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Abstract: Clinical trials with cannabidiol
(CBD) in healthy volunteers, insomniacs, 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 testsl (EKG, blood
pressure, and blood and urine analysis) revealed no sign of
toxicity. Doses of 40, 80s, 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.
An advertisement published in 1905 by a Brazilian
newspaper advised the use of "Cigarros Indios" prepared
from Cannabis indica to treat insomnia, among other
diseases. Anecdotal reports also claim that Queen Carlota
Joaquina of Portugal, while living in Brazil at the
beginning of the last century, used to drink a tea of
"Maconha" (Brazilian name for marihuana) to calm herself.
These uses of marihuana in the past were by no means
restricted to Brazil. Its use for sedative, hypnotic,
anesthetic, and antiepileptic effects goes back to ancient
times and all continents. (1-3)
In our times, the unraveling of the chemistry of
Cannabis sativa brought renewed interest in old reports
concerning the therapeutic properties of marihuana, and
much new research has been carried out. Quite expectedly,
the attention has focused on delta-9-tetrahydrocannabinol
(THC), considered the main active principle of marihuana,
due to its remarkable psychotropic properties. Its hypnotic
and anticonvulsive effects in animals and in man have been
reported by several laboratories, (4-11) but eventual
medical use of THC would be hindered by its hallucinogenic
effects. Furthermore, THC also possesses convulsant
activity. (12-14)
Cannabidiol (CBD), on the other hand, lacks
hallucinogenic properties and is therefore a better
candidate for therapeutic use. In fact, work carried out
with laboratory animals has shown that cannabidiol has
depressant effects on the central nervous system in such
tests as potentiation of barbiturate sleeping time and
decrease of spontaneous motor activity. (15, 16) It has
been further demonstrated that cannabidiol possesses a
rather potent protective effect against certain types of
experimental convulsions in animals (17-20) and an
hypnotic-like effect in the rat. (21)s Therefore, trial of
cannabidiol in humans was in order.
This report reviews data obtained in our laboratory from
1972 up to the present dealing with the effects of acute
and chronic administration of cannabidiol to healthy
volunteers and to insomniacs and epileptic patients. More
detailed information of these experiments can be found
elsewhere. (22-25)
ACUTE ADMINISTRATION OF CANNABIDIOL TO HEALTHY
VOLUNTEERS (Phase I Studies)
Three experiments were performed on different
occasions.
Experiment 1 (performed November 1972). Four physicians,
three psychologists, and three biologists, all staff
members of the Department of Psychobiology, varying in age
from 23 to 42 years (four females and six males)
volunteered. On the first day of the experiment, they
underwent a complete medical checkup, including clinical
and neurologic examinations, EKG and EEG, blood tests
(hematocrit, hemoglobin, leukocyte and erythrocyte counts,
bilirubin, oxaloacetic and puruvic transaminases, and
creatinine) and urine tests (osmolarity, pH, albumin,
leukocyyte and erythrocyte counts, cylinders, and
crystals). All volunteers were in good health, showing
neither clinical nor laboratory evidence of cardiovascular,
renal, hepatic, or other impairment.
On the morning of the seventh day, two volunteers were
randomly assigned, in a blind procedure, to receive
identical gelatin capsules containing either glucose or 10,
40, 80, or 160 mg cannabidiol. The sample of crystalline
cannabidiol was kindly supplied by the National Institutes
of Health, United States. At 30, 90, 240, and 480 minutes,
EKGs were again performed. EEGs were also obtained 240 and
480 minutes after the dose, and so were blood and urine
samples for laboratory procedures. These examinations were
repeated in the morning of the following day.
All laboratory results obtained on days 7 and 8 were
within normal limits and similar to the values obtained on
the first day, without drug. Physical and neurologic
examinations revealed no abnormalities, and the volunteers
did not complain of untoward effects.
Experiment 2 (January 1976). Two male physicians, aged
37 and 47 years, from the staff of the Department of
Psychobiology received 600 mg cannabidiol for two days, 300
mg in the morning and 300 mg in the evening. The drug was
furnished by R. Mechoulam, Department of Natural Products,
University of Jerusalem, Israel. The experimental protocol
was identical to that of experiment 1, with the exception
that EEG and blood and urine tests were not performed. With
the exception that one volunteer reported having slept more
heavily on the nights after taking the drug, no abnormal
finding was detected.
Experiment 3 (February and June 1978). The overall
design of this experiment included a study of the
interaction between cannabidiol and alcohol on psychomotor
and psychologic functions of healthy volunteers. In the
present review only data concerning the effects of
cannabidiol and placebo will be compared. Details
concerning cannabidiol-alcohol interactions can be found
elsewhere. (23)
Ten healthy postgraduate students volunteered (sic males
and four females), 21 to 33 years of age and weighing 52 to
85 kg. Crystalline cannabidiol (supplied by R. Mechoulam,
Israel) and glucose, 200 mg each, were formulated
separately in opaque gelatin capsules. The experiment
comprised four different drug administrations, at weekly
intervals, one being with glucose and another with
cannabidiol. The other two were alcohol and alcohol plus
cannabidiol administration and will not be further referred
to here. Inasmuch as drug administration was given randomly
in a double-blind procedure, glucose and cannabidiol
ingestions were from one to three weeks apart. The
experiments began at 11:00 A.M. and continued until 4:00
P.M. The subjects were submitted to objective and
subjective tests 1/2, 1, 2, and 4 hours after cannabidiol
or glucose ingestion. The following battery of tests,
taking about 25 minutes per session, was applied:
cancellation test, differential aptitude test (Form A, the
Psychological Corporation, New York, N.Y.), time production
task, finger tap test, and a subjective drug reaction
scale. Details of these tests are given elsewhere. (23)
Table I presents the results of the first four tests in
a condensed form. For each test the data obtained at times
30, 60, 120, and 240 minutes after drug ingestion were
similar and were therefore pooled. It is seen that in the
cancellation test the volunteers reacher very close to the
total of 40 possible correct responses, regardless of
whether they were under placebo or cannabidiol. Also with
both treatments they have a near-perfect performance in the
differential aptitude test and reached above 300 presses
per minute in the finger tap test. Finally, Table I shows
that treatment did not influence the capacity of the
volunteers to produce ddd1-minute time. The results
obtained with the subjective drug reaction scale also
confirmed the lack of effects of cannabidiol on the
subjective functioning of the volunteers, as they felt
equally sober, non-drugged, alert, and nondizzy under
either cannabidiol or glucose.
Chronic Administration of Cannabidiol to Healthy
Volunteers (Phase I Studies)
Two experiments were performed on different
occasions.
Experiment 4 (December 1972 and January 1973). Due to
the small amount of cannabidiol available (remaining NIH
material from experiment 1 and a sample supplied by Prof.
R. Mechoulam, Israel), only four male volunteers from the
Department of Psychobiology staff were selected -- two
physicians, one biochemist, and one psychologist, age range
23 to 30 years. The experiment was run double-blind, and on
day 1 complete medical checkups and complementary
laboratory tests were done as in experiment 1. Two
volunteers were randomly assigned to receive 10 mg
cannabidiol daily for 20 days (two gelatin capsules
containing 5 mg each, one to be ingested at 9:00 A.M. and
the other at 5:00 P.M. every day). The third volunteer
received two identical capsules with glucose for 20 days,
and the fourth ingested cannabidiol during the first 10
days and was crossed over to placebo for the last 10 days.
Drug ingestion began on day 7, extending to day 26, and
medical and laboratory examinations were repeated in the
morning of days 8, 15, 22, and 27 (corresponding to days 1,
8, 15, and 21 after the beginning drug ingestion).
The two volunteers receiving 10 mg cannabidiol for 20
days and the one who received it for the fist 10 days did
not complain of any physical discomfort or psychologic
disturbnance. However, two volunteers complained of
somnolence with cannabidiol, one after day 3 and another
after day 4; the symptom subsided by day 15s. Physical and
neurologic examinations, EEG, EKG, and blood and urine
tests were all within normal limits and did not differ in
the same volunteer regardless of being performed before or
at different times after the beginning of drug ingestion.
Further details of these results can be found elsewhere.
(25)
Experiment 5 (between February and April 1976). Sixteen
adult volunteers (11 men and five women), aged 22 to 35
years, with an average weight of 65 kg. were chosen from
the staff of Escola Paulista de Medicina. They were all in
apparent good health, which was confirmed on day 1 when
they were subjected to complete medical and laboratory
examinations as described in experiment 1.
On day 7 (having given informed consent), they were
randomly divided into two groups of eight. Each group
received capsules containing either glucose or cannabidiol.
Crystalline cannabidiol was supplied by R. Mechoulam,
Israel. The experiment was performed on a double-blind
basis, and the subjects were instructed to ingest the
assigned capsules, one in the morning and one in the
afternoon. Each capsule contained an amount of cannabidiol
equivalent to 1.5 mg/kg, i.e., a daily dosage of 3.0 mg/kg.
On days 3, 7, 31 and 37 after the beginning of drug
ingestion, the volunteers returned to undergo the medical
and laboratory examinations as described above.
The results confirmed the absence of toxic effects of
cannabidiol Thus, of the eight volunteers receiving
placebo, one withdrew on the 21st day for personal reasons;
a second placebo subject complained of sudoresis and
"palpitations" from days 7 to 10 in the veins of the feet.
Clinical and laboratory examinations were normal, and the
symptoms subsided after day 11 without intervention being
required on the part of the investigators. On the other
hand, none of the eight cannabidiol volunteers complained
of any symptom suggestive of psychotropic effect during the
entire period of the experiment. However, two of them
reported somnolence--one during the first week and the
other throughout the 30 days of drug ingestion. A third
subject, with a history of mild insomnia, reported better
sleep during the first week of medication.
For the 16 subjects (placebo and cannabidiol groups),
neurologic and clinical examinations, EEG and EKG tracings,
and blood and urine analysis were within normal limits
before, during and after the experiment. Detailed accounts
of these results have been published recently. (24)
Clinical Trial of Cannabidiol as an Hypnotic
Drug
The lack of toxicity of cannabidiol observed in our
Phase I studies (experiments 1, 2, 4, and 5) and the
complaints of somnolence by several volunteers receiving
the drug (experiments 2, 4, and 5), together with the
reported hypnotic-like effect of cannabidiol in rats, (21)
encouraged us to give a first trial of cannabidiol as an
hypnotic agent in humans. This experiment was carried out
during June--November 1977. A detailed account of the
findings was previously published. (22)
A new sample crystalline cannabidiol, kindly supplied by
NIH, was incorporated into gelatin capsules in amounts of
40, 80, and 160 mg. Pills containing 5 mg nitrazepam
(Mogadon kindly supplied by Roche Laboratories) were
crushed and encapsulated. As placebo, 200 mg glucose was
encapsulated in identical gelatin capsules.
After physical examination and psychiatric interview, 15
relatives of staff members of Escola Paulista de Medicina
were selected. They were chosen on the basis of (a)
complaints of difficulty in falling asleep (at least 1
hour) and poor sleep throughout the night; (b) history of
previous good physical and mental health; (c) no previous
history of nonmedical use of drugs; and (d) no prescribed
medicines for at least 15 days before.
In a double-blind procedure and in random order, once a
week, the volunteers were instructed to ingest one assigned
capsule. At dinner of the chosen days, they were requested
to refrain from alcohol and coffee, and to ingest the
capsule 30 minutes before going to bed, between 10:00 and
10:30 P.M. All volunteers received all treatments, that is,
placebo, 5 mg nitrazepam, and the three dosages of
cannabidiol Therefore, the experiment lasted five weeks. In
the mornings of days after drug administration, the
volunteers answered a ten-point questionnaire, adapted from
Bloomfield et al., (26) and were briefly interviewed. The
questions sought information on induction of sleep
(questions 1 and 2), sleep quality (questions 3, 4, and 5),
dream recall (questions 6 and 7), and reawakening
(questions 8, 9, and 10). Answers to questions 1, 2, 3, 4,
and 8 had five possibilities, scored from 0 to 4, score 4
indicting the best hypnotic effect. For example, the five
possible answers to question 1, "How much time elapsed
between going to bed and onset of sleep?" were: less than
15 minutes (grade 4), between 15 and 30 minutes (grade 3),
between 30 and 45 minutes (grade 2), between 45 and 60
minutes (grade 1) and more than 60 minutes (grade 0).
Answers to questions 5, 6, 7, 9, and 10 were not
transformed into scores, as they had only two options, yes
and no.
The results are condensed in Table II. The first
noticeable finding was the placebo effect, which is rather
common in this kind of research. Thus, before starting drug
administration all patients took at least 1 hour to fall
asleep (score 0). However, under placebo, six patients
scored grades 3 and 4--five reported having slept within 15
to 30 minutes after going to bed (grade 3) and one in less
than 15 minutes (grade 4). Cannabidiol, and also 5 mg.
nitrazepam, did not produce a positive sleep induction
effect in the volunteers. Thus, although eight subjects
reported grades 3 and 4 for 160 mg cannabidiol and 5 mg
nitrazepam, this number fell short of statistical
significance when compared to the large value also found
for placebo. The quality of sleep induction, assessed by
the answers to question 2, "What was the effect o the
medication before you fell asleep?" also was not influenced
by the treatments. Thus, the majority of the volunteers
answered "nil" to that question, and only a few volunteers
(see second row of Table II) answered "pleasant" (grade 3).
It is interesting that Bloomfield et al (26) also reported
that secobarbital failed to influence sleep induction.
Sleep quality was significantly influenced by 160 mg
cannabidiol, as two thirds of the subjects slept more than
7 hours, scoring 3 and 4 in answer to question 3.
Furthermore, most subjects had few interruptions of sleep
(question 4) and reported having a good night's sleep
(question 5).
The three doses of cannabidiol were effective in
significantly reducing dream recall of the volunteers. This
could have occurred because cannabidiol may decrease the
capacity to dream in itself, that is, the volunteers
dreamed less. Conversely, cannabidiol may also have reduced
dream recall, that is, the volunteers dreamed as usual but
could not remember. The latter possibility would indirectly
indicate that cannabidiol may have decreased the frequency
of small awakening periods during the night sleep which
facilitates remembering the oneiric events.
Finally, the last four questions of Table II indicate
that cannabidiol did not induce nightmares or symptoms that
could indicate hangover the following morning.
Antiepileptic Effects of Cannabidiol
This experiment was done between May 1976 and March
1978, and the results were recently published. (24)
Fifteen epileptic patients (11 women and four men), aged
14 to 49 years (average 24 years) with a documented history
of frequent convulsions for at least one year were
selected. These patients were not responding satisfactorily
to their prescribed antiepileptic drugs. The patients were
diagnosed as cases of secondary generalized epilepsy; EEG
tracings revealed irritative activity with temporal
projections. They had at least one generalized convulsive
crisis weekly. In the two weeks before cannabidiol 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 eight
(control) and another group of seven )cannabidiol). One
week later, each group began to receive placebo or
cannabidiol capsules in a double-blind procedure in
addition to the antiepileptic drugs they were already
receiving. The patients were instructed to take two or
three capsules daily (containing 100 mg cannabidiol 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 score scale of 0 to 3, which took into
consideration absence of convulsive crises or absence of
generalization and self-reported subjective improvement. On
this scale, a score of 3 meant no improvement, that is, no
reduction in crises and no self-reported subjective
improvement; a score of 2, small improvement or
self-reported subjective improvement; a score of 1, partial
improvement or absence of generalization of crisis and
self-reported improvement; finally, a score of 0, complete
improvement or total absence of convulsive crisis and
self-reported subjective improvement. According to these
criteria, all patients had a score of 3 during the pre drug
phase (baseline).
The results are seen in Table III. At the end of placebo
treatment, seven patients had a median score of 3 (i.e., no
improvement), whereas one patient (patient 7) showed
complete improvement (median score 0). Placebo patients 2
and 3, with no improvement, received the capsules for the
fourth week of treatment but did not return. Three other
placebo patients (1, 4, and 5) remained under treatment for
12, 12, and eight weeks, respectively, after which they
were withdrawn from the experiment and underwent a change
in the prescribed antiepileptic drugs in an attempt to
improve their condition. Finally, patient 8 remained on
placebo for four weeks with no improvement (median score 3)
and wanted to give up, being transferred without her
knowledge to cannabidiol with a small improvement (median
score 2).
Of the eight patients receiving cannabidiol, four
(patients 10, 11, 12, and 15) showed considerable
improvement (median score 0); however, in one case (patient
15) this was achieved by increasing the dosage to 300 mg
daily. Patient 11, who showed much improvement from the
first week, moved to another city after completing six
weeks of treatment. Patient 9 improved partially (median
score 1) although he attained score 0 ( no convulsive
crisis and subjective improvement) in seven out of the 16
weeks of treatment. Finally, two of the three remaining
patients had a median score of 2 (only self-reported
subjective improvement), whereas the last patient, 14, did
not improve at all in spite of increasing cannabidiol to
300 mg daily for the last two weeks of treatment.
Clinical examination proved normal for all cannabidiol
patients, and the pulse, cardiac, and respiratory rates
remained constant during the course of the experiment. Also
cannabidiol did not alter the creatinine, bilirubin, or
transaminase values in the eight patients. However, four
patients complained of somnolence during the
experiment.
General Comments
The first relevant finding of these studies concerns the
rather remarkable lack of toxicity from acute and chronic
administration of cannabidiol Thus, in five experiments
with healthy volunteers there was no subjective or physical
symptom suggestive of toxic effect. The same conclusion was
also reached after the laboratory examinations. Although in
some experiments the number of subjects was low due to the
limited availability of cannabidiol, taken all together the
data strongly support our contention, regarding the
excellent toleration of cannabidiol Furthermore, the acute
administration of the drug to the insomniacs and the 3 to
4.5 months of treatment of the epileptics confirm the lack
of toxicity.
Concerning the eventual hypnotic effect of cannabidiol,
our preliminary data with 15 subjects tend to confirm that
it has such potential use. In fact, 160 mg cannabidiol
significantly increased the number of hours the subjects
slept, and all three doses decreased dream recall, which
could be the consequence of less sleep interruptions during
the night's sleep. It is significant in this respect that
several healthy volunteers complained of somnolence when
under cannabidiol, a fact also reported by four of the
eight epileptic patients. It is interesting that 5 mg
nitrazepam (the amount commercially available in sleeping
pills in Brazil), did not differ in its effect from
placebo. Other authors have reported clear hypnotic effects
with 10 mg nitrazepam. (27,28)
A note is in order about the method used to measure
hypnotic effect of cannabidiol The use of self-reported
questionnaires to evaluate hypnotic effects is considered a
subjective method, in opposition to the objective methods
such as the inspection of the volunteers in
inpatient-settings throughout the night or the obtention of
continuous EEG recordings. Both methods have enthusiastic
followers. (29,30)
The clinical trial of cannabidiol as an eventual
antiepileptic agent was conducted with eight cases of
severely ill patients, refractory to all known
antiepileptic drugs. The results indicate that cannabidiol
has a beneficial effect in patients suffering from
secondary generalized epilepsy with temporal focus who do
not benefit from known antiepileptic drugs. The mechanism
by which cannabidiol benefited our epileptic patients is
not known. One possibility is that cannabidiol potentiates
the action of the other anticonvulsants since enhancement
by cannabidiol of the anticonvulsant activity of
phenobarbital and phenytoin in animals has been
demonstrated. (18, 31,32) In man however, 50 to 500 mcg/kg
cannabidiol given in cigarette form is not able to alter
plasma concentrations of secobarbital. (33) The possibility
that cannabidiol acts per se should also be taken into
consideration, as shown by several reports describing its
direct anticonvulsant effects in animals. In this respect
it is important to note that Tamir et al. (34) have
reported that cannabidiol and phenytoin both possess
similar stereochemical requirements for anticonvulsant drug
action.
Discussion of the Paper
Dr. Cornwell: Why did you use weekly doses of CBD for
your insomnia study? Was there any differential effect in
terms of improvement in sleep for the 7 nights between the
doses?
Dr. Carlini: We used single doses of CBD 40, 80, and 160
mg at weekly intervals mainly because we had only a very
small supply of CBD. I have no data on differential effects
on sleep since the patients were interviewed only at weekly
intervals.
Dr. Benowitz: We studied 10 patients receiving 600 mg of
CBD per day for up to 12 days (Benowitz, NL, et al. Clin
Pharmacol Therap. 1980; 28: 115-120) We found no
psychophysiological, sedative hypnotic, nor EEG effects.
Consistent with findings from experiments in animals,
barbiturate metabolism was inhibited (35-40% reduction of
hexobarbital clearance). Is it possible that some of the
hypnotic and anticonvulsant effects of CBD might be due to
inhibition of metabolism of co-administered anticonvulsant
drugs?
Dr. Carlini: That is a real possibility, since all
patients were also receiving phenobarbital, mehpobarbital,
or phenytoin. The first hypothesis would be that CBD
interferes with metabolism, potentiating the action of
these drugs as you suggest. The second of course would be
that CBD had an action by itself. We have no data to
address these two possibilities.
Dr. Karler: The sedative effects appear to be real,
because some normal volunteers were sedated by CBD in the
absence of any coexisting drug therapy. Why is it, however,
that Dr. Benowitz did not see sedative effects in his
patients? Was that due to a dose-differential? Dr.
Benowitz: In our study, 600 mg a day was administered in
divided 100 mg doses.
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