Consroe/Epilepsy/1975

ANTICONVULSANT NATURE OF MARIHUANA SMOKING

Journal of the American Medical Association Oct 20, 1975---Vol 234, No 3:
306-307

Paul . Consroe, PhD: George C. Wood, PhD; Harvey Buchsbaum, MD

>From the departments of pharmacology (Dr. Consroe) and pharmaceutical
sciences (Dr. Wood), College of Pharmacy, and the Neurology Department,
Tucson Medical Center (Dr. Buchsbaum), University of Arizona, Tucson

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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