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Marihuana smoking, in conjunction with therapeutic doses
of pheno-barbital and diphenylhydantoin, was apparently
necessary for controlling seizures in one 24-year-old
epileptic patient.
ANECDOTAL accounts of beneficial therapeutic effects of
Cannabis sativa have been known throughout recorded
history. (1) The classic description by O'Shaughnessy (2)
in 1842 of the ameliorative effects of marihuana extract on
"infantile convulsions," "hydrophobia," and "lockjaw"
invite speculation as to the anticonvulsant effect of the
drug. Other 19th century physicians reported that marihuana
preparations were of benefit in controlling various spastic
and seizure states, (3,4) although entirely useless in
states of "true chronic epilepsy" such as petit mal. (4)
Synthetic derivatives of delta-9-tetrahydrocannabinol, the
main psychoactive ingredient of marihuana, have been
reported to be of val;ue in the treatment of human
epilepsy, although explicit details are absent in the
abstract-report. (3) Finally, there is also a published
report in which grand mal convulsions in a 20-year-old man
were exacerbated by smoking marihuana. (4)
These references are essentially the only available
literature on the relationship between marihuana and human
convulsions, which obviously indicates a paucity as well as
a contradiction of information. The following case report
describes the possible beneficial effect of marihuana in
human epilepsy.
Report of a Case
A 24-year-old man has been seen in a neurology
outpatient clinic for a period of eight years for control
of his epileptic seizures. His history included febrile
convulsions at 3 years of age and epileptic seizures since
the age of 16. Since that age, the patient has been taking
diphenylhydantoin sodium, 100 mg four times a day, and
phenobarbital, 30 mg four times a day. Control seizures
with this regimen was incomplete, and the patient
complained of attacks about once every two months. From the
age of 16 to 22, the incidence of seizures increased to one
attack per month to one per week.
At 22 years of age, the patient began smoking marihuana
(two to five joints per night) while continuing the
prescribed anticonvulsant drug therapy. During this period,
attack did not occur as long as the patient continued to
take the combination of all three drugs. The patient's
condition could not be maintained on marihuana alone,
because on two occasions he experienced an attack three to
four days after running out of his prescribed
medication.
Neurological work-up has recently been done on the
patient and he has been thoroughtly interviewed, because of
the possible association between marihuana and epileptsy.
The patient was found to have abnormal paroxysmal bursts of
spike and slow-wave electroencephalographic discharges
bilaterally, and his condition was diagnosed as grand mal
epilepsy. The patient showed no other physical or emotional
disability and did not admit to smoking cigarettes,
drinking alcohol, or taking any other drugs. Plasma level
of diphenylhydantoin was 7.4 mcg / ml; ohenobarbital level
was 11 mcg /ml; and folic acid, 4.5mcg / ml.
The patient apparently complies with his dosage regimen,
since he has a history of regular clinic visits and
refilled drug prescriptions.
Comment
This case suggests that marihuana may possess an
anticonvulsant effect in human epilepsy. Previous reports
have alluded to this possibility. (1-3,5) Moreover, the
antiseizure properties of delta-9-tetrahydrocannabinol have
been demonstrated in a wide variety of experimental animal
species. (7-9) It has been shown in laboratory-animal
seizure models that the tetrahydrocannabinols show a
differential activity against major seizures without
altering the sequelaw of minor seizures. (7) Thus, the
present case appears to bear out the prediction from the
animal studies while at the same time possibly explaining
marihuana's observed lack of effect in petit mal epilepsy.
(4)
Theoretical calculations can be made to elucidate the
probable blood level range for
delta-9-tetrahydrocannabinol. A sample of the patient's
marijuana was analyzed for tetrahydrocannabinol content by
gas chromatography, and was found to contain 1.2% by weight
total cannabinoids. One twelfth of the total cannabinoids,
or 0.1% by weight, was accounted for by
delta-9-tetrahydrocannabinol. Assuming 1 gm of marihuana
per joint and correcting for pyrolysis (50%) and
lung-absorption losses (20%), the inhalation dose of
delta-9-tetrahydrocannabinol to the patient (weight, about
65 kg [143]) would be 6.15 mcg / kg. It is known that doses
of 5 mcg to 7 mcg / kg of delta-9-tetrahydrocannabinol
produce psychological and physiological effects in steady
marihuana smokers. (10) Moreover, after an intravenous
bolus of delta-9-tetrahydrocannabinol, marihuana smokers
show lower blood levels and shorter half-lives (28 hours)
for the drug than nonusers (half-life, 57 hours). (10)
Since the half-life is 28 hours in steady smokers and this
patient used two to five joints per evening, little of the
drug would be eliminated and the blood levels would be
expected to climb rapidly during the evening.
The subtherapeutic blood level of diphenylhydantoin in
this patient, 7.4 mcg / ml (normal range, 10 to 25) was not
unexpected, since phenobarbital is know to induce the
formation of enzymes that metabolize diphenylhydantoin.
Even when the blood levels of diphenylhydantoin are less
than the normal range, the combination of the two drugs is
known to be clinically effective. (11) The blood level of
11 mcg / ml of phenobarbital found in this patient is
within the normal therapeutic range (10 to 20).
In summary, marihuana smoking in conjunction with
routine doses of phenobarbital and diphenylhydantoin was
apparently necessary for controlling seizures in one
24-year-old patient. However, the present case is in direct
contrast to the single previously reported case of
marihuana smoking exacerbating seizures in one patient with
grand mal epilepsy. (6) The possibility that
delta-9-tetrahydrocannabinol or other cannabinoids may be
useful or detrimental in major seizures needs further
investigation.
This investigation was supported in part by National
Institute of Mental Health grant MH23414 The analysis of
marihuana for tetrahydrocannabinol was performed by Pharm
Chem Laboratories, Palo Alto, Calif.
References
1. Mikurya TH: Marijuana in medicine, past, present, and
future. Calif Med 110: 34-40, 1969.
2. O'Shaughnessy WB: On the preparation of Indian hemp
or gunjah. Trans Med Physiol Soc Bengal 421-461, 1842.
3. Shaw J: On the use of Cannabis indica in tetanus,
hydrophobia, cholera with remarks on its effects. Madras
Medical Journal 5: 74-80, 1843.
4. Reynolds JR: Therapeutic uses and toxic effects of
Cannabis indica. Lancet 1: 637-638, 1890.
5. Davis JP, Ramsey HH: Antiepileptic actions of
marijuana-active substances. Fed Proc 8: 284, 1949.
6. Keeler MH, Reifler CF: Grand mal convulsions
subsequent to marijuana use. Dis Nerv Syst 28: 474-475,
1967.
7. Consroe PF, Man D: Effects of delta-8- and
delta-9-tetrahydrocannabinol on experimentally induced
seizures. Life Sci 13: 429-439, 1973.
8. Sofia RD, Soloman TA, Barry H: The anti-convulsant
activity of delta-1-tetrahydrocannabinol in mice. Fed Proc
13: 305, 1971.
9. Killam KF, Killam EF: The action of
tetrahydrocannabinol on EEG and photomyoclonic seizures in
the baboon, in: Fifth International Congress of
Pharmacology, San Francisco, Abstracts of Volunteer Papers.
Bethesda, Md, American Society of Pharmacology and
Experimental Therapeutics, 1972, p. 124.
10. Lemberger L, Tamarkin N, Axelrod J, et al:
Delta-9-tetrahydrocannabinol: Metabolism and disposition in
long-term marijuana smokers. Science 173: 72-74, 1971.
11. Hansten PD; Drug Interactions. Philadelphia, Lea
& Febiger Publishers, 1972, pp 53-54.
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