Epilepsia, m36S -315. 1919.

Raven Press, New York

The Influence of Cannabidiol and

A9-Tetrahydrocannabinolon Cobalt
Epilepsy in Rats

Pauline Chiu, Donna M. Olsen, Henry K. Borys, Ralph Karler,

and Stuart A. Turkanis
Departments of Pharmacology and Family and Community Medicine,
University of Utah College of Medicine, Salt Lake City, Utah 84132

Summary: The mechanisms of the anticonvulsant activity of cannabidiol

(CBD) and the central excitation of Ay-tetrahydrocannabinol(A9-THC) were
investigated electrophysiologically with conscious, unrestrained cobalt epilep-
tic rats. The well-known antiepileptics, trimethadione (TMO), ethosuximide
(ESM), and phenytoin (PHT), were included as reference drugs. Direct mea-
surements were made of spontaneously firing, epileptic potentials from a pri-
mary focus on the parietal cortex and convulsions were monitored visually.
ESM and TMO decreased the frequency of focal potentials, but PHT and CBD
exerted n6 such effect. Although CBD did not suppress the focal abnormality,
it did abolish jaw and limb clonus; in contrast, Ay-THCmarkedly increased the
frequency of focal potentials, evoked generalized bursts of polyspikes, and
produced frank convulsions. 11-OH-AY-THC,the major metabolite of AY-THC,
displayed only one of the excitatory properties of the parent compound: pro-
duction of bursts of polyspikes. In contrast to A9-THC and its 11-OH metabolite,
CBD, even in very high doses, did not induce any excitatory effects or convul-
sions. The present study provides the first evidence that CBD exerts anticon-
vulsant activity against the motor manifestations of a focal epilepsy, and that
the mechanism of the effect may involve a depression of seizure generation or
spread in the CNS.

Both A9-tetrahydrocannabinol (Ag-THC) diovascular effects in humans, but also

and cannabidiol (CBD) have anticonvulsant
activity (Garriott et al., 1968; Izquierdo
and Tannhauser, 1973; Karler et al.,
1973;1974u;b;c;d; Consroe et al., 1976;
Karler and Turkanis, 1976a;b); Ag-THC
however, is more toxic than CBD (Hollis-
ter, 1973; Perez-Reyes et al., 1973; Karler
et al., 1974u;d). The toxicity of AQ-THCde-
rives not only from its psychic and car-
from its CNS depressant and excitatory
properties in animals (Karler et al., 1974d;
Turkanis et al., 1974;1977; Feeney et al.,
1976; Martin and Consroe, 1976; Turkanis
et al., 1979). The CNS depressant effect,
which has been described in terms of motor
toxicity, is important in defining the selec-
tivity of the anticonvulsant activity relative
to the neurotoxic activity (Karler et al.,

Received September 18, 1978.

Key words: Cannabidiol-As-Tetrahydrocannabinol-Cannabinoids-Cobalt epilepsy-Anticonvulsants.

365
366 P. CHIU ET A L .

1974a;d; Turkanis et al., 1979). The ex- Two electrically connected reference-
citatory properties may be significant in re- ground screw electrodes were inserted in
lation to the illicit use of marihuana by the cranium: one over the cerebellum and
epileptics, for it is possible that such ex- the other over a frontal sinus. A conven-
citatory effects may exacerbate certain tional head pedestal was fastened to each
epilepsies (Keeler and Reifler, 1967). CBD, rat’s skull as described by Turkanis et al.
on the other hand, lacks the conspicuous (1979).
liabilities of As-THC, and, therefore, it has To induce an epileptic focus, a piece of
been proposed as a potentially useful an- cobalt wire, 1 mm in diameter and 1.5 mm
tiepileptic (Karler and Turkanis, 1976a ; in length, was positioned on the dura at the
Karler and Turkanis, 1979). time of electrode implantation (Colasanti et
The present work was designed to inves- al., 1974). The cobalt-induced focus sub-
tigate mechanisms of the anticonvulsant ac- sequently developed within 6- 12 days.
tion of CBD, as compared with AS-THCand Control animals were prepared in a similar
other anticonvulsants, for few studies have manner, except that the cobalt wire was
addressed the problem (Corcoran et al., omitted.
1973; Izquierdo et al., 1973; Wada et al.,
1975; Turkanis and Karler, 1975;1976). In Experimental Procedures and
order to identify these mechanisms, the Equipment
cobalt epilepsy model was selected because The experiments were carried out 6-19
it provides a rapidly developing, reproduc- days after cobalt implantation; in the pres-
ible, spontaneously firing, discrete focus ent study, focal epileptic potential fre-
that develops characteristic epileptic poten-
quency during predrug control periods had
tials in the electrocorticogram (Dow et al.,a mean and standard deviation of 27 f 8
1962;1973; Colasanti et al., 1974). The potentials/min. Some of the epileptic rats
preparation permits the direct measurement also exhibited jaw and limb clonus. In order
from a primary focus of spontaneously for a potential to be classified as a cobalt-
firing epileptic potentials in unre- caused epileptic response, it had to exhibit
strained, conscious animals, and these clearly recognizable shapes, as depicted in
measurements may elucidate the elec- Fig. 3, and, in general, it had to have an
trophysiological mechanisms of both the amplitude at least 2.5-fold greater than that
excitatory and anticonvulsant effects of theof the background electrocorticogram. In
cannabinoids. support of these criteria for potential selec-
METHODS tion, the large amplitude potentials were
readily abolished by ethosuximide (ESM)
Experimental Animals (Figs. 1 and 2), as described by Dow et al.
The studies were carried out with male (1973) and Scuvte-Moreau et al. (1977).
Sprague-Dawley rats (140- 170 g). In order During an experiment, the rat was un-
to mount permanent stainless steel screw anesthetized, awake and unrestrained, and
electrodes (0-80, 1.6 mm, Plastic Products, placed in a clear acrylic cage (20 x 32 x 32
Roanoke, Virginia) in the cranium, the rats cm) which was kept within a shielded
were anesthetized with sodium pentobarbi- chamber. The electrocorticograms were re-
tal (40 mg/kg, i.p.) Recording electrodes corded differentially against a grounded
were stereotactically positioned over both reference electrode by high impedance
frontal cortices (3 mm anterior to bregma capacitance-coupled preamplifiers and a
and 3 mm lateral to the midline) and over polygraph (Grass Instrument Company,
both parietal cortices (3 mm posterior to model 5). Electrical activity was measured
bregma and 3 mm lateral to the midline). from each frontal and parietal electrode si-

Epilepsie, Vol. 20, August 1979

 CANNABINOIDS A N D COBALT EPILEPSY
0 1
;
a 201 a**
601 VEHICLE TRIMETHADIONE 400rng/Kg
20
a. ..am
0 I I
'****a*..a*
, , , , , , ,
*.,. , ,
CONTROL 0 30 60 90
MINUTES AFTER TREATMENT
FIG. 1. Influence of vehicle, As-THC, ethosuximide,
and trimethadione on the frequency of epileptic poten-
tials at a cobalt-induced focus in the left parietal cor-
tex. Each time-effect relationship depicts the resulti
from 1 animal; each point represents the mean fre-
quency during a 5 min period. The arrows indicate the
time of vehicle or drug administration.
multaneously; focal epileptic activity was
directly recorded from a primary focus,
which developed at the site of cobalt im-
plantation in the left parietal cortex. Inde-
pendent foci in the contralateral cortex
rarely occurred, and rats with such foci
were excluded.
Drug Preparations
Ultrasound was used to disperse Ag-
THC, 11-OH-A9-THC,CBD, and phenytoin
(PHT) in isotonic saline solution with
Tween 80, as previously described (Tur-
kanis et al., 1974). Trimethadione (TMO),
ESM, and penylenetetrazol (FTZ) were dis-
367
solved in an isotonic saline-Tween 80 solu-
tion; all drug and vehicle preparations con-
tained a final concentration of 3% Tween 80
and were administered i.p. The injection
volume, except for TMO and ESM, was 0.1
nV100 g body weight; in the TMO and ESM
experiments, 0.2 d l 0 0 g body weight was
used. Each animal was subjected to only
one drug experiment in order to avoid the
potential complications of drug interac-
tions.
RESULTS
Time-Effect Relations
The control data at the top of Fig. 1 illus-
trate the general experimental design. The
first vehicle dose was administered 15 min
after the beginning of the experiment; the
second dose, 45 min after the first dose.
Subsequently, the electrocorticograms
were recorded for an additional 120 min.
This time-effect relation seen in Fig. 1 is
representative of six other control studies.
, In short, potential frequency provides a rel-
120 atively stable parameter for the phar-
macological evaluation of anticonvulsant
drugs.
The drug studies in Fig. 1 were identical
in design to the controls, except that a drug
preparation was substituted for the second
vehicle dose. The time-effect relations of
the drugs indicate that, except for CBD and
PHT, substantial alterations in frequency
occurred following drug administration:
A9-THC markedly enhanced the frequency
of focal potentials, whereas both ESM and
TMO reduced focal activity. Generally
speaking, there were also some similarities
among the three drugs. In the majority of
experiments, the drug responses began
within 15 min, persisted for at least 60 min,
and concluded within 120 min. In a few ex-
periments, the drug effects were still ap-
parent at the end of the drug test period.
Time-effect relations, such as those shown
in Fig. 1, were used to determine the
maximum response produced by a drug
dose. From the maximum response data,
Epilepsia. Vol. 20, August 1979
368
@.
14.0 PHENY TO I N
3
0
I100
3 0
I
x 80
a
= 6
0 5
1 7 7 - 10 15 25
mg /Kg
FIG.2. Influence 3f ethosuximide, phenytoin, As-THC, and CBD on the frequency of focal epileptic potentials
at a cobalt-induced focus in the left parietal cortex. Each point represents the results from 1 animal and is the
maximum frequency expressed as a percentage of predrug control. The lines were calculated by least-squares
regression.
the dose-response relations illust?ated in
Fig. 2 were derived.
Dose-Effect Relations
The dose-effect relations shown in Fig. 2
included doses that are known to exert an-
ticonvulsant activity in various rat test sys-
tems: A9-THC, 1-10 mg/kg (Consroe and
Man, 1973; Corcoran et al., 1973; Karler et
al., 1974d); CBD, 1-50 mg/kg (Izquierdo
and Tannhauser, 1973; Karler and Tur-
kanis, 1976~;Turkanis et al., 1979); ESM
and TMO, 100-400 mg/kg (Goodman et al.,
1949; Dow et al., 1973); and PHT, 5-10
mg/kg (Petty and Karler, 1965). As illus-
trated in Fig. 2, ESM diminished the fre-
quency of focal potentials in a dose-related
manner; although the data are not shown,
TMO in additional experiments yielded
ESM-like results. PHT, in contrast, exerted
no suppressant effect on cobalt-induced
epileptic potentials (Fig. 2).
A9-THCraised the frequency of focal po-
tentials in a dose-related fashion, while
CBD, like PHT, had no effect (Fig. 2). The
Epilepsia, Vol. 20, August 1979
P . CHIU ET AL.
CBD
0
.:*
50
I 1 1 1
5 10 25 50 100200
1 1
mg/Kg
data indicate that CBD, A9-THC,and PHT,
even in doses 5- 10 times greater than their
anticonvulsant dosezovalues (as determined
by the maximal electroshock test), did not
display an ESM-like decrease in frequency.
Focal Potential Frequency Increase and
Bursts Caused by A9-THC
As described above, As-THC, unlike
CBD and PHT, greatly enhanced the fre-
quency of focal potentials. Two different
electrocorticographic phenomena at the
focal recording site were noted after Ag-
THC, and both contributed to the overall
increase in frequency. First, Ag-THCraised
the frequency of cobalt-produced epileptic
potentials at the focus (Fig. 3B1), but no
epileptic potentials appeared at the other
three recording sites (Fig. 3B2-B4). Be-
cause this drug response was confined to
the focus, the data suggest that A9-THC
selectively activated the epileptic focus.
Second, another type of epileptiform
electrical potential contributed to the Ag-
THC-induced frequency increase. These
 CANNABINOIDS A N D COBALT EPILEPSY
FIG. 3. Influence of A@-THCon the electrocortico-
gram of an epileptic rat. The recordings were obtained
20 min after either vehicle or drug. Each dot below the
focal recordings (A 1 and B 1) indicates an epileptic po-
tential.
potentials exhibited several features that
distinguish them from the cobalt-induced
spikes depicted in Fig. 3. First, they oc-
curred in intermittent, discrete bursts of
polyspikes (high-voltage multiphasic poten-
tials) (Fig. 4A-C); the modal duration of
the bursts in eight experiments ranged from
1.5-4.0 sec. Second, the bursts resembled
afterdischarges (ADS) produced by focal
electrical stimulation of the cortex (Racine,
1975); and, compared with cobalt-induced
spikes, the individual potentials within each
burst exhibited a more symmetrical shape
than that of the focal potentials (Figs. 3 and
4). Third, the bursts did not occur prior to
369
treatment, but began to develop 45-60 min
after drug and persisted for the remainder
of the 120 min test period (Fig. 5). Fourth,
the bursts were generalized phenomena
that were usually detectable from all four
cortical recording sites. The bursts, how-
ever, did not appear to originate exclusively
at the cobalt-induced focus because they
were occasionally seen in one or more of
the nonfocal electrocorticograms, while ab-
sent at the focus. Finally, the bursts made a
relatively small contribution to the As-
THC-caused increase in focal frequency.
For example, over a range of 0.5-25 mg/kg
of As-THC, the potentials associated with
bursts amounted to less than 2% of the total
number of epileptic-like potentials re-
corded; at 50 and 100 mg/kg, they were 8.2
and 18.0%, respectively. The findings also
suggest that moderate burst production re-
quires relatively high doses of As-THC.
Other investigators have reported that
marihuana extracts or AY-THCinduced
polyspikes in normal animals (Pirch et al.,
1972; see Truitt and Braude, 1975, for a re-
view); accordingly, in 10 experiments car-
ried out with control rats (no cobalt focus),
Ag-THC (1 - 100 mg/kg) caused polyspikes
that were similar to those previously de-
scribed by Pirch et al. (1972). The poly-
spikes were visually distinguishable from the
cobalt-induced focal epileptic potentials
and were always generalized and not focal
in nature. Therefore, the data clearly dem-
onstrate that As-THC did not induce focal
potentials, such as those exhibited by a
cobalt epileptic focus. In contrast, many of
the polyspikes in normal animals resembled
the As-THC-caused bursts in epileptic ani-
mals; however, normal rats, unlike epilep-
tic rats, often displayed so much variability
in the shapes of these potentials that dis-
crete bursts of polyspikes were frequently
difficult t.0 identify. Thus, the ll-OH-As-
THC and PTZ experiments described be-
low were carried out in epileptic animals so
that both focal phenomena and gener-
alized bursts could be reliably measured.
Epilepsie, Vol. 20, August 1979
370 P. CHIU ET AL.

FIG.4. AD-Like bursts produced by As-THC, 11-OH-As-THC,and PTZ.Responses A, B, and C were obtained
81-90 min after As-THC; responses D, E,and F, 15-60 min after 11-OH-A9-THC;responses G,H, and I, 16-20
min after FTZ.

11-Hydroxy-A9-THCStudies
A limited supply of 11-OH-A9-THC,the
major metabolite of A9-THC, restricted the
experiments to 3 animals and to a dosage
range of 10-20 mg/kg. In spite of such lim-
0 30 60 90 120
itations, the studies provided a valuable
comparison of the pharmacological prop-
erties of the metabolite and its parent com-
pound. The 11-OH metabolite, unlike Ag-
THC, did not produce a consistent effect on
cobalt-caused focal epileptic potentials: an
increase in frequency was found in one ex-
periment, a decrease in another, and no
change in the third. The 11-OH metabolite's
dose may have been insufficient to cause an
enhancement of the frequency of epileptic
potentials. Raising the dose, however, was
0 30 60 90 120
not possible because 20 mg/kg produced
MINUTES AFTER DRUG
marked toxicity. For example, at this dose,
the 11-OH-A9-THC produced persistent
FIG.5. Time course of AD-like bursts produced by
A8-THC, 11-OH-A'-THC, and FTZ in epileptic rats. circling behavior, which, under the condi-
Each time-effect relationship represents the results tions of the present investigation, did not
from 1 animal. Vehicle was given 15 min after the occur with either A9-THC or CBD.
beginning of the control period; drug, at the beginning
of 120 min test .period; and additional dose of PTZ (20 In addition, the 11-OH compound (Fig.
mg/kg) was given at 45 min. 4D-F) produced generalized bursts, which

Epllepsia, Vol. 20, August 1979

 CANNABINOIDS AND COBALT EPILEPSY 371

were similar to those evoked by A9-THC.A rats displayed limb and jaw clonus. Al-
major difference between the two drugs though there are too few observations from
was the 11-OH-metabolite’s shorter onset the ESM, TMO, and PHT experiments to
time. Time-course data contrasting the dif- warrant discussion, the vehicle and can-
ferences in onset time between the two nabinoid studies did provide valuable in-
drugs are illustrated in Fig 5: 11-OH-A’- formation. In seven vehicle control experi-
THC produced bursts in 15-30 min; Ag- ments, 4 rats exhibited clonic activity
THC, in 45-60 min. throughout the 180 min test, and vehicle
treatment did not alter or induce convul-
Pentylenetetrazol Studies sions in any of the epileptic rats. In eight
PTZ was included in the present investi- A’-THC studies, one animal, during the
gation as a reference drug, because A’-THC predrug control period, displayed clonus,
and PTZ are known to exert similar central which was exacerbated by A’-THC, 100
excitatory responses in some electro- mg/kg. Three other animals developed per-
physiological test systems (Boyd et al., sistent clonic activity only after treatment
1971a;b;1974; Turkanis et al., 1977). PTZ with A’-THC (25 or 50 mg/kg). In contrast,
experiments were carried out in a manner in eight experiments, CBD in doses of 1-50
identical to that of the other drug studies, mgkg abolished seizures in the 4 rats that
except that multiple doses of PTZ were exhibited clonus, and CBD in doses as high
usually administered during each experi- as 200 mgkg did not produce convulsions in
ment due to its relatively short duration of any of the epileptic rats. The data suggest
action. PTZ, unlike A’-THC, seldom en- that CBD abolished seizures without affect-
hanced focal activity: In five multidose ex- ing the focal abnormality. In contrast,
periments, PTZ in subconvulsant doses A9-THCexacerbated both the electrical and
(10-40 mgkg) only augmented focal fre- motor manifestations of cobalt-caused
quency once. In contrast, PTZ, like epilepsy.
A’-THC and 11-OH-A9-THC, consistently
produced generalized bursts, such as those DISCUSSION
seen in Fig. 4G-I. The time course of The results of the cannabinoid experi-
PTZ-caused bursts (Fig. 5 ) illustrates PTZ’s
ments on a cobalt-induced epileptic focus in
rapid onset of action. the rat parietal cortex have provided infor-
The data suggest that the bursts of poly-
mation relative to the mechanism of the an-
spikes produced by Ag-THC or its 11-OH ticonvulsant action of CBD, as well as to
metabolite are manifestations of their cen-the toxicity of A’-THC. Despite the well-
tral excitatory properties. First, these can-
documented anticonvulsant activity of
nabinoids elicited generalized bursts similar
A9-THC (Karler and Turkanis, 1976a), the
to those produced by the central excitatorydrug produced several CNS excitatory ef-
drug, PTZ. Second, the bursts caused by allfects: it increased the frequency of focal
three drugs resemble electrically evoked epileptic potentials; it produced generalized
cortical ADS (Racine, 1975). In contrast, bursts of epileptiform polyspikes; and, fi-
neither CBD nor PHT, even in high doses, nally, it caused frank seizures. None of
induced any Ag-THC-likebursts. these excitatory effects was associated with
CBD, even in very high doses.
Influence of the Cannabinoids on A’-THC’s propensity for producing ex-
Motor Seizures citatory effects has been described previ-
A comprehensive study of the drug influ- ously (Boyd et al., 1971a;b;1974; Feeney et
ence on convulsions was not feasible, be- al., 1973;1976; Karler et al., 1974d; Stad-
cause only a small number of the epileptic nicki et al., 1974; Karler and Turkanis,

Epilepsia, Vol. 20, August 1979

 372 P. CHIU ET AL.

1976~;Martin and Consroe, 1976; Turkanis Brady and Carbone, 1973; Gill et al., 1973;
et al., 1977;1979). Although the mechanism Karler et al., 1974~;Turkanis and Karler,
of this CNS excitation is unknown, the 1975;1976; Karler and Turkanis, 1976~).
present data demonstrate that AS-THC di- Although previous studies of CBD have
rectly activates an epileptic focus, which, in emphasized the similarity between its an-
turn, suggest that marihuana may exacer- ticonvulsant properties and those of PHT
bate focal epilepsies and, therefore, would (Karler and Turkanis, 1976u;b;1979), there
be contraindicated in certain epileptics. is evidence that against limbic seizures
One report in the literature links the use of CBD shares properties with both ESM and
marihuana to the precipitation of grand ma1 PHT (Turkanis et al., 1979). In the cobalt
seizures in a single patient (Keeler and model, however, CBD resembles only
Reifler, 1967); in another patient, however, PHT. In this system, neither drug affected
marihuana smoking enhanced the an- focal potentials, which were characteris-
tiepileptic activity of phenobarbital and tically suppressed by ESM; CBD did,
PHT (Consroe et al., 1976). The diversity of however, block convulsions. From the
these very limited clinical observations may standpoint of mechanism of action, the data
reflect the complexity of As-THC’s known indicate that the anticonvulsant effect of
effects in animals: the drug not only pro- CBD, under the conditions of the present
duces numerous excitatory effects, but it study, does not derive from a suppression
also effectively blocks convulsions in some of the focal abnormality; rather, it may de-
types of antiseizure tests (Karler and Tur- rive from a central blockade of seizure
kanis, 1976a;b). Whether the use of generation or spread. In addition, the
marihuana by epileptics will affect seizure mechanism of action of PHT has also been
control remains to be deterplined; neverthe- related to its ability to suppress seizure
less, epileptic patients should be made spread without abolishing focal activity
aware of the potential hazards. (Louis et al., 1968). CBD, therefore, more
Our investigation of the excitatory prop- closely resembles PHT than ESM. The
erties of As-THC was further extended to its numerous similarities between CBD and
principal metabolite, 11-OH-As-THC,which PHT, both in a variety of anticonvulsant
evoked only one consistent excitatory ef- tests (Karler and Turkanis, 1976u;b) and in
fect: the production of generalized epilep- mechanism of action, suggest that CBD
tiform bursts of polyspikes. The onset time may be useful clinically in the treatment of
of the effect, however, was shorter in the those epilepsies responsive to PHT.
case of the metabolite than it was in the
parent compound, a difference which may ACKNOWLEDGMENT
indicate that the polyspike effect of As-THC
The authors are indebted to Dr. Monique
is caused, at least in part, by its rapidly
C. Braude, Division of Research, NIDA,
produced primary metabolite (Karler and
for supplying the cannabis derivatives and
Turkanis, 1976~).Conversely, the limited
for her advice and encouragement. The
excitatory response to the 11-OH derivative
work was supported by USPHS Research
is evidence that the other excitatory effects
Grant DA-00346.
of As-THC, that is, an increase in focal
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RESUME
Une etude electrophysiologique des mecanismes
de I’activite anticonvulsivante du cannabidiol
(CBD) et de I’effet d’excitation centrale du delta 9-
tetrahydrocannabinal (As-THC) a ete effectuee chez
des rats conscients et non maintenus presentant une
epilepsie au cobalt. Des antiepileptiques, bien connus
comme la trimethadione (TMO), I’ethosuccimide
(ESM), et la phenytoine (PHT), ont ete utilises comme
drogues de reference. Les decharges spontanees de
potentiels epileptiques au niveau d’un foyer primaire
du cortex parietal ont ete enregistrees directement et
les convulsions ont ete contrdees de visu. L’ESM et
la TMO diminuent la frequence des potentials focaux
alors que la PHT et CBD n’ont pas cet effet. Bien que
le CBD ne supprime pas les anomalies focales, il fait
disparaitre les clonies des mlchoires et des membres;
a I’inverse le As-THC augmente nettement la frequence
des potentiels focaux, entraine I’apparition de
decharges generalisees de polypointes, e t est a
Epilepsia. Vol. 20, August 1979
I’origine de convulsions. Le 11-OH-As-THC,principal
metabolite du As-THC, est a I’origine de I’une seule
des proprietes excitatrices de la drogue: la production
de decharges de polypointes. A I’inverse du An-THC
et de son metabolite 11-OH, le CBD, mtme a tres
hautes doses, n’entraine aucun effet excitateur, ni
aucune convulsion. Cette etude apporte pour la
premiere fois la preuve que le CBD exerce une activite
anticonvulsivante a I’encontre des manifestations
motrices d’une epilepsie focale, et que le mecanisme
de cet effet peut concerner une depression de la
genese ou de la propagation de la crise dans le systeme
nerveux central.
(J .-L. Gastaut, Marseilles)
RESUMEN
En ratas libres y conscientes convertidas en epilep-
ticas mediante cobalto, se han investigado elec-
trofisiologicamente 10s mecanismos de la actividad
anticonvulsiva del cannabidiol (CBD) y la excitacion
central del A’-tetrahidrocannabinol. Como referencia
se han incluido las bien conocidas drogas antiepilep
ticas trimetadiona (TMO), etosuximida (ESM), y
fenitoina (PHT). Se realizaron medidas directas de las
descargas espontkneas y 10s potenciales epilepticos del
foco primario en la corteza parietal. Las convulsiones
se monitorizaron visualmente. La ESM y la TMO re-
dujeron la frecuencia de 10s potenciales focales y la
PHT y el CBD no ejercieron tal efecto. A pesar de que
el CBD no suprimio la anormalidad focal, elimino el
clonus mandibular y de las extremidades; con-
trariamente, el An-THCaumento marcadamente la fre-
cuencia de 10s potenciales focales, de 10s brotes
evocados generalizados de polipuntas y produjo fran-
cas convulsiones. El II-OH-As-THC, el mayor
metabolito del As-THC, solo mostro una de las prop-
iedades excitatorias del compuesto de origen: la pro-
duccion de 10s brotes de polipuntas. En contraste con
el A’-THC y su 11-OH metabolito, el CBD incluso a
muy elevadas dosis, no indujo ningun efecto ex-
citatorio ni convulsiones. Este estudio proporciona la
primera evidencia de que el CBD ejerce una actividad
anticonvulsiva contra las manifestaciones motoras de
la epilepsia focal y que el mecanismo de este efecto
puede incluir una depresion de la generacion o prop
agacion de las descargas en el SNC.
(A. Portera Sanchez, Madrid)
ZUSAMMENFASSUNG
Die Mechanismen der antikonvulsiven Wirkung des
Cannabidiols (CBD) und die zentrale Reizung durch
Delta-9-Tetrahydrocannabinols(Delta-9-THC)wurden
elektrophysiologisch bei bewuhseinsklaren, frei sich
bewegenden, durch Kobalt epileptisch gemachten
Ratten untersucht. Die wohlbekannten Antiepileptika
Trimethadion (TMO), Ethosuximid (ESM), und
Phenytoin (PHT) wurden als Referenzdrogen mitun-
tersucht. Direkte Messungen der spontan auftretenden
epileptischen Potentiale eines primaren Fokus im
parietalen Cortex wurden durchgefuhrt und die
Krampfe auf einem Monitor aufgezeichnet. Die Fre-
 CANNABINOIDS AND COBALT EPILEPSY
quenz der fokalen Potentiale wurden durch ESM und
TMO vermindert. nicht aber durch PHT und CBD.
Obwohl CBD die fokalen Besonderheiten nicht unter-
driickte, liell es Kloni der Kiefer und der Glieder ver-
schwinden. Im Gegensatz hierzu vermehrte Delta-9-
THC deutlich die Frequenz der fokalen Potentiale, rief
generalisierte Ausbriiche von Poly-spikes hervor und
verursachte Krampfe. I 1-Hydroxy-Delta-9-THC, der
Hauptmetabolit des Delta-PTHC zeigte nur eine der
excitatorischen Eigenschaften der Muttersubstanz:
Die Auslosung von Ausbriichen von Poly-spikes. Im
375
Gegensatz zu Delta-9-THC und seinem 1 I-Hydroxy-
Metaboliten induzierte das CBD sogar in sehr hohen
Dosen keinerlei Reizerscheinungen oder Krampfe. Die
gegenwartige Untersuchung liefert den ersten Hin-
weis, dall CBD eine antikonvulsive Wirkung gegen die
motorische Manifestation der fokalen Epilepsie besitzt
und dall der Wirkungsmechanismus eine Vermin-
derung der Krampfentladung oder ihrer Ausbreitung
im ZNS beeinflusst.
(D. Scheffner, Heidelberg)
Epilepsia, Vol. 20, August 1979