|
T o early man, Cannabis sativa L. was a
source of food ( hemp seed and oil) and of fibre (ropes),
though, according to mythology, the Emperor Shen Nung (4000
B.C.) knew that it contained a potent drug. Hindus (20) and
Arabs (21) used it in a medley of diseases, and in
Victorian times it had a therapeutic vogue in Europe.
Tincture of cannabis, taken orally, was occasionally
effective as a sedative in psychosomatic disorders and even
for the control of fits, asthma, migraine, choreiform
conditions, and "psychosis." After a review by REYNOLDS
(22) in 1890, British medicine heard little of the
drug---because of unreliability of available material, the
onrush of chemotherapy by synthetic drugs, and not least
the classification of Cannabis, with opium, as a narcotic
in need of legal restriction.
Herbal cannabis (marihuana or "pot"), or the resin
collected from the flowering tops (hashish), varies greatly
(23) in its content of each active principle or
cannabinoid, but the important ones are
tetrahydrocannabinol (THC, numbered as delta-1 or delta-9,
according to the school of chemistry) and some analogues;
cannabinol (CBN); cannabidiol (CBD)); and cannabigerol
(CBG). Synthetic compounds are now being assessed: an early
attempt, demethylheptylpyran (DMHP), is an anticonvulsant
of some potency in man. (24) THC is highly lipophilic,
absorbed rapidly when inhaled and more slowly when
ingested, and is quickly oxidised in stages through an
active metabolite to more polar but inactive products.
These are cleared very slowly from the body in urine and
feces. At present cannabis and the cannbinoids are
controlled drugs in the UK, scheduled in the Misuse of
Drugs Act of 1971; a personal licence (which can be
obtained readily enough from the Home Office for legitimate
purposes) is required in order to gain exemption from the
provisions of this Act.*
Among established pharmacological properties of
cannabinoids which may be capable of therapeutic
application are the sedative or tranquillising effect;
analgesia; anticonvulsant, hypothermic, and hypotensive
effects; stimulation of appetite; lowering of intraocular
tension; relaxation of smooth muuscle; and cytotoxic or
immunosuppresive actions. There has been particular
interest in the effects on airways. A prolonged and
significant reduction in airways resistance was noted by
VACHON et al. (25) in experienced young males who inhaled 9
litres of smoke in air from herbal cannabis which contained
1% or 2.6% THC. Tachycardia and a rise in specific airways
conductance followed at once, the airways effect peaking at
20 minutes and persisting for some hours.
TASHKIN et al. (24) confirmed this observation and
estimated that the smoke from cannabis of 2% THC content
was more effective than 1.25 mg of isoprenaline. The next
step was to show that THC in sesame oil was active taken
orally in doses of 10-20 mg. The effect took about 1 hour
to peak and persisted for 6 hours. TASHKIN et al (27)
examined 10 subjects with reversible airways obstruction of
varying severity but whose disability was quiescent. They
were asked to smoke placebo herb, or 7 mg per kg cannabis
of 2% THC content, or to ingest 15 mg of THC. Airways
conductance rose immediately and the effect persisted much
longer than that of isoprenaline.
The two teams have confirmed these results, (28,29) but
there are two minor reservations which may be made about
their work. Firstly, all the subjects tested had previously
smoked marihuana and therefore expected some effect from
it, which may have induced adrenal medullary activity;
cannabis-naive individuals may not respond in this way.
Secondly, a highly sensitive whole-body plethysmograph was
used which detects modest changes in dynamic lung values.
With these reservations in mind, DAVIES et al (30) gave a
crude extract of cannabis orally in ethanol, added to fruit
juice immediately before swallowing, to 16 drug-naive
patients with reversible airways obstruction. The extract
was analysed by gas / liquid chromatography so that the
dose of THC was known---nil, 2.5 mg, and 10 mg, with 4 mg
salbutamol for comparison. FVC, FEV, PEFR, and MEFR were
measured in addition to self-rating mood scales,
blood-pressure, pulse-rate, and so on. With THC there was a
dose-related trend towards bronchodilation, less than that
after salbutamol and not significantly different from
placebo. Further work with higher dosage is called for. A
brief trial of the effect of inhalingl aerosol-THC failed
because the drug is insoluble in water and poorly soluble
in 40% ethanol (which is just tolerable for inhalation);
oil, in which it is soluble, harms the lung.
The best medium may be some non-irritant smokable
carrier. Herbal cannabis is unsuitable because of the
irritant (31) and cytotoxic (32) properties of the
smoke.
Cannabinoids inhibit the incorporation of amino-acids
into nucleotides. They are, therefore, immuno-suppressive
and antimitotic; and they inhibit the growth of Lewis lung
cancer in mice. In a pilot trial DAVIES et al. (33) gave 10
mg oral THC (in alcohol / fruit juice) once daily for
periods of a week to patients with inoperable bronchogenic
carcinoma treated by radiation and who were distressed. A
single-blind crossover pattern was applied, with a week on
drug or placebo followed by a week of rest. There were no
very dramatic changes; the principal effects were
drowsiness, improved sleep, a more relaxed state of mind,
reduced demand for analgesics and hypnotics, and fewer
problems of management. The second was reported by REGELSON
and his colleagues (34) at a symposium at Savannah,
Georgia. They gave 0.1 mg per kg THC three times a day
orally in oil to outpatients with inoperable cancer of
several types. Dizziness and drowsiness were troublesome
but, with improved appetite, weight-loss was checked or
reversed, and stress was relieved.
One of the drawbacks to treatment with THC is the
readiness with which tolerance develops. This may reduce
its efficacy, but THC, or more probably some derivative,
may well find a place as an adjuvant to isoprenaline, since
the action on bronchial smooth muscle differs from that of
isoprenaline, or as an anodyne in the management of
terminal carcinoma.
REFERENCES
20. Chopra, G.S. Int.J. Addict. 1969, 4, 215.
21. Souief, M.I. Bull. Narcotics, 1971, 33,
17
22. Reynolds, J.R. Lancet, 1890, i, 637.
23. Fairbarn, J.W., Hindmarsh, I., Simic, S., Tylden, E.
Nature, 1974, 249, 276.
24. Davis, J.P., Ramsay, H.H. Fedn Proc. 1949, 8,
284.
25. Vachon, L., Fitzgerald, M.X., Solliday, N.H., Gould,
I.A., Gaensler, E.A. New Engl J. Med. 1973, 288,
985.
26. Tashkin, D.P., Shapiro, B.J., Frank, I.M. ibid. 1973
, 289, 336.
27. Tashkin, D.P., Shapiro, B.J., Frank, I.M. Am Rev.
resp. Dis. 1974, 109, 420.
28. Tashkin, D.P., Shapiro, B.J., Frank, I.M.
Pharmacology of Marihuana. Baltimore (in the
press).
29. Vachon, L., Mikus, P., Morrissey, W., Fitzgerald,
M., Gaensler, E.ibid. (in the press).
30. Davies, B.H., Radcliffe, S., Seaton, A.,
Graham, J.D.P. Thorax (in the press).
31. Henderson, R.L., Tennant, F.S., Quarry,
R. Arch Otolar. 1972, 95, 248.
32. Leuchtenberger, C., Leuchtenberger, R.,
Ritter, N. Nature, 1973, 242,403.
33. Davies, B.H., Weatherstone, R.M.,
Graham, J.D.P., Griffiths, R.D. Br. J. clin. Pharmac. 1974,
1, 301.
34. Regelson, W., Butler, J.R., Schulz, J., Kirk, T.,
Peek, L., Green M.L. Pharmacology of Marihuana. Baltimore
(in the press).
|
