CHRONIC ADMINISTRATION OF CANNABIDIOL TO HEALTHY VOLUNTEERS AND EPILEPTIC PATIENTS

Pharmacology 21: 175-185 (1980)

Jomar M. Cunha, E.A. Carlini, Aparecido E. Pereira, Oswaldo L. Ramos,
Camilo Pimentel, Rubens Gagliardi, W.L. Sanvito, N. Lander and R. Mechoulam

Departments de Psicobiologia, Departamento de Medicina, Departamento de
Neurologia, Escola Paulista de Medicina; Departamento de Neurologia,
Faculdade de Medicina da Santa Case, Sao Paulo, [Brazil] and Department of
Natural Products, Pharmacy School, Hebrew University, Jerusalem

This work was supported by grant No. ROI DA 00875 from the US National
Institutes of Mental Health (principal investigator: E.A. Carlini).

Key words. Cannabidiol--Epilepsy--Healthy volunteers

Abstract. In phase 1 of the study, 3 mg / kg daily of cannabidiol
(CBD) was given for 30 days to 8 healthy 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 as
long 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.

Anecdotal reports on the antiepileptic properties of marihuana
(Cannabis sativa) are known since ancient times (Li, 1974). Rosenthal
(1971) mentioned medieval Arab manuscripts in which cannabis is described
as a treatment for epilepsy. During the 19th century several medical
reports were published on the ameliorative effects of cannabis extracts on
several forms of convulsions (O'Shaughnessy, 1842; Shaw, 1843;
Reynolds, 1890).

In spite of these promising results and its low toxicity, the use
of cannabis preparations for medical purposes progressively decreased.
This was due to the absence of standardized preparations, the unknown
chemical composition, and the psychotropic secondary effects produced by
cannabis.

Cannabidiol (CBD) is the major neutral nonpsychoactive
cannabinoid in most cannabis preparations. It was first isolated by Adams
et al, in 1940 but its structure was elucidated only 23 years later
(Mechoulam and Shvo, 1963). The main active component of cannabis is
delta-1-tetrahydrocannabinol (delta-1-THC) which was isolated in pure
form and its structure was determined by Gaoni and Mechoulam in 1964. It
is also named delta-9-THC. Numerous other natural cannabinoids are known
today (Mechoulam, 1973; Mechoulam et al, 1976).

The unraveling of the chemistry of C. sativa brought a new interest
in its pharmacology, and quite expectedly many laboratories studied the
anticonvulsant properties of its components especially since early reports
had shown that some natural and synthetic cannabinoids protected rats from
convulsions (Loewe and Goodman, 1947) and were of therapeutic value in
epileptic children (Davis and Ramsey, 1949). More recently many reports
have appeared attributing anticonvulsant properties to delta-1-THC and
other cannabinoids, in a variety of experimental procedures (Garriott et
al, 1968; Sofia et al, 1971; Consroe and Man, 1973; Karler et al, 1973,
1974; Plotnikoff, 1976). As a rule, delta-1-THC was the most studied
compound. Most of the results obtained confirmed the rather potent
anticonvulsant property of this drug. Its possible use as an antiepileptic
drug in humans has, however, been hindered by its known psychotropic
effects.


Since Brazilian workers (Carlini et al, 1973; Izquierdo et al,
1973) first demonstrated the anticonvulsant effects of CBD, there have
been several additional reports on the effectiveness of CBD and its
derivatives in protecting experimental animals from convulsions induced by
various procedures (Karler et al, 1973; Turkanis et al, 1974; Carlini et
al, 1975; Karler and Turkanis, 1976; Consroe and Wolkin, 1977). Consroe
and Wolkin (1977) demonstrated that CBD has a high protective index
comparable to that of phenobarbital and a spectrum of anticonvulsant
activity in rodents similar to that of phenytoin. CBD also enhances the
anti-convulsant potency of both phenytoin and phenobarbital (Consroe and
Wolkin, 1977; Chesher and Jackson, 1974; Chesher et al., 1975).

In addition to its favorable anticonvulsant effects and absence of
toxicity in animals, CBD seems to be devoid of psychotropic activity and
other undesirable side effects in humans. The lack of toxicity of CBD in
animals was demonstrated by intraperitoneal injection of 50 mg / kg daily
for 90 days in mice, oral ingestion of 5-20 mg / kg daily for 90 days and
50 mg / kg for 27 days by rats and intravenous injection of 1,000 mg / kg
in rabbits. No toxicity was observed (Cunha and Carlini, to be
published). In man, oral intake of doses from 15 to 160 mg / day (Karniol
et al, 1974; Hollister, 1973; Carlini et al, 1979), inhalation of 0.15 mg
/ kg (Dalton et al, 1976a), and intravenous injection of 30 mg
(Perez-Reyes et al, 1973; Hollister, 1973) were not followed by ill
effects. Chronic oral administration of 10 mg daily for 21 days did not
induce any change in neurological (including EEG), clinical (including
ECG), psychiatric, blood and urine examinations (Mincis et al, 1973).

Another recent investigation in our laboratory (Consroe et al.,
1979) showed that CBD neither interferes with several psychomotor and
psychological functions in humans nor potentiates alcohol effects on these
functions.

The above data led us to undertake the present investigation which
was performed in two phases. In phase 1, 3--6 mg / kg of CBD (roughly
corresponding to 200--400 mg / subject) was administered daily to healthy
human volunteers for 30 days. In phase 2, patients suffering from
secondary generalized epilepsy with temporal irritative activity received
200--300 mg of the drug for periods of up to 4.5 months.

Experiment 1 (Phase 1 of Study)

Material and Methods

Subjects
16 adult volunteers (11 men and 5 women) aged 22-35, with an
average weight of 65 kg were chosen from the staff of Escola Paulista de
Medicina. They were in good health showing neither clinical nor laboratory
evidence of cardiovascular, renal, hepatic or other impairments. The
institutional review committee at Escola Paulista de Medicina previously
approved the protocol of the experiments.

On the first day of the experiment the patients were submitted to
a complete medical check-up, including clinical and neurological
examinations, EEG, ECG, blood tests (hematocrit, hemoglobin, leukocyte and
erythrocyte counts, bilirubin, oxaloacetic and puruvic transaminases and
creatinine) and urine tests ; (osmolarity, pH, albumin, leukocyte and
erythrocyte counts, cylinders and crystals) in the Department of Medicine
of the Hospital Sao Paulo of Escola Paulista de Medicina. On the 7th day,
they returned to the hospital, signed the informed consent and were
randomly divided in two groups of 8. Each group started the ingestion of
identical gelatine capsules containing either glucose as placebo (control
group) or CBD (experimental group). The experiment was performed on a
double-blind basis and the subjects were instructed to ingest the assigned
capsules, one in the morning and the second in the afternoon for 30 days.
Each capsule contained an amount of CBD (or glucose) equivalent to 1.5 mg
/ kg, i.e. a daily dosage of 3.0 mg / kg. 1 volunteer took 4 capsules of
CBD daily (6 mg / kg) on the last 3 days of the experiment.

On the 3rd, 7th, 15th, 31st and 37th days after the beginning of
drug ingestion, the subjects returned to the hospital to undergo the
examinations described above.



Drug

Cannabidiol, in crystalline from (m.p. 66--67) was isolated from
hashish of undetermined age. It was of Lebanese origin and was supplied by
the Israeli Police. The isolation procedure has been described (Gaoni and
Mechoulam, 1971). Part of the CBD was a gift from Makor Chemicals, P.O.B.
6570, Jerusalem

Results

General Observations
During the entire period of the experiment, the subjects did not
report any symptoms suggestive of psychotropic effect of CBD. Of the 8
volunteers receiving the placebo, 1 gave up on the 21st day of the
experiment for personal reasons; a second placebo subject reported
sudoresis and 'palpitations' from the 7th to the 10th day in the veins of
the feet, legs and head, stating that he had to uncover his feet to feel
the palpitations less in order to sleep. Clinical and laboratory
examinations were normal and the symptoms subsided after the 11th day
without any measures on the part of the investigators.

Of the 8 volunteers receiving CBD, 2 reported somnolence, 1 during
the first week and the other throughout the entire period of the
experiment. A 3rd subject, with a history of mild insomnia, reported being
able to sleep better during the first week of medication.

Neurological and clinical examinations, EEG and ECG tracings, and
blood and urine analyses (detailed above) were within normal limits in
the 16 subjects before, during and after the experiment.

Comments

It has been suggested that delta-1-THC and other cannabinoids may
possess therapeutic potential as antidepressive drugs in patients with
cancer (Regelson et al., 1975) or in the treatment of glaucoma (Hepler
and Frank, 1971), asthma (Tashkin et al., 1972), etc. For a recent review
see Mechoulam and Carlini (1978). However, acute administration of 20--60
mg of delta-1-THC induces a marked psychic change and has peripheral
effects such as an increase in heart rate (Isbell et al., 1967; Kiplinger
et al., 1971; Karniol et al., 1975) which would limit its therapeutic
use.

In contrast, the present experiment shows that 3 mg / kg / day of
CBD administered for 30 days (1 volunteer received 6 mg / kg / day during
the last 3 days of experiment) did not induce any psychic or other side
effects and was well tolerated by the 8 subjects. Thus CBD does not appear
to have any toxic effect in humans when administered at the above dosage
over a long period. This confirms our previous data obtained in animal
(Cunha and Carlini, to be published).

In our opinion these findings justified the trial of the drug in
epileptic patients.
Experiment 2 (Phase 2 of Study)

Material and Methods

Subjects
15 Epileptic patients, 11 women and 4 men, aged 14-49 (average 24
years), with a documented history of frequent convulsions for at least 1
year, were selected. These patients were not reacting satisfactorily to
the prescribed antiepileptic drugs they were receiving (table 1) in spite
of special care to assure that the patients were taking them properly. The
patients were diagnosed as cases of secondary generalized epilepsy; EEG
tracings revealed irritative activity with temporal projection. They had
at least one generalized convulsive crisis weekly. Clinical and laboratory
examinations showed no signs of renal, cardiovascular or hepatic disease.
The experiment was performed in the Neurology Out-Patient Clinics of the
Hospital Sao Paulo (8 patients) and the Hospital da Santa Case (t
patients). Each patient was followed by the same investigator, beginning 2
weeks before first drug administration and then throughout the whole period
of drug administration. In the 2 weeks before CBD or placebo
administration, the number of focal and generalized convulsive crises was
recorded and considered as the baseline to evaluate treatment. On the
first day of the experiment, the patients were submitted to the
examinations described in experiment 1. They were randomly divided into
one group of 8 (control group) and another group of 7 (CBD group) and
returned to the hospital for 2 more days. After 1 week each group received
placebo or CBD capsules in a double-blind procedure in addition to the
antiepileptic drugs they were already receiving (see table 1). 1 placebo
patient (Z.S.M.) was transferred to the CBD group after 1 month. Half of
each group of patients was treated in each hospital. The patients were
instructed to take 2 or 3 capsules daily (containing 100 mg of CBD or
glucose) and to return to the hospital every week for clinical and / or
laboratory examinations.

Clinical evaluation of drug treatment was made weekly using a scale
with score 0-3, which took into consideration absence of convulsive crises
or absence of generalization and self-reported subjective improvement (see
tableII). According to this criterion all patients were scored 3 during
the predrug phase (baseline).

Results

General Observations
During the curse of the experiment none of the 8 patients receiving
CBD showed evidence of behavioral alterations which could be suggestive of
a psychotropic effect. The minimum and maximum times of drug
administration were 8 and 18 weeks for most patients (control and CBD
groups). 2 of the placebo patients did not return after the end of the 4th
week and 1 CBD patient after the 6th week. 1 placebo patient (Z.S.M.)
whose condition remained unaltered during 4 weeks, wanted to give up the
experiment, but remained in it after crossing over to the CBD group.

4 patients under CBD and 1 receiving placebo complained of
somnolence during the experiment. Another CBD patient (M.C.P.)
complained of painful gastric sensations after drug ingestion at the 6th
week. These symptoms disappeared after prescription of an antacid and did
not return throughout the experiment.

Table II. Criteria used to evaluate clinical efficacy of cannabidiol in
epileptic patients

Score 0......complete improvement
Score 1......partial improvement
Score 2......small improvement
Score 3......without improvement

0 = Total absence of convulsive crises and self-reported subjective
improvement.
1 = Absence of generalization of crises and self-reported subjective
improvement.
2 = Only self-reported subjective improvement.
3 = No reduction in crises and no self-reported improvement.


Neurological Examination and EEG
Before drug treatment 1 CBD patient (N.D.) showed paresthetic
walking towards the right, with spastic hypomotility of the right arm and
leg, mainly of the right hand. He also presented a decrease in psychomotor
functions. 2 other patients in the CBD group (A.A.S. and Z.S.M.) showed
in examinations prior to the experiment some mental underdevelopment.
Neurological examinations of all other patients were within normal limits.

Table III shows the results of the EEG analysis in a condensed
form. Of the patients receiving CBD, 3 showed improvement in EEG pattern
with signs of decrease in frequency of crises throughout the experiment. 2
placebo patients also had improved EEG patterns (J.O.R., and J.S.V.) on
one occasion, with a return to their previous condition on subsequent
examination.

Clinical Evaluation of Treatment
Clinical evaluation was performed weekly, scoring 0 - 3 points to
each patient compared to its own baseline (see table II and 'methods' for
details). At the end of the treatment, the median of weekly score for each
patient was calculated. The results are presented in table IV. During the
first week of treatment there was general improvement in almost all
patients (placebo and CBD groups), but from the second week, all placebo
patients with one exception (M.D.M.S.) returned to their previous clinical
state. At the end of the placebo treatment, 7 patients had a median of 3
(i.e. no improvement) whereas patient M.D.M.S. showed complete
improvement (median 0). 2 placebo patients (J.S. and M.G.S.) with no
improvement received the capsules for the 4th week of treatment but did not
return. 3 other placebo patients (J.O.R.; J.S.V.; M.L.M.) remained under
treatment for the period stated in table IV, after which it was decided to
withdraw them from the experiment and to change the antiepileptic drugs
they were receiving (see table I) in an attempt to improve their
condition. Patient R.C. remained in the placebo group for 18 weeks and
received all known antiepileptic drugs without success. Patient Z.S.M. was
on placebo for 4 weeks without improvement and was subsequently transferred
to 200 mg of CBD daily for 6 weeks (without her knowledge) with a small
improvement (median 2).

Of the 8 patients receiving CBD, 4 showed considerable improvement
in their clinical condition (median 0). However, in 1 case (M.C.P.) this
was achieved by increasing the dosage to 300 mg daily. Patient A.A.S., who
showed much improvement from the first week, unfortunately moved to another
city after completing 6 weeks of treatment with CBD. The 5th patient
(F.R.F.) improved only partially (median 1) although he attained score 0
in clinical evaluation (no convulsive crisis and subjective improvement)
in 7 out of the 16 weeks of treatment. 2 of the 3 remaining patients
showed improvement (score 2) whereas the last patient (N.D.) did not
improve at all in spite of increasing CBD to 300 mg daily for the last 2
weeks of treatment.

Table IV

JOR placebo 3
JS placebo 3
MGS Placebo 3
JSV placebo 3
MLM placebo 3
RC placebo 3
MDMSplacebo 0
ZSM placebo 3

ZSM CBD200 2
FRF CBD200 1
OEBNCBD200 0
AAS CBD200 0
ASR CBD200 2
NP CBD200
300 3
MCP CBD200
300 0

0 = complete improvement
3 = no improvement


Discussion

Treatment of epilepsy is based mainly on anticonvulsant drugs.
However, even when properly administered in well-diagnosed cases, these
drugs succeed in helping only about 70-75% of the epileptic patients,
whereas about 30% of the patients do not benefit at all (Robb, 1975).
Furthermore, all clinically effective antiepileptic drugs induce
undesirable side effects at normal dosage (osteomalacia, megaloblastic
anemia; gingival hyperplasia) or due to overdose (nystagmus, motor
incoordination, coma and death) or to idiosyncratic reactions (Kutt and
Louis, 1972).

As already stated in the introduction, many ancient reports mention
the antiepileptic properties of cannabis. More recently Consroe et al.
(1975) described an epileptic patient receiving phenobarbital and phenytoin
without good results, who benefited by smoking marihuana. These accounts
indicate that marihuana contains chemical entities which may possess
anti-epileptic properties.

According to the present data, CBD may turn out to be a useful
drug for the treatment of some cases of epilepsy. There is hardly any
toxicity as shown in our phase 1 study; there were no changes in EEG, ECG,
blood and urine analyses and neurological and clinical examinations were
normal in 8 healthy volunteers receiving 3 mg / kg of CBD daily for 30
days. A similar absence of toxicity was also noted in our phase 2 study in
which 8 epileptic patients received 200 or 300 mg for up to 4 1/2 months.
Furthermore, none of the 16 subjects receiving CBD showed any psychic
delta-1-THC-type effects. The present data obtained after long-term
administration also confirm previous reports showing the absence of
toxicity in acute studies (Hollister, 1973; Carlini et al, 1979).

Somnolence reported by 3 healthy volunteers and 4 epileptic
patients (43% of the subjects receiving the drug) was the only CBD side
effect noted. A certain hypnotic effect is frequently observed with drugs
which possess antiepileptic properties. We have in fact recently
demonstrated that CBD does induce better sleep in human volunteers
(Carlini et al., 1979). On the other hand, CBD induced a remarkable
improvement (median 0) in 4 of 8 epileptic patients who remained almost
free of convulsive crises during the entire period of the experiment. In a
5th patient (median 1), the crises were absent in 7 of the 16 weeks of
treatment. All of these patients (as well as their relatives) reported
subjective improvement. A similar subjective effect was also reported by 2
more patients and only in 1 patient CBD failed to induce any form of
clinical benefit. This is in striking contrast to the results obtained
with the 8 patients receiving placebo of whom 7 showed no improvement in
their clinical condition.

However, EEG results were not as consistent as the clinical
evaluation. As seen in table III, clinical improvement was not always
followed by positive changes in the tracings. As the International League
against Epilepsy (Commission on Antiepileptic Drugs) does not consider
EEG mandatory in this type of research (Penry, 1973), EEG data were not
included in the overall clinical evaluation of CBD effects. It should also
be emphasized that the abnormal EEGs were present from the beginning of the
experiment even though all patients were receiving known antiepileptic
drugs. Furthermore, phenytoin and barbiturates fail to control the EEG
abnormalities of epileptics in spite of being able to abolish their
behavioral convulsions; phenytoin may even increase the prominence of
focal spikes (Morrel et al., 1959; Millichap, 1969).

Wall et al. (1976) have reported pharmacokinetic studies in man
with 3H-CBD injected intravenously into 5 healthy volunteers. They
observed that 8% of the total initial dose (20 mg of CBD) was present in
plasma 30 min after injection, to fall to 3% after 60 minutes. 3 days
later, 33% was excreted in the feces and 16% in the urine, with 50%
remaining in tissues and organs. Therefore, CBD seems to have a relatively
long half-life, which favors its use as a drug in epileptics.

However, in spite of the large number of reports showing beneficial
effects of cannabis and its preparations in many forms of experimental
convulsions and in human epilepsy, a few reports claim the contrary.
Feeney et al. (1976) showed that delta-1-THC in cats induced EEG changes
resembling those observed in convulsions, and Perez-Reyes and Wingfield
(1974) described a similar effect of CBD in man. In neither case,
however, were behavioral convulsions observed. It is interesting in this
context that phenytoin may increase activity of focal spikes (Millichap,
1969). To the best of our knowledge there is only one report attributing a
worsening of an epileptic convulsive crisis (grand mal) following use of
marihuana smoking (Keeler and Reifler, 1967), and we do not know of any
cases described for CBD. Furthermore, in none of our 8 epileptic patients
did we observe deterioration of clinical symptomatology or of EEG, but
rather the opposite effect was true.

The mechanism by which CBD benefited our epileptic patients is not
known. All 8 patients were also receiving known antiepileptic drugs which
were by themselves, however, ineffective. One possibility is that CBD
potentiated their action since enhancement by CBD of anticonvulsant
activity of phenobarbital and phenytoin in animals has been demonstrated
(Consroe and Wolkin, 1977; Chesher and Jackson, 1974; Chesher et al.,
1975). In man, however, 50--500 mcg / kg CBD given in cigarette form is
not able to alter plasma concentrations of secobarbital (Dalton et al.,
1976b). The possibility that CBD acts per se should also be taken into
consideration, as shown by several reports describing its direct
anticonvulsant effects in animals.

In conclusion, we have found that CBD had a beneficial effect in
patients suffering from secondary generalized epilepsy with temporal foci,
who did not benefit from know anti-epileptic drugs. Further research with
more patients and other forms of epilepsy is needed to establish the scope
of the antiepileptic effects of CBD in humans.

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Jomar M. Cunha, Departamento de psicobiologia, Escola Paulista de Medicina,
Rua Botucatu 862, 04023 Sao Paulo (Brasil)



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