Jacob Bell
New Member
International Journal of Neuroscience, 1986, Vol. 30, pp. 277-282.
Paul Consroe, Reuven Sandyk and Stuart R. Snider
Department of Pharmacology and Toxicology, and Neurology University of
Arizona Medical Center, Tucson, Arizona 85721, U.S.A.
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.
REFERENCES
Bloom, A.S. Effects of cannabinoids on neurotransmitter receptors in the
brain. In S. Agurell, W. L. Dewey & R.E. Willette, (Eds.) The
Cannabinoids: Chemical, Pharmacologic and Therapeutic Aspects, Orlando:
Academic Press, 1984, 575-589.
Brennan, M.J. W., Ruff, P., & Sandyk, R. Efficacy of a combination of
sodium valproate and baclofen in Meige's disease (Idiopathic orofacial
dystonia). British Medical Journal. 1982, 285, 853
Burke, R.F., Fahn, S., Marsden, C.D., Bressman, S. B., Moskowitz, C., &
Friedman J. Validity and reliability of a rating scale for the primary
torsion dystonias. Neurology, 1985, 35, 73-77.
Clifford, D.R. Tetrahydrocannabinol for tremor in multiple sclerosis.
Annals of Neurology, 1983, 13, 669-671.
Consroe, P., Benedito, M.A.C., Leite, J.R., Carlini, E.A, & Mechoulam,R.
Effects of cannabidiol on behavioral seizures caused by convulsant drugs or
current in mice. European Journal of Pharmacology, 1982, 83, 293-298.
Cunha, J.M., Carlini, E.A., Pereira, A.E., Ramos, O.L., Pimentel, C.,
Gagliardi, R., Sanvito, W.L., Lander, N., & Mechoulam, R. Chronic
administration o0f cannabidiol to healthy volunteers and epileptic
patients. Pharmacology, 1980, 21, 175-185.
Marsden, C.D. Treatment of torsion dystonia. In A. Barbeau, (Ed.)
Disorders of Movement, Current Status of Modern Therapy, Vol. 8,
Philadelphia: Lippincott, 1981, 81-104.
Moss, D.E., Montgomery, S.P., Salo, A.A., & Steiger, R.W.
Tetrahydrocannabinol effects on extrapyramidal motor behaviors in an animal
model of Parkinson's disease. In S. Agurrell, W.L. Dewey & R.E. Willette,
(Eds.) The Cannabinoids: Chemical, Pharmacologic, and Therapeutic
Aspects, Orlando: Academic Press, 1984, 815-822.
O'Shaughnessy, W.B. On the Preparation of Indian hemp or gunjah.
Transactions of the Medical and Physical Society of Bombay. 1842, 8llll
421-461.
Pakkenberg, H. & Pedersen, B. Medical treatment of dystonia. In D.E.
Casey, T.N. Chase, A.V. Christensen & J. Gerlach (Eds.)
Dyskinesia-Research and Treatment, Berlin: Springer-Verlag, 1985, 111-117.
Perry, T.L. Levels of glutamine, glutamate and GABA in CSF and brain under
pathological conditions. In L. Hertx, E. Kvamme, E.G. McGeer & A.
Schousbee, (Eds.) Glutamine, Glutamate and GABA in the Central Nervous
System, New York: Alan R. Liss, 1983, 581-594.
Petro, D.J. & Ellenberger, C., Jr. Treatment of human spasticity with
delta=9-tetrahydrocannabinol, Journal of Clinical Pharmacology, 1981, 2l1,
413s-416s.
Revuelta, A.V., Cheney, D.L., Wood, P.L., & Costa, E. Gabergic mediation
in the inhibition f hippocammpal acetylcholine turnover rate elicited by
delta-9-tetrahydrocannabinol. Neuropharmacology, 1979, 18, 525-530.
Revuelta, A.V., Moroni, F., Cheney, D.L., & Costa,E. Effect of
cannabinoids on the turnover rate of acetylcholine in rat hippocampus,
striatum and cortex. Naunyn-Schmiedeberg's Archives of Pharmacology, 1978,
304, 107-110.
Reynolds, J.R. Therapeutic uses and toxic effects of Cannabis indica.
Lancet, 1890, 1, 637-638.
Snider, S.R. & Consroe,P. Treatment of Meige syndrome with cannabidiol.
Neurology, 1984, 34, (Suppl 1), 147.
Snider, S.R. & Consroe, P. Beneficial and adverse effects of cannabidiol
in a Parkinson patient with Sinemet-induced dystonic dyskinesia.
Neurology, 1985, 35 (Suppl 1), 201.
Stahl, S.M. & Berger, P.A. Bromocriptine, physostigmine, and
neurotransmitter mechanisms in the dystonias. Nuerology, 1982, 32,
889-892.
Source: Open Label Evaluation Of Cannabidiol In Dystonic Movement
Paul Consroe, Reuven Sandyk and Stuart R. Snider
Department of Pharmacology and Toxicology, and Neurology University of
Arizona Medical Center, Tucson, Arizona 85721, U.S.A.
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.
REFERENCES
Bloom, A.S. Effects of cannabinoids on neurotransmitter receptors in the
brain. In S. Agurell, W. L. Dewey & R.E. Willette, (Eds.) The
Cannabinoids: Chemical, Pharmacologic and Therapeutic Aspects, Orlando:
Academic Press, 1984, 575-589.
Brennan, M.J. W., Ruff, P., & Sandyk, R. Efficacy of a combination of
sodium valproate and baclofen in Meige's disease (Idiopathic orofacial
dystonia). British Medical Journal. 1982, 285, 853
Burke, R.F., Fahn, S., Marsden, C.D., Bressman, S. B., Moskowitz, C., &
Friedman J. Validity and reliability of a rating scale for the primary
torsion dystonias. Neurology, 1985, 35, 73-77.
Clifford, D.R. Tetrahydrocannabinol for tremor in multiple sclerosis.
Annals of Neurology, 1983, 13, 669-671.
Consroe, P., Benedito, M.A.C., Leite, J.R., Carlini, E.A, & Mechoulam,R.
Effects of cannabidiol on behavioral seizures caused by convulsant drugs or
current in mice. European Journal of Pharmacology, 1982, 83, 293-298.
Cunha, J.M., Carlini, E.A., Pereira, A.E., Ramos, O.L., Pimentel, C.,
Gagliardi, R., Sanvito, W.L., Lander, N., & Mechoulam, R. Chronic
administration o0f cannabidiol to healthy volunteers and epileptic
patients. Pharmacology, 1980, 21, 175-185.
Marsden, C.D. Treatment of torsion dystonia. In A. Barbeau, (Ed.)
Disorders of Movement, Current Status of Modern Therapy, Vol. 8,
Philadelphia: Lippincott, 1981, 81-104.
Moss, D.E., Montgomery, S.P., Salo, A.A., & Steiger, R.W.
Tetrahydrocannabinol effects on extrapyramidal motor behaviors in an animal
model of Parkinson's disease. In S. Agurrell, W.L. Dewey & R.E. Willette,
(Eds.) The Cannabinoids: Chemical, Pharmacologic, and Therapeutic
Aspects, Orlando: Academic Press, 1984, 815-822.
O'Shaughnessy, W.B. On the Preparation of Indian hemp or gunjah.
Transactions of the Medical and Physical Society of Bombay. 1842, 8llll
421-461.
Pakkenberg, H. & Pedersen, B. Medical treatment of dystonia. In D.E.
Casey, T.N. Chase, A.V. Christensen & J. Gerlach (Eds.)
Dyskinesia-Research and Treatment, Berlin: Springer-Verlag, 1985, 111-117.
Perry, T.L. Levels of glutamine, glutamate and GABA in CSF and brain under
pathological conditions. In L. Hertx, E. Kvamme, E.G. McGeer & A.
Schousbee, (Eds.) Glutamine, Glutamate and GABA in the Central Nervous
System, New York: Alan R. Liss, 1983, 581-594.
Petro, D.J. & Ellenberger, C., Jr. Treatment of human spasticity with
delta=9-tetrahydrocannabinol, Journal of Clinical Pharmacology, 1981, 2l1,
413s-416s.
Revuelta, A.V., Cheney, D.L., Wood, P.L., & Costa, E. Gabergic mediation
in the inhibition f hippocammpal acetylcholine turnover rate elicited by
delta-9-tetrahydrocannabinol. Neuropharmacology, 1979, 18, 525-530.
Revuelta, A.V., Moroni, F., Cheney, D.L., & Costa,E. Effect of
cannabinoids on the turnover rate of acetylcholine in rat hippocampus,
striatum and cortex. Naunyn-Schmiedeberg's Archives of Pharmacology, 1978,
304, 107-110.
Reynolds, J.R. Therapeutic uses and toxic effects of Cannabis indica.
Lancet, 1890, 1, 637-638.
Snider, S.R. & Consroe,P. Treatment of Meige syndrome with cannabidiol.
Neurology, 1984, 34, (Suppl 1), 147.
Snider, S.R. & Consroe, P. Beneficial and adverse effects of cannabidiol
in a Parkinson patient with Sinemet-induced dystonic dyskinesia.
Neurology, 1985, 35 (Suppl 1), 201.
Stahl, S.M. & Berger, P.A. Bromocriptine, physostigmine, and
neurotransmitter mechanisms in the dystonias. Nuerology, 1982, 32,
889-892.
Source: Open Label Evaluation Of Cannabidiol In Dystonic Movement
