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THERAPEUTIC POSSIBILITIES IN CANNABINOIDS  

THE LANCET, MARCH 22, 1975 P. 667-69  

EDITORIAL  

To 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).

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