Petro/MS/1981

TREATMENT OF HUMAN SPASTICITY WITH DELTA-9-TETRAHYDROCANNABINOL

Denis J. Petro, M.D., and Carl Ellenberger, Jr., M.D. Bronx, NY

J Clin Pharmacol. 1981; 21: 413S--416S

Abstract: Spasticity is a common neurologic condition in patients with
multiple sclerosis, stroke, cerebral palsy or an injured spinal cord.
Animal studies suggest that THC has an inhibitory effect on polysynaptic
reflexes. Some spastic patients claim improvement after inhaling cannabis.
We tested muscle tone, reflexes, strength and performed EMGs before and
after double-blinded oral administration of either 10 or 5 mg THC or
placebo. The blinded examiner correctly identified the trials in which the
patients received THC in seven of none cases. For the group, 10 mg THC
significantly reduced spasticity by clinical measurement (P<0.01).
Quadriceps EMG interference pattern was reduced in those four patients with
primarily extensor spasticity. THC was administered to eight other
patients with spasticity and other CNS lesions. Responses varied, but
benefit was seen in three of three patients with "tonic spasms." No
benefit was noted in patients with cerebellar disease.

Several patients with multiple sclerosis reported to us that their
spasticity improved after smoking marihuana. Preliminary uncontrolled
observations of these patients before and after inhalation of the drug
suggested to us that the improvement in spasticity was a specific effect of
the marihuana and not merely a result of the well-recognized euphoria or
altered perception experienced by social users of the drug.

Methods

We entered nine patients with spasticity, presumably of spinal
origin and related to multiple sclerosis, into a double-blinded pilot
study. The blinded observer examined each patient on three separate days,
before and at 1 1/2-hour intervals after oral administration of a capsule
containing either 10 mg, 5 mg, or no synthetic delta-9-tetrahydrocannabinol
(THC). Absorption of oral THC is variable, about 90 per cent, but
generally slower than that of inhaled THC. Blood levels and psychologic
effects peak at 3 hours after ingestion. Because blood level determination
is costly and may be unreliable, we did not determine levels.
The examiner rated deep tendon reflexes, muscular resistance to
stretch in the legs, and abnormal reflexes each on a scale of 0 (absent) to
4 (abnormally increased) and tabulated the total divided by the number of
observations as the "spasticity score" at 1 1/2 -hour intervals. For
example, if both knee jerks were 3+, both ankle jerks were 3+, and both
adductor jerks were 3+, the total was 18 and the spasticity score was 18/6=
3.0. Babinski signs were rated as 4+, their absence as 3+.
The examiner viewed the EMG interference pattern of the quadriceps
muscle as the knee joint was flexed from 0 to 90 degrees at varying
velocities. The examiner also assessed walking ability, inquired about the
patient's subjective response and side effects of the drug, and measured
vital signs.

Results

Three patients reported feeling "loose" and better able to walk
after receiving either 5 or 10 mg THC. The changes in spasticity scores
for the treated and placebo groups are illustrated in Fig. 1. Differences
between the groups at 180 minutes are significant (P<0.01); summed scores
for the two treated groups differed significantly from summed scores of the
placebo group (P<0.005). The spasticity scores of four patients improved
more than two standard deviations from the mean after either 5 or 10 mg
THC; one patient improved after placebo. Only two of the three patients
who felt improved actually did so by objective criteria. On the basis of
the spasticity scores, the blinded examiner identified correctly the
placebo trials in seven of the nine patients.
The EMG index of spasticity proved to be impractical in five
patients---in three because resistance to stretch was too severe and in two
because electrical activity was too little to record. Among the remaining
four patients, the interference pattern, by visual inspection, was reduced
after treatment from the pretreatment pattern at comparable velocity of
stretch.
Side effects of the 5- or 10-mg oral dosage were minimal. One
patient reported feeling "high" after 10 mg, and another reported a "high"
after placebo. No other patients reported side effects at the relatively
low doses we used.

Discussion

Our preliminary results suggest that THC or one of its synthetic
derivatives warrants further study as a potential treatment for spasticity.
Although many previous investigators have studied the effects of marihuana
on complex motor tasks, we were not able to find previous studies of the
effects of marihuana on spasticity in the medical literature. Experimental
studies in animals suggest that THC has an inhibitory effect on
polysynaptic reflexes mediated through the spinal cord. The results of
differential sectioning of the neuraxis in cats by Dagirmangian and Boyd
(1) suggest that the ability of several tetrahydrocannabinols to decrease
polysynaptic flexion reflexes relates to its action in the region between
the mesencephalon and first cervical segment. Kayaalp et al. (2) postulate
that THC has an effect on both nerve conduction and skeletal muscle
contraction. Sullivan (3) and colleagues found a dose-dependent loss of
reflexes and muscular weakness in dogs.
Although THC has proved to be clinically useful in the treatment of
nausea induced by cancer chemotherapy and in reducing intraocular pressure
in glaucoma, the results of these trials have demonstrated several
disadvantages of the drug. The first is its potential for psychologic
effects that limits usage in higher doses than those we employed. The
second drawback to regular clinical use of the drug and of its many
derivatives is the observation that many of its therapeutic effects may
diminish after a relatively short period of regular usage.

References

1. Dagirmangian R, Boyd ES. Some pharmacological effects of two
tetrahydrocannabinols. J Pharmacol Exp Therap. 1962; 135: 25-33.

2. Kayaalp SA, Kaymakcalan S, Verimer T, Ilhan M, Onur R. In vitro
neuro-muscular effects of delta-9-trans-tetrahydrocannabinol (THC). Arch
Int Pharmacodyn. 1974; 212: 67-75.

3. Sullivan MF, Willard DH. The beagle dog as an animal model for
marihuana smoking studies. Toxicol Appl Pharmacol. 1978; 45: 445-462.



Discussion of the Paper

Dr. Nahas: Were the subjects that you studied naive toward marijuana, and
did you observe tolerance?

Dr. Petro: All of our patients were naive to marijuana. Anecdotally,
other patients claim that they have been using marijuana for periods up to
15 years for control of spasticity, but research needs to cover a larger
and better controlled sample before any definitive statement would be
possible. No chronic studies have been done to evaluate drug tolerance in
spasticity.

Dr. Ungerleider: Did you, as blinded examiner, interview the patients and
perform the tests?

Dr. Petro: I did all of the evaluations of neurologic function.

Dr. Ungerleider: Did you know that they felt better before you evaluated
them objectively?

Dr. Petro: No; I used only objective measures, the EMG criteria and the
spasticity scores.

Dr. Lindblom: Have you considered the use of patients other than those
with multiple sclerosis (MS)? We studied the effect of baclofen on
spasticity, and found much spontaneous variability in MS patients. In
addition, some are euphoric from the disease and cannabis might add to the
euphoria and confuse the results with unspecific effects. Furthermore,
there are several types of spasticity, and in the case of baclofen, we
found that gamma-spasticity was reduced but alpha-spasticity was
unaffected.

Dr. Petro: We had a population of MS patients that was rather large and
readily accessible. Certainly, in subjects with significant cerebellar
disease, marijuana (or its derivatives) would appear to be
contra-indicated because of relaxant effects. We examined the patient
population readily available for study, which was MS patients, but as you
suggest this is not the ideal group to study.
Dr. Gilbert: Poly-synaptic reflexes in the dog are very sensitive to THC.
In the morphine-dependent animal during abstinence there is an increased
activity in the hind limbs. That activity can be blocked with very low
doses of THC, nantradol and nabilone, before we see any other effects of
the drugs (see Gilbert et al., this monograph).

Dr. Dow: Could you elaborate on your conclusion that THC is not the ideal
drug for spasticity?


Dr. Petro: Patients that report effects from marijuana don't like taking
THC; after smoking a marijuana cigarette, they clearly have an improvement
that is different from that seen from THC. As other related substances
with more specific CNS effects become available, these should be studied
;in the treatment of spasticity.


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