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Cannabidiol (CBD) a nonpsychoactive cannabinoid of
Cannabis, was given to 5 patients with dystonic movement
disorders in a preliminary open pilot study. Oral doses of
CBD rising from 100 t 600 mg/day over a 6 week period were
administered along with standard medication. Dose-related
improvement in dystonia was observed in all patients and
ranged from 20 to 50%. Side-effects of CBD were mild and
included hypotension, dry mouth, psychomotor slowing,
lightheadedness, and sedation. In 2 patients with
coexisting Parkinsonian features, CBD at doses over 300
mg/day exacerbated the hypokinesia and resting tremor. CBD
appears to have antidystonic and Parkinsonism-aggravating
effects in humans.
As early as 1842, O'Shaughnessy reported that oral
Cannabis blocked tetanic convulsions and reduced muscular
spasms in his patients afflicted with epilepsy, tetanus or
rabies, while in 1890 Reynolds claimed that oral Cannabis
was useful in the management of "choreoid and epileptoid
clonic spasms." During the latter 19th century, Cannabis
was commonly employed as a general antispasmodic agent, and
several recent reports appear to provide some justification
for this use. In 1981, Petro and Ellenberger reported that
delta-9-tetrahydrocannabinol (THC), the major psychoactive
cannabinoid of Cannabis, reduced spasticity of multiple
sclerosis, and in 1983 Cliffored reported that THC reduced
tremor in a few patients with the same disease. Also in
1980 Cunha et al. reported that cannabidiol (CBD), a major
nonpsychoactive cannabinoid of Cannabis, prevented
convulsions in epileptic patients who were largely
refractory to standard antiepileptic drugs.
Recently, it has been mentioned that patients with
idiopathic dystonia (a group of disorders characterized by
abnormal movements and postures produced by prolonged
spasms of muscle contractions) improved with Cannabis
smoking (Marsden, 1981). In addition, findings of potent
effects of cannabinoids on reserpine-induced hypokinesia in
rats led to the suggestion that cannabinoids might have
antidystonic properties in humans (Moss et al., 1984). In
light of the above, we initiated an open trial of CBD in a
patient with Meige's syndrome (Blepharospasm-oromandibbular
dystonia) (Snider & Consroe, 1984) and a patient with
levodopa-induced dystonia (Snider & Consroe, 1985). We
now present the results of our preliminary open study of
oral CBD in these two cases and in three additional
patients with primary dystonia.
METHODS
Five patients with dystonic movement disorders
participated in our approved study (University of Arizona
Human Subjects Committee and the U.S. Food and Drug
Administration) after receiving informed consent. Patients
No. 1, 3 and 5 were currently taking antidystonic
medication but were only partialy controlled by these
agents. Patient Nol 4 had persistent disabling generalized
dystonia despite trials to reduce the dosage of his current
antiparkinsonism medication. Finally, Patient No. 2 was
presently taking only antihypertensive medication. The
clinical characteristics of the patients are shown in Table
I.
Oral CBD (in capsules with sesame oil vehicle) was
started at 100mg/day and subsequently increased weekly by
100 mg/day to a maximum of 600 mg/day. Clinical response to
treatment with CBD was assessed by using a standard
dystonia movement scale, ranging from 0 to 120 (Burke et
al., 1985). Patients were evaluated "live" by 1 neurologist
(S.R.S.) at baseline (1 day before CBD administration), 6
weekly intervals during CBD administration, and 2 and 7
days after the cessation of CBD; examinations of patients
were carried out at the same time of day. The therapeutic
results were expressed as a percentage change from the
baseline dystonia movement score. Patients were also
vidiotaped according to a standard format (Burke et al.,
1985), and the presence or absence of improvement to CBD
therapy was assessed independently by another neurologist
(R.S.) Side-effects and other subjective impressions were
obtained from patients and/or their guardians who
maintained a daily log of their treatment responses.
Further, blood pressures and pulse rates were measured at
every clinic visit, and blood counts and chemistries were
evaluated at baseline and 7 days after the cessation of CBD
administration.
RESULTS
Table 2 presents the results of the trial. Although
there were individual differences in the response to CBD,
improvement of the dystonia disability was generally
dose-related with maximal improvement ranging from 20 to
50%. Two patients with associated Parkinson's signs
experienced exacerbation of their hypokinesia and/or
resting tremor with the highler doses of CBD. Side-effects
of CBD were mild, generally variable, and were recorded or
reported only occasionally during the trial. However,
cardiovascular side-effects appeared to be the most
consistent since a drop (10 to 20 mm Hg) in standing blood
pressure (without tachycardia) was recorded in all
patients.
Improvement of dystonia of each patient was confirmed by
videotape assessment. Additionally in all patients,
discontinuation of CBD at the end of the trial resulted in
a noticeable increase of the dystonic features within 48
hours, and a return to baseline dystonic levels by 1 week
after the cessation of the drug. The patients' subjective
reports of improvement on CBD and exacerbation of the
dystonic features following discontinuation of the drug
correlated with our objective evaluations. No abnormalities
of blood counts or chemistries were found in any of the
patients after discontinuation of CBD.
DISCUSSION
Our findings in the above 5 cases suggest that chronic
oral CBD in combination with other drugs may be useful for
dystonic movement disorders. Symptomatic improvement
ranging from 20-50%, occurred in patients with both focal
(Meige's syndrome; spasmodic torticollis) and generalized
(dystonia musculorum deformans; levodopa-induced dystonia)
forms of dystonia, and included both phasic and tonic
components, dystonic "tremor" and postures along with pain.
Although there were individual differences in the maximum
response to CBD, improvement was generally dose-related.
Side-effects (xerostomia, sedation, psychomotor slowing,
lightheadedness and hypo-tension without tachycardia) of
CBD were mild, and no abnormalities of blood counts or
chemistries were found. The low systemic toxicity of CBD in
our patients is consistent with similar findings of other
studies employing acute or repeated daily administration of
CBD (Cunha et al., 1980). However, CBD in higher doses
exacerbated the hypokinesia and/or resting tremor of the 2
patients with coexisting Parkinsonian features. These
effects were particularly marked in the patient with
primary Parkinsonism (Patient No. 4); this, together with
findings of a CBD increase of reserpine-induced hypokinesia
in rats (Moss et al., 1984), suggests that this disease may
be a contraindication to the use of CBD.
The pathophysiology of the dystonias is largely unknown
but increased acetylcholine (ACH), increased or decreased
dopamine (DA), and decreased gamma-aminobutyric acid (GABA)
functions in the basal ganglia are postulated (Stahl &
Berger, 1982; Brennan et al., 1982). In Parkinsonism,
relative DA deficiency and ACH excess are well known; GABA
deficiency or, alternately, GABA overactivity, may also be
involved (Perry, 1983). Interestingly, CBD has been
reported to affect all three of these neurotransmitters in
rodents. CBD reduces ACH turnover (Revuelta et al.,
1978),decreases the binding of both DA agonists and
antagonists to DA receptors (Bloom, 1984), and increases
GABA turnover (Revuelta et al., 1979), in the basal
ganglia; it also effectively prevents tonic convulsions
caused by GABA blocking drugs (Consroe et al., 1982).
Although these effects may have relevance for the
antidystonic and Parkinsonism-aggravating effects of CBD in
our patients, the precise mode of action of CBD remains
unknown.
While our findings suggest that CBD may benefit some
patients with dystonia, inherent limitations of the open
design and possible day-to-day fluctuations of individual
patient symptoms during our trial preclude any definitive
conclusions. However, our findings coupled with the often
disabling clinical symptoms and lack of consistent
effective pharmacological treatment (Pakkenberg &
Pedersen, 1985) indicate that controlled studies with CBD
are warranted to establish its efficacy in dystonic
movement disorders.
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