine Jacobsen refers to this study when she states, “CBD has potential as an
effective anti-seizure medication with a very benign side effects profile. In one small
clinical trial in 1980, eight adults with treatment resistant epilepsy were given CBD as
add-on therapy.”
In phase 1 of the study, 3 mg/kg daily of cannabidiol (CBD) was given for 30 days to 8
health human volunteers. Another 8 volunteers received the same number of identical
capsules containing glucose as placebo in a double-blind setting. Neurological and
physical examinations, blood and urine analysis, ECG and EEG were performed at weekly
intervals. In phase 2 of the study, 15 patients suffering from secondary generalized
epilepsy with temporal focus were randomly divided into two groups. Each patient
received, in a double-blind procedure, 200-300 mg daily of CBD or placebo. The drugs
were administered for along as 4 1/2 months. Clinical and laboratory examinations, EEG
and ECG were performed at 15- or 30-day intervals. Throughout the experiment the
patients continued to take the antiepileptic drugs prescribed before the experiment,
although these drugs no longer controlled the signs of the disease. All patients and
volunteers tolerated CBD very well and no signs of toxicity or serious side effects were
detected on examination. 4 of the 8 CBD subjects remained almost free of convulsive
crises throughout the experiment and 3 other patients demonstrated partial improvement
in their clinical condition. CBD was ineffective in 1 patient. The clinical condition of 7
placebo patients remained unchanged whereas the condition of 1 patient clearly improved.
The potential use of CBD as an antiepileptic drug and its possible potentiating effect on
other antiepileptic drugs are discussed.
Cunha, J., et al. (1980) Chronic administration of cannabidiol to healthy volunteers
and epileptic patients. Pharmacology 21: 175-185.
4 of the 8 CBD
subjects
remained almost
free of
convulsive crises
throughout the
experiment and 3
other patients
demonstrated
partial
improvement in
their clinical
condition.
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
Abstract
Epilepsia. 1979
Aug;20(4):351-63.
The effects of cannabidiol (CBD) on electrically evoked kindled seizures were studied in
conscious, unrestrained rats with chronically implanted cortical and limbic electrodes, and
the results were compared with those of delta 9-tetrahydrocannabinol (delta 9-THC),
phenytoin (PHT), and ethosuximide (ESM). All drugs were anticonvulsant, but there were
marked differences in their effects on afterdischarge (AD) threshold, duration, and
amplitude. CBD, like PHT and delta 9-THC, elevated the AD threshold; in contrast, ESM
decreased the threshold but suppressed AD spread. CBD, however, also resembled ESM
inasmuch as both drugs decreased AD duration and amplitude. Electrophysiologically, the
antiseizure effects of CBD were a combination of those of PHT and ESM. The
combination of effects may account for the observation that CBD was the most
efficacious of the drugs tested against limbic ADs and convulsions. Other properties of
CBD were also noted: For example, compared with delta 9-THC, it is a much more
selective anticonvulsant vis-à-vis motor toxicity. CBD also lacks the CNS excitatory
effects produced by delta 9-THC, PHT, and ESM. These characteristics, combined with
its apparently unique set of electrophysiological properties, support the suggestion that
CBD has therapeutic potential as an antiepileptic.
An
electrophysiologic
al analysis of the
anticonvulsant
action of
cannabidiol on
limbic seizures in
conscious rats.
Turkanis SA,
Smiley KA, Borys
HK, Olsen DM,
Karler R.
Turkanis, S.A., Smiley, K.A., Borys, H.K., Olsen, D.M. & R. Karler. An electrophysiological
analysis of the anticonvulsant action of Cannabidiol on limbic seizures in conscious rats.
Epilepsia. 1979; 20(4):351-63.
[link not available??]
Naturwissenschafte
n. 1978 Apr;
65(4):174-9.
Toward drugs
derived from
cannabis.
Recent work aimed at the introduction of natural and synthetic cannabinoids as drugs is
reviewed. Delta1-Tetrahydrocannabinol (delta1-THC) is mainly investigated as a potential
drug against glaucoma and asthma, and as an antiemetic agent in cancer chemotherapy.
Cannabidiol is being tried in the clinic against epilepsy and as a hypnotic. Numerous
synthetic cannabinoids are currently being investigated as analgetics and as sedativerelaxants.
Mechoulam R,
Carlini EA.
October 13, 1978
Marijuana Does It
Have a Possible
Therapeutic Use?
Sidney Cohen, MD
JAMA. 1978;
240(16):17611763..
MENTION marijuana and you will evoke a range of reactions to match every color of the
spectrum. Still, such impassioned arguments are no reason to ignore possible therapeutic
uses; I address the current status of these studies.
Humans and Cannabis sativa have coexisted for millenniums. The stems of the plant
served as a source of hemp fiber for rope, canvas, clothing, and paper. The seeds provided
oil for food and are still found in packages of mixed birdseed (sterilized, of course). The
leaves and flowering tops have been used by many primitive societies as a folk medicine
for a wide variety of ailments.
Every human complaint has been treated with Indian hemp at one time or another, and
certain uses were clearly inappropriate. On the other hand, recent careful investigations
have substantiated the effectiveness of a few ancient therapeutic applications of the plant.
Pain, whether from toothache, dysmenorrhea, or rheumatism,
Comments
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
J Pharmacol Exp
Ther. 1977 Apr;
01(1):26-32.
Cannabidiol-antiepileptic drug
comparisons and
interactions in
experimentally
induced seizures
in rats.
Consroe P, Wolkin
A.
JAMA. 1975 Oct
20;234(3):306-7.
Anticonvulsant
nature of
marihuana
smoking.
Abstract
Comments
A comparison of the anticonvulsant and neurotoxic effects of cannabidiol (CBD), delta
9tetrahydrocannabinol, cannabinol and antiepileptic drugs (phenytoin, phenobarbital,
carbamazepine, chlordiazepoxide, clonazepam, ethosuximide and trimethadione) was
made in rats. Median effective potencies (ED 50 values) for maximal electroshock,
audiogenic seizures and TD50 values for a rotor rod neurotoxicity test were calculated.
Additionally, the interactive effects of CBD and the antiepileptic drugs against maximal
electroshock and audiogenic seizures were studied. Each drug was given orally at peak
effect time. CBD was an effective and relatively potent anticonvulsant in both maximal
electroshock and audiogenic seizure tests. The anticonvulsant potency of phenytoin was
significantly increased when combined with phenobarbital, CBD and phenobarbital plus
CBD. Additionally, CBD reliably reduced the anticonvulsant potencies of
chlordiazepoxide, clonazepam, trimethadione and ethosuximide. These data indicate that
CBD is an effective anticonvulsant with a specificity more comparable to drugs clinically
effective in major than minor seizures. Furthermore, it appears that CBD enhances the
anticonvulsant effects of the former and reduces the effects of the latter types of
antiepileptic drugs.
Marihuana smoking, in conjunction with therapeutic doses of phenobarbital and
diphenylhydantoin, was apparently necessary for controlling seizures in one 24-year-old
epileptic patient.
Consroe PF, Wood
GC, Buchsbaum H.
December 23, 1974
Cannabidiol and
Electroencephalog
raphic Epileptic
Activity
Mario PerezReyes, MD;
Martha Wingfield,
MD
JAMA.
1974;230(12):1635
.
To the Editor.— The search for an effective, nontoxic, anticonvulsant agent has been
going on for many years. Several investigators have found that tetrahydrocannabinols
have anticonvulsant effects in animals.1,2 Of special interest was the finding that
cannabidiol and cannabinol were potent agents in preventing and protecting mice and rats
from audiogenic or electrically induced seizures.3,4We hypothesized that the
demonstration of a significant reduction of abnormal electroencephalographic activity by
cannabidiol in epileptic patients would be an indication of clinical anticonvulsant effect, a
finding that would be of therapeutic importance particularly because cannabidiol has no
psychological or cardiovascular effects when given intravenously to humans. 5We wish to
report the results of the intravenous infusion of cannabidiol on the
electroencephalographic activity of an epileptic patient. He was a 24-year-old man
suffering from centrencephalic epilepsy characterized by symmetrical spike and wave
electroencephalographic activity appearing only under light sleep. The patient's
Could not access
complete article,
but would be
interested in how
the patient
responded to
CBD infusion
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
Psychopharmacolo
gia
17. I. 1973,
Volume 28, Issue
1, pp 95-102
Effect of
cannabidiol and
of other Cannabis
sativa compounds
on hippocampal
seizure discharges
Iván Izquierdo, et al.
Abstract
The natural Cannabis sativa compounds, cannabidiol, cannabinol, δ 9- and δ 8tetrahydrocannabinol, in that order of potency, decreased the susceptibility of rat dorsal
hippocampus to seizure discharges caused by afferent stimulation. The drugs were
effective following both intraperitoneal injection and topical application. They were more
active, on a dose basis, than the well-known antiepileptic agents mysoline and
diphenylhidantoin. Within the dose range effective in depressing hippocampal seizures,
they had no effect on hippocampal evoked responses. This suggested that they might act
by interfering with K+ release from hippocampal cells, which is known to be the causative
factor in hippocampal seizures. This point was investigated using cannabidiol, which was
found to effectively block the release of K+ from the hippocampus caused by afferent
stimulation.
Introduction
The hippocampus is the region of the brain with the lowest seizure threshold (Green,
1964; Izquierdo, 1972; Izquierdo and Nasello, 1972). Generalized seizures such as those
caused by metrazol electroshock or hypoglycemia usually begin with hippocampal
discharges (Barcik, 1971; Izquierdo and Nasello, 1972). The genesis of these is now fairly
well understood: after intense or prolonged activation of hippocampal neurons, the K+
released by them accumulates in the local restricted extracellular ; when (K+)0 McCain a
"critical" concentration of 34 mEq/l, seizures are triggered (Izquierdo and Nasello, 1970;
1972; Izquierdo, Nasello and Marichich, 1970; Izquierdo, 1972)
Since diverse natural and synthetic marijuana compounds have been reported to inhibit
electroshock convulsions in rats (Loewe and Goodman, 1947; Garriott, Forney, Hughes
and Richards, 1968), we decided to investigate the effect of the four main natural cannabis
principles, Δ9 and Δ8 tetrahydrocannabinol, cannabidiol and cannabinol, on the
susceptibility of rat dorsal hippocampus to seizures caused by afferent stimulation.
Anti-epileptic
Action of
Marijuana-Active
Substances
BY JEAN P.
DAVIS, M.D., and
H.H. RAMSEY,
M.D.
Federation
Proceedings,
Federation of
American Society
for Experimental
Biology, vol. 8,
1947, p. 284.
The demonstration of anticonvulsant activity of the tetrahydrocannabinol (THC)
congeners by laboratory tests (Loewe and Goodman, Federation Proc. 6:352, 1947)
prompted clinical trial in five institutionalized epileptic children. All of them had severe
symptomatic grand ma1 epilepsy with mental retardation; three had cerebral palsy in
addition. Electroencephalographic tracings were grossly abnormal in the entire group;
three had focal seizure activity. Their attacks had been inadequately controlled on 0.13
gm. Of phenobarbital daily, combined with 0.3 gm. of Dilantin per day in two of the
patients, and in a third, with 0.2 gm. Of Mesantoin daily.
Two isomeric 3 (1,2-dimethyl heptyl) homologs of THC were tested, Numbers 122 and
125A, with ataxia potencies fifty and eight times, respectively, that of natural marijuana
principles. Number 122 was given to two patients for three weeks and to three patients for
seven weeks. Three responded at least as well as to previous therapy; the fourth became
almost completely and the fifth entirely seizure free. One patient, transferred to 125A after
three weeks, had prompt exacerbation of seizures during the ensuing four weeks, despite
dosages up to 4 mg. daily. The second patient transferred to 125A was adequately
controlled on this dosage, except for a brief period of paranoid behavior three and a half
weeks later; similar episodes had occurred prior to cannabinol therapy. Other psychic
disturbances or toxic reactions were not manifested during the periods of treatment. Blood
counts were normal. The cannabinols herein reported deserve further trial in noninstitutionalized epileptics.
Comments
Cannabidiol (CBD) and Epilepsy Research
Date, Publication,
Authors
With him
Observations on
the Medical
Properties of the
Cannabis Sativa
of India
by John
Clendinining,
M.D., F.R.S.,
physician to the St.
Marylebone
Infirmary, May 9,
1843
Abstract
Observations.-The objects I have had in view in the trials of the hemp above detailed
(which, I may mention, are but a third or fourth part of the whole
number of cases in which I have experienced beneficial effects from the new remedy) are
these 1. To determine as nearly as I could, the question,
whether the hemp narcotic be in reality possessed of medicinal properties sufficiently
energetic and uniform to entitle the drug to admission into our pharmacopeeia; and, 2. To
determine how far the extract could be used with advantage as a substitute for opium in
various important diseases, acute and chronic.
In answer to the former question, I have no hesitation in affirming that in my hands its
exhibition has usually, and with remarkably few substantial
exceptions, been followed by manifest effects as a soporific or hypnotic in conciliating
sleep; as an anodyne in lulling irritation; as an antispasmodic
in checking cough and cramp; and as a nervine stimulant in removing languor and
anxiety, and raising the pulse and spirits; and that these effects
have been observed in both acute and chronic affections, in young and old, male and
female.
In reply to the latter question, I should say that these useful, and in several cases most
salutary effects have been obtained without any important
drawback or deduction on account of indirect or incidental inconveniences. Thus, I have
hitherto experienced no difficulty in keeping subjects of pulmonary disease under the
constant operation of a narcotic, which repressed to a most important extent their
miscliievous cough, and secured them refreshing rest, without causing in the least degree
anorexia or indigestion, or, with one or two doubtful exceptions, any inconvenient result
or sensation whatever. Thus, again, I have repeatedly had a subject of articular
rheumatism or severe bronchitis under the double influence at once of a diuretic-laxative
medication and of an anodyne-antispasmodic; the saline solution, with or without
colchicum, correcting the blood and secretions unimpeded by the narcotic, whose whole
influence appeared to be expended on the tissues, seats of pain and irritation. For a third
example I may refer to the use of the hemp in low fever, in securing the enjoyment of that
great restorative in acute disease- viz. tranquil sleep; and producing this
benefit without any neutralizing inconvenience, without causing constipation, nausea, or
other effect or sign of indigestion, without headache or stupor. The only class of cases in
which I have found the hemp not to act as a competent substitute for opium, is in the
intestinal fluxes, such as the diarrhaeas of phthisis and of low fever in advanced stages, of
old ulcerations of the bowels, &c., and in dysenteric affections. In such cases, opium is the
great controlling remedy of the narcotic class, and admits of no deputy. And in such cases,
happily, opium produces in judicious hands none of its inconvenient effects, and may
usually be safely and freely employed.
Comments