Jim Finnel
Fallen Cannabis Warrior & Ex News Moderator
A look at the medical uses of Cannabis.
Medicine in the western world has forgotten almost all it once knew about the therapeutic properties of cannabis. As a result of cannabis prohibition we have lost not only a valuable agricultural crop but a valuable medicine also. The history of cannabis in western medicine lasted from the 1840s to the 1940s, during which period it was extensively used to treat a wide variety of diseases.(1) According to Prof. A.D.McDonald of Manchester University, writing as recently as 1941: "In the clinical experience of many alienists, a good preparation of hemp is incomparably the best drug for depressive mental conditions."(2) It was equally widely used in the treatment of physical conditions.
NIDA Official JointsThe western experience with cannabis as a therapeutic substance must be seen against a background of traditional use of the plant as a folk-medicine over many thousands of years. Although the details are obscure it seems that such use was established in China, India and the Middle East during the first millennium BC.(3) It continues today throughout South Asia, Southern and Eastern Africa, South America and the West Indies.(4) Cannabis is one of the mainstays of the Unani Tibbi and Ayurvedic systems of medicine which in 1965 were estimated to be the only form of medical care available to 80 per cent of the population of India.(5) It was from India that cannabis as a medicament was introduced to Europe and North America, although the plant has been cultivated in these areas for fibre production for many centuries. Surprisingly, it seems certain that neither its intoxicant nor its medicinal properties were generally known in the West at the beginning of the nineteenth century, although there are a number of earlier references in herbals, particularly Culpeper's of 1652.(6)
The therapeutic use of cannabis was introduced into Western medicine in 1839 through a forty-page article by W B. O'Shaughnessy, a thirty-year-old physician serving in Bengal.(7) His discussion of the history of the use of cannabis products in the East reveals an awareness that the drugs had not only been used in medicine for therapeutic purposes, but had also been used for recreational and religious purposes.
After studying the literature on cannabis and conferring with contemporary Hindu and Muslim scholars, O'Shaughnessy tested the effects of various hemp preparations on animals, before attempting to use them to treat humans. Satisfied that the drug was reasonably safe, he administered preparations of cannabis extract to patients, and discovered that it had analgesic and sedative properties. O'Shaughnessy successfully relieved the pain of rheumatism and stilled the convulsions of an infant with this strange new drug. His most spectacular success came, however, when he quelled the wrenching muscle spasms of tetanus and rabies with the fragrant resin. Psychic effects resembling a curious delirium, when an overdose was given, were treated with strong purgatives, emetics with a blister to the nape of the neck, and leeches on the temples.
O'Shaughnessy
W.B. O'Shaughnessy M.D. Professor of Chemistry and Natural Philosophy, Medical College, Calcutta.
"In 1839, W.B. O'Shaughnessy, MD., a thirty-year-old graduate of the medical school in Edinburgh, under service to the British East India Company, published his monograph 'On the Preparation of the Indian Hemp, or Gunjah.'
This marked the introduction of hemp into conventional 19th Century western medicine. O'Shaughnessy's monograph provided a summary of all the knowledge available to him and reviewed his experiments with animals before he performed human experiments with diseases, including rheumatism, cholera, rabies and tetanus.
Some seven years before, at the end of his medical training in Scotland, O'Shaughnessy invented intravenous fluid and electrolyte replacement therapy during a cholera epidemic. In the years following his hemp research, he went on to publish a pharmacopeia of Indian medicines. He then changed careers, becoming an engineer, and brought the telegraph to India, a service for which he was knighted. He then returned to England, changed his name, and was married three times before dying at the age of eighty-one." (The Marijuana Papers, ed. Mikuriya, 1973)
The use of cannabis derivatives for medicinal purposes spread rapidly throughout Western medicine, as is shown in the report of the Committee on Cannabis Indica of the Ohio State Medical Society, published in 1860. In that report physicians told of success in treating stomach pain, childbirth psychosis, chronic cough, and gonorrhea with hemp products.(8) A Dr Fronmueller, of Fuerth, Ohio, summarized his experiences with the drug as follows:
I have used hemp many hundred times to relieve local pains of an inflammatory as well as neuralgic nature, and judging from these experiments, I have to assign to the Indian hemp a place among the so-called hypnotic medicines next to opium; its effects are less intense, and the secretions are not so much suppressed by it. Digestion is not disturbed; the appetite rather increased; sickness of the stomach seldom induced; congestion never. Hemp may consequently be employed in inflammatory conditions. It disturbs the expectoration far less than opium; the nervous system is also not so much affected. The whole effect of hemp being less violent, and producing a more natural sleep without interfering with the actions of the internal organs, it is certainly often preferable to opium, although it is not equal to that drug in strength and reliability. An alternating course of opium and Indian hemp seems particularly adapted to those cases where opium alone fails in producing the desired effect.
It seems to have been assumed for some years that only Indian hemp (then known as Cannabis indica) was of medicinal value. The fact that American and European hemp (Cannabis sativa) were capable of producing the same effects was not established until 1869, when Wood tried the extract of 1.5 ounces of Kentucky-grown cannabis on himself and found the effects unmistakable (they lasted for 24 hours). About one per cent of this dose was found to be therapeutically effective in cases of neuralgia.(9) In spite of this clear demonstration that American cannabis could be as effective as the best Indian (also, incidentally, that the male plant is as active as the female), the pharmacopoeia specifications continued to require Indian hemp and the material used in the preparation of extracts and tinctures used in American and European medicine continued to be obtained from India.
Effective in Treating Many Illnesses
Cannabis was used during these years, with varying degrees of success in the treatment of dysmenorrhoea,(10) strychnine poisoning(11), menorrhagia(12), pericarditis following rheumatic fever(13), delirium tremens(14), chloral and opium addiction(15), insomnia(16), dyspepsia, indigestion and other stomach disorders(17), persecution mania(18), phthisis(19), migraine and other headaches(20). The purpose for which it chiefly established itself, however, was as a sedative and hypnotic, in which role its superiority to the opiates was established to the satisfaction of many physicians, notably Suckling(18) and Mattison(21). According to Suckling:
With a wish for speedy effect, it is so easy to use that modern mischief-maker, hypodermic morphia, that they (young physicians) are prone to forget remote results of incautious opiate giving.
Would that the wisdom which has come to their professional fathers through, it may be, a hapless experience, might serve them to steer clear of narcotic shoals on which many a patient has gone awreck.
Indian hemp is not here lauded as a specific. It will, at times, fail. So do other drugs. But the many cases in which it acts well, entitle it to a large and lasting confidence. My experience warrants this statement: cannabis indica is, often, a safe and successful anodyne and hypnotic.(18)
The most influential of the nineteenth-century reports on the therapeutic uses of cannabis was probably that of J. Russell Reynolds, published in 1890. The author's position as Physician in Ordinary to HM Queen Victoria and President of the Royal College of Physicians, in addition to his thirty years of clinical experience with the drug, all served to give credence to his emphatic statement that "Indian hemp, when pure and administered carefully, is one of the most valuable medicines we possess". Reynolds carefully listed both those conditions in which he had found cannabis useful and those which he had not. He recommended it in senile insomnia, neuralgia, migraine, gouty pains, epileptoid and other spasms and convulsions (as distinct from true epilepsy), spasmodic asthma and spasmodic dysmenorrhoea.
Advantages and Disadvantages
In their study of the medical applications of cannabis, physicians of the nineteenth century repeatedly encountered a number of difficulties. Recognizing the therapeutic potential of the drug, many experimenters sought ways of overcoming these drawbacks to its use in medicine, in particular the following:
* Cannabis products are insoluble in water.
* The onset of the effects of medicinal preparations of cannabis takes an hour or so; its action is therefore slower than that of many other drugs.
* Different batches of cannabis derivatives vary greatly in strength; moreover, the common procedure for standardization of cannabis samples, by administration to test animals, is subject to error owing to variability of reactions among the animals.
* There is wide variation among humans in their individual responses to cannabis.
Despite these problems regarding the uncertainty of potency and dosage and the difficulties in mode of administration, cannabis has several important advantages over other substances used as analgesics, sedatives, and hypnotics:
* The prolonged use of cannabis does not lead to the development of physical dependence. There is minimal development of tolerance to cannabis products(11,13,14,24)
* Cannabis products have exceedingly low toxicity(24,9,21,22,23) (The oral dose required to kill a mouse has been found to be about 40,000 times the dose required to produce typical symptoms of intoxication in man.)(21,24)
* Cannabis produces no disturbance of vegetative functioning, whereas the opiates inhibit the gastro-intestinal tract, the flow of bile and the cough reflex.(12,24,44,46,25)
Psychic Effects
Besides investigating the physical effects of medicinal preparations of cannabis, nineteenth-century physicians observed the psychic effects of the drug in its therapeutic applications. They found that cannabis first mildly stimulates and then sedates the higher centres of the brain. Hare suggested in 1887 a possible mechanism of cannabis' analgesic properties:
During the time that this remarkable drug is relieving pain a very curious psychical condition manifests itself; namely, that the diminution of the pain seems to be due to its fading away in the distance, so that the pain becomes less and less, just as the pain in a delicate ear would grow less and less as a beaten drum was carried farther and farther out of the range of hearing.
This condition is probably associated with the other well-known symptom produced by the drug; namely, the prolongation of time.(16,26)
Reynolds stressed the necessity of titrating the dose of each patient, increasing gradually every third or fourth day, to avoid 'toxic' effects:
The dose should be given in minimum quantity, repeated in not less than four or six hours, and gradually increased by one drop every third or fourth day, until either relief is or the drug is proved, in such case, to be useless. With these precautions I have never met with any toxic effects, and have rarely failed to find, after a comparatively short time, either the value or the uselessness of the drug.(22)
Synthetic Drugs Take Over
The unchallenged position of cannabis as the remedy of choice in cases of migraine was recognised in 1916 by its inclusion in Osler's standard textbook.(27) The flurry of papers in the medical journals, particularly notable in the 1880s and 1890s, died away as cannabis took its place as a routine prescription for many conditions. By this time, however, there was increasing competition from new synthetic drugs, and the extensive use of cannabis was coming to be the mark of a rather conservative, and probably elderly doctor. According to Walton:
This popularity of the hemp drugs can be attributed partly to the fact that they were introduced before the synthetic hypnotics and analgesics. Chloral hydrate was not introduced until 1869 and was followed in the next thirty years by paraldehyde, sulfonal and the barbitals. Antipyrine and acetanilide, the first of their particular group of analgesics, were introduced about 1884. For general sedative and analgesic purposes, the only drugs commonly used at this time were the morphine derivatives, and their disadvantages were very well known. In fact, the most attractive feature of the hemp narcotics was probably the fact that they did not exhibit certain of the notorious disadvantages of the opiates. The hemp narcotics do not constipate at all, they more often increase than decrease appetite, they do not particularly depress the respiratory center even in large doses, they rarely or never cause pruritis or cutaneous eruptions and, most important, the liability of developing addiction is very much less than with opiates.(44)
Cannabis Under Attack
The addiction liability of the opiates had been dramatically increased by the introduction in the 1850s of the hypodermic syringe, which enabled water-soluble drugs to be administered intravenously, with virtually instantaneous effect. The fact that cannabis, being non-soluble, could not be administered in this new, more 'scientific' way was doubtless held against it by some members of the medical profession, as indeed it still is today.
By the 1930s, when the scare campaigns against marihuana smoking by Mexicans in the New Orleans area and elsewhere were beginning to get under way,(28) cannabis was regarded among the medical profession as an obscure and unexciting traditional drug on which little original research had been done for more than thirty years and which was notoriously variable both in composition and in effect. Furthermore, the intoxication occasionally seen with medicinal doses, which was well recognised by the nineteenth century practitioners, who invariably pointed out that it was quite harmless(20,22), was now looked at in quite a different light in view of the increasingly lurid reputation attached to recreational cannabis use, which was being described at this time as the major cause of insanity in both India and Egypt.(29) However, when international control of the cannabis traffic was established under the terms of the Geneva Convention of 1925 the continuation of its medical use was provided for. During the 1930s cannabis continued to be found as a constituent of many proprietary medicines(30), of which Chlorodyne became the best known. However, cannabis was never a major source of income for the pharmaceutical companies; the semisynthetic derivatives, such as Cannabin, which was first marketed in the 1890s(31), never replaced the natural extract and tincture, on which profits were inevitably much lower than on synthetic drugs. American-grown cannabis was introduced onto the US pharmaceutical market in 1918 in competition with the Indian product, which was heavily taxed.(32) In spite of the enactment of prohibitory legislation in many states, the American Medical Association continued to defend the medicinal use of cannabis:
... there is positively no evidence to indicate the abuse of cannabis as a medicinal agent or to show that its medicinal use is leading to the development of cannabis addiction. Cannabis at the present time is slightly used for medicinal purposes, but it would seem worthwhile to maintain its status as a medicinal agent for such purposes as it now has. There is a possibility that a re-study of the drug by modern means may show other advantages to be derived from its medicinal use.(33)
The AMA vigorously opposed the passage of the Marihuana Tax Act of 1937(34), arguing that it would make the continued therapeutic use of cannabis impossibly difficult. Their forebodings soon proved correct. In 1941 cannabis was dropped from the US National Formulary: the Federal Bureau of Narcotics subsequently was able to eliminate therapeutic use by the simple expedient of refusing any licences for the manufacture of cannabis preparations, after which the only legal source of the drug for any purpose was the Bureau itself.(35)
The Chemistry of Cannabis
Outside the USA the medicinal use of cannabis continued to be legally possible, although increasingly rare. Surprisingly, the ten years following the Marihuana Tax Act saw an upsurge of cannabis research for the first time since the 1890s. Little of this was directed towards therapeutic uses, although the 1940s saw major advances in understanding the chemistry of cannabis as a result of the work of Adams in Chicago(36) and of Todd at Cambridge(37). Adams and his group proceeded to develop synthetic homologs and analogs of the natural cannabis constituents which were up to 500 times as strong, as measured by animal tests.(38) The subsequent history of research on these compounds is interesting. The last published paper, in 1950, was a brilliant study of 11 different THC homologs for potency, analgesia, anticonvulsant activity, and hypnotic qualities. More than twenty years of silence followed. In fact the work continued, under US Army auspices, at Edgewood Arsenal, Maryland and through sub-contractors Arthur D. Little and Co. and the University of Michigan, the purpose now being the production of effective 'incapacitating agents' for chemical warfare purposes. In the event, nothing of military interest resulted; the existence of this research was revealed in 1967(39) and the results were declassified in 1971(40). As well as confirming the anticonvulsant activity first reported by O'Shaughnessy, suggesting that cannabis might be a potent anti-epileptic, this research also showed THC homologs to be powerful hypothermogenic agents, producing a reduction in body temperature which could be valuable as an adjunct to surgery.(41)
Research in the Forties and Fifties
To return to the 1940s, the other main research effort of those years was commissioned by Mayor La Guardia of New York.(42) Publication of the results aroused much controversy, since the report dismissed many of the supposed ill-effects of marihuana smoking which had been generally accepted up to that time. The Journal of the AMA, which had always consistently supported the therapeutic use of cannabis(43), now reversed its position and, in the course of a violent attack on the report, supported such critics as Commissioner Anslinger by describing the treatment of opiate addiction with cannabis as 'the substitution of one addiction for another.'(44) The Journal has maintained a strongly anti-cannabis stance from that day to this.
Between 1945 and 1956 such therapeutic research as there was (which was very little) concentrated on psychiatric uses, primarily in the treatment of depression. Although some spectacular successes were seen(45), the results taken as a whole seemed unpromising(46). By this time research with cannabis in the USA was no longer encouraged, and all the American workers in this field used Adams' synthetics. Interestingly, it was the two programmes in which real cannabis was used (Rolls and De Groot) which produced some of the best results; but by this time it was of course LSD which was the favoured drug for work of this kind.
It seems quite likely that the work of Rolls and Stafford-Clarke in 1953 (with one patient) was the only use of the therapeutic potential of cannabis by the medical profession anywhere in the 'developed' world between 1942 and the 1960s. The low point was reached in 1956; in the same year as the US Congress passed the Boggs Act, introducing 20 year minimum sentences for cannabis offences, the United Nations decided to take the opportunity of the forthcoming conference to draft a 'single convention' on international drug control to recommend the complete abolition of the medical and quasi-medical use of cannabis throughout the world. No sooner had this decision been made than the bureaucrats were thrown into a flurry by the appearance of a very detailed report from Czechoslovakia which suggested that cannabis might have a completely new therapeutic application—as an antibiotic(47). This was entirely unexpected, although it is possible in retrospect to see that the nineteenth century reports of cannabis as a cure for gonorrhoea might not be so silly as they had seemed for so long.(48)
Antibiotic Effects Ignored
The Czech team established without any possibility of doubt that extracts of hemp grown in Czechoslovakia had bactericidal properties. They further succeeded in isolating the substance mainly responsible for this activity (cannabidiolic acid), although they also noted that the extract itself was more effective than any single constituent.(49) It was effective , against Staphylococcus, Streptococcus, Pneumococcus, and many other Gram positive bacteria. It was inactivated by blood serum and was therefore useful only for external use(50). It was, however, found superior to penicillin in the treatment of sinusitis(51), used successfully on a large scale in dentistry(52), applied in the treatment of ear infections(53), and used to achieve complete cure of an infected thumb which had been threatened with amputation after the failure of standard antibiotics(54). This work, however, was not too difficult to ignore, especially since most of it was never translated from the Czech.(55) The World Health Organisation had committed itself in 1952 to the flat statement that "there is no justification for the medical use of cannabis preparations."(56) In 1955 they recommended "extension of the effort towards the abolition of cannabis from all legitimate medical practice"(57), and in the same year was "pleased to note the decision . . . to place cannabis drugs . . . together with heroin and ketobemidone, in . . . Schedule IV . . . in the . . . Single Convention"(58) (which in the draft convention involved the prohibition of medical use.) It was not until 1961 that the Czech work was reviewed in detail.(59) The resulting report laid great stress on the fact that, six years after first publication, there was still no product on the market (although in view of the international legal climate this was hardly surprising), as well as on the existence of other antibiotics (particularly neomycin and bacitracin) which could duplicate the effects obtained with cannabis.
Although unbiased medical opinion might have take the view that a new antibiotic, even if limited in its applications, would be a useful thing to have, the WHO group "concluded that at present the case has not been proved in favour of making cannabis resin available for the extraction of drugs. The opinion expressed in our third report (in 1952) remains unchanged. Cannabis and its preparations are practically obsolete, and there is no justification for their medical use."(60) The Czechs seem to have accepted their defeat; a few years later their team's leading chemist turned to applying his talents to the development of new analytical techniques for use by law-enforcement agencies(61).
"A Thoroughly Vicious Drug"
In spite of having so easily disposed of the Czechs, the UN master plan for world-wide cannabis prohibition came to grief after all. It was defeated by the opposition of the British government, which had been defeated on this issue in 1956, to any attempt to prohibit the medical use of heroin, as well as the determined opposition of the governments of India and Pakistan to any measure which would deprive their people of the only type of medical care available to many of them. The Indian representative referred pointedly to the need for underdeveloped countries to make use of their natural resources (instead, presumably, of importing expensive pharmaceuticals from the West)(62). The result was a complicated compromise. The new convention(63), signed in 1961, provided that the prohibition of medical use of Schedule IV drugs (including cannabis and heroin) should be merely recommended, rather than obligatory. Extracts and tinctures of cannabis were placed in Schedule I, so that this recommendation did not apply to them, and the 'quasi-medical' or 'traditional' use of cannabis in India and Pakistan was to be phased out over 25 years.
In spite of the compromises they had had to make, the framers of the Single Convention could be reasonably sure that the medical use of cannabis was on its way out at last. The signatories of the Convention effectively endorsed the view of cannabis which had established itself since the 1930s; that "it is in fact a thoroughly vicious and dangerous thing of no value whatever to humanity, and deserving of nothing but the odium and contempt of civilised people."(64)
Influence of Increased Recreational Use
No sooner had this victory been won than the whole situation was radically changed by the explosive growth of recreational cannabis use throughout North America and western Europe, and soon all over the world. It should be remembered that up to this time cannabis smoking had, at least according to official figures, been on the decline for more than half a century and an early end to it was confidently looked forward to. In the new situation, in which the harmfulness or otherwise of cannabis had suddenly become a political issue, the possible medical uses began to be looked at again. In England, in the 1960s, extracts and tinctures of cannabis could still legally be prescribed, and some doctors began to show an interest in using them in the treatment of alcoholism and addiction, as they had been used in the nineteenth century. Some doctors, also, were inclined to regard relief of the paranoia induced by fear of being arrested as a reasonable ground for prescribing them to those who would otherwise smoke illegally obtained cannabis. The Wootton Committee, in the course of their study of the cannabis situation, were impressed by the therapeutic potential of the drug and recommended that the power of doctors to prescribe it in the ordinary way should be retained(65). In the event, it lasted only until 1973, when new legislation came into force which required medical use of any cannabis preparation to be licensed.
New Research
The increase of cannabis use was followed by an increase in cannabis research, the first result of which was the successful isolation of a considerable number of cannabis constituents. As in the 1940s the irrational belief that research on pure chemicals was somehow more 'scientific' immediately diverted most cannabis researchers to working with THC. As interest in Cannabis Plantpossible new pharmaceuticals derived from cannabinoids began hesitatingly to develop, the revival of medical use of cannabis itself seemed, in the late 1960s, to be more unlikely than ever. The discovery which was completely to change the situation was made, like many important scientific discoveries, entirely by accident. In 1971, in the course of a study of the effects of cannabis on driving, it was observed that the smoking of cannabis lowers intraocular pressure(66). The application of this effect to the treatment of glaucoma, which many sufferers from that condition had had to discover for themselves, was now something which medicine could no longer ignore.
The 1970s saw the discovery or rediscovery of a whole range of therapeutic possibilities for cannabis, hampered throughout by a bitterly fought rearguard action by those who clung to the received view that 'cannabis has no medical uses.' In the USA cannabis and its derivatives were officially classified as 'investigational new drugs', thus requiring the consent of a multitude of regulatory bodies to any research; this classification simply ignored the whole mass of scientific and medical data accumulated over more than a century and required researchers to begin again from the beginning as if it had never existed(67). The initiatives which led to the investigation of the therapeutic possibilities of cannabis in cases of glaucoma, cancer chemotherapy, epilepsy and spasticity in the 1970s came not from the government or the medical profession but from individual sufferers from these conditions who discovered beneficial effects for themselves.(68)
Current Therapeutic Uses(69): Glaucoma
There is now no doubt that the cannabinoids produce reduced intraocular pressure. This effect is seen with cannabis, with THC, with THC metabolites and with synthetic THC analogs, and with administration intravenously, topically, orally or by smoking.(70) It seems, however, that the THC eyedrop currently being tested is less effective than smoked cannabis.(71) The application of cannabis to the treatment of glaucoma was described in Hepler's original 1971 paper as 'obvious', and in view of the fact that this disease is responsible for 14 per cent of all cases of blindness its application might have been expected to be treated as a priority. Nothing of the sort occurred, and glaucoma patients were left, as they still are, to obtain supplies illicitly. In 1975 Bob Randall, who had been treating himself in this way for three years, was charged with unlawful possession of marihuana and acquitted on the basis of the common-law defence of 'necessity'. He was then allowed to enroll as a volunteer in a research programme, as 'a politically acceptable way of supplying me with marihuana,' as he put it. In 1978, after his supply was interrupted, he brought proceedings for an injunction against the federal government agencies concerned, which were settled on the basis that cannabis from government sources would in future be prescribed to him within the framework of the normal doctor-patient-pharmacist relationship. He remains the only person in the USA to be supplied cannabis legally other than for research purposes.(72) According to the National Institute on Drug Abuse 'the long-term safety and efficacy of marihuana-related drugs administered chronically to glaucoma patients has not been established, nor is there any data from long-term controlled studies to demonstrate whether these preparations can actually preserve visual function in such individuals.'(73)
Cancer Therapy
The second established modern therapeutic application for cannabis is as an adjunct to cancer chemotherapy. The drugs used in cancer, treatment produce severe nausea and vomiting; sometimes so severe that patients are unable to continue with the only treatment which may save their lives. Various anti-emetic drugs are commonly given in an attempt to control this reaction: it now seems that cannabis is successful in a substantial number of cases in which standard anti-emetics are ineffective.(74) According to NIDA this "is probably the single most promising application of these drugs."(75) Again, it is being used by many patients, often on medical recommendation(76), from illicit sources and illegally, while legal supplies are, confined to research purposes.
It also seems likely that cannabis may be effective in reducing muscular spasticity in cases of multiple sclerosis. Although formal research is at a very preliminary stage this again arises from reports from patients who have used it on a do-it-yourself basis and found it effective.(77)
Prospects and Possibilities
There are a number of other possible therapeutic applications, suggested by nineteenth-century uses, modern research on animals, or both. Some are currently receiving research attention, but a number unfortunately, are not.
1. Antiepileptic. This was an area of nineteenth century interest, although findings were never entirely consistent(7,18,22,78). A very brief research report of 1949 found a synthetic cannabinoid more effective than a standard anticonvulsant in a group of epileptic children.(79) Both THC and CBD (which is a natural cannabinoid without psychoactivity) have been shown to have anticonvulsant effects in animals, and favourable preliminary results have also been obtained in humans with CBD.(80) A study of social cannabis-smoking among epileptics failed to find any effect, whether adverse or beneficial.(81)
2. Gastrointestinal effects. Appetite stimulation is one of the best known effects of cannabis, and the drug was often prescribed for this purpose in the nineteenth century(7,8). One of the unsung research triumphs of the 1970s was solemnly to 'confirm' this piece of common knowledge by establishing that under controlled laboratory conditions "subjects given 0.5 mg./kg. orally drank a greater quantity of a chocolate milkshake preparation compared to those receiving placebo."(82) This effect has recently been applied in the treatment of anorexia nervosa, with some degree of success.(83) In addition to the now well-known antiemetic effect the cannabinoids have a antidiarrhoeal effect, at least in animals.(82) One or other of these effects, or both, may explain the success achieved in treating indigestion and dyspepsia in the 1890s(l7), as well as stomach ulcers, for which cannabis appears to have been given at Guy's Hospital during the 1940s.(84) After many years' neglect it has recently been shown that cannabis appears to produce significant lowering of stomach acidity; this has led to the suggestion that cannabis consumption may have been a major factor in the substantial reduction of the incidence of stomach ulcers which has been observed in a number of western countries in recent years. More work in this field seems overdue.
3. Anti-asthmatic. Cannabis smoking undoubtedly causes acute bronchodilation, with beneficial results in asthma attacks, although chronic heavy smoking can produce the opposite effect as a result of the irritant effect of the smoke.(82) Thus another traditional use, well-established in the nineteenth century(78), is confirmed by modern research. Work on aerosol preparations is under way.(85)
4. Sedative/Analgesic. The older work(7,8,18,21,22,26,78) suggests that cannabis, in addition to its sedative action, has a specific pain-relieving effect. This has been confirmed by modern research on animals, in which cannabinoids have produced effects comparable to morphine, and in cancer and surgery patients. It also seems that they have value in combatting fever and inflammation(82) as suggested by U.S. Defense Department studies.(40)
5. Treatment of Addiction. The older work on alcohol and opiate withdrawal and substitution(15,18,21,42) has been followed up to some slight extent. Although the history of substitution therapies in opiate addiction is not encouraging, recent animal work does suggest that THC can inhibit the morphine abstinence syndrome in animals(82). With alcoholics synthetic cannabinoids(86), cannabis tincture(87) and illicitly obtained cannabis(88) have all been used with some success.
6. Anti-depressant. Since the 1950s(45,46) there has been only one study using THC, which was not encouraging(89). More work in this area may still be justified(82).
7. Migraine/Headache/Neuralgia. In this area, where cannabis was once the standard treatment(27), there seems to have been no modern follow up at all.
8. Cough suppressant. The nineteenth century observations(8,26) have been confirmed in modern animal studies(90).
9. Menstrual Abnormalities. Confirmation of the once well-known results in this field(10,12) has been rendered impossible by the prohibition in the USA of all cannabis research on women of childbearing age. There is however one modern observation which confirms the effect to some extent; it seems that the menstrual irregularity induced by heroin use is less marked in women who also use cannabis(91). Recent, as yet unpublished, preliminary findings on a study of female cannabis users in New York indicate that cannabis does indeed affect the menstrual cycle, possibly producing a reduction in fertility. In accordance with the modern tradition of cannabis research this is now interpreted as an adverse effect on health rather than a possible therapeutic application.
10. Childbirth. The use of cannabis in childbirth is traditional in Southern Africa and elsewhere(92). The sedative and analgesic effects are clearly relevant; it has also been suggested that uterine contractions are directly stimulated(93).
11. Antibiotic. There has been no follow-up on the Czech results(49-61) since 1965(94).
12. Antihypertensive. The use of cannabis in treatment of high blood pressure has been suggested; the effect is related to that on intraoccular pressure(82,95).
13. Anaesthesia. Cannabis is a sedative and potentiates the action of a number of anaesthetics, suggesting a possible application in premedication(82).
14. Cancer treatment. Apart from the well-established use in connection with chemotherapy, and the possible use as an analgesic, both discussed above, there is a rather speculative possibility that the direct anti-tumour effect of some of the cannabinoids may be clinically useful(82).
Where do we go from here?
From the above description of the present state of knowledge a number of questions suggest themselves, namely:
* Why is there such determined resistance to the provision of cannabis drugs for therapeutic purposes?
* Why is there such pressure in favour of the use of synthetics or THC rather than natural cannabis, to the extent that researchers who wish to use the latter are forced to use the former instead?
* Why is nothing happening anywhere outside the USA?
In relation to the first two questions the fundamental problem is the irrational insistence that cannabis is a new drug in the same sense that a substance synthesised yesterday in the laboratory of a pharmaceutical company is a new drug. The only possible basis for this approach is that the legal classification of the drug as having no therapeutic use outweighs three thousand years of experience to the contrary. A great deal follows from this classification, for all countries require new drugs to undergo extensive tests before they are allowed to be put on the market; in the USA these tests are particularly stringent and invariably take several years and cost several million dollars.
There is nothing unreasonable about this in the case of a genuinely new drug; the pharmaceutical company which develops the drug will finance the tests and recoup the cost out of profits on subsequent sales. The synthetic cannabinoid analogs are certainly new drugs and no-one denies that this procedure should be applied to them; the delay before the drug is made available for therapeutic use is the price which must be paid for ensuring the safety of the product. In the case of cannabis itself, however, two factors completely change the situation; the first is that the drug has already been tested far more thoroughly than any pharmaceutical by several hundred million willing, indeed enthusiastic, volunteers; the second is that cannabis, being a natural product, is not patentable, and hence there is no incentive to any company to spend its funds on the necessary work.
In reality the 'new drug' classification of cannabis fulfils one purpose and one purpose only; protection for the pharmaceutical industry, which is devoting a great deal of effort to the synthetics, against the risk of having to compete with a natural product which could otherwise be on the therapeutic market before their own much more expensive and much more profitable preparations are ready(96). The other effect of this policy is that large numbers of cancer and glaucoma patients are left without legal access to a substance which can certainly benefit them and possibly save their eyesight or their lives and which is simultaneously being used by millions of people for pleasure and is available on any street corner. In these circumstances it is hardly surprising that a fair number of reputable physicians have felt that they had no alternative to advising their patients of the possible benefits and leaving them to obtain their own (illegal) supplies. Guides have even been published to how best to use material obtained in this way(76).
The lunacy of this situation has led to a widespread revolt against the official line, ably co-ordinated by the U S. National Organisation for Reform of Marihuana Laws. Twenty-four states have now passed special legislation to make cannabis available for therapeutic purposes, in disregard of the categories established by federal law, although difficulties are still encountered where supplies must be obtained from federal agencies(97).
The reason for the lack of action outside the USA has been simply that cannabis research of any kind is now almost entirely an American preserve. Therapeutic effects have been discovered or rediscovered entirely as an unintended (and to some unwelcome) spin-off of a 35 million dollar research programme designed primarily to identify the deleterious effects of recreational cannabis use(98), and which came into existence in response to public pressures for cannabis law reform. The extensive results of this programme are now, of course, available to be applied anywhere, although it is remarkable to see that in the UK even the basic research which is needed to allow the American information on cannabis and health to be applied to the British situation has not been done(99). The only British therapeutic research yet published consists of work on the use of THC as a sedative in lung cancer patients and a study of the bronchodilator effects of cannabis extract, both carried out at the Welsh National School of Medicine. There are currently seven researchers holding Home Office licenses in this field, of whom six are working on cancer chemotherapy and one on glaucoma(100). These research workers are apparently expected to maintain a low profile; their names and affiliations are not available. It does not seem that anyone wishes to be known to be working with such a disreputable substance and the less publicity these licenses get the less likely it is that more doctors will apply for them.
All these researchers are working with THC; there appears to he no official source of natural cannabis for therapeutic research in the UK. However, now that the therapeutic possibilities of cannabis have been forcibly placed before the British medical profession(101) it may be that action will follow. For the sake of the patients involved it is certainly to be hoped that it will. Since it is only seven years since a British pharmaceutical company was distributing extract and tincture of cannabis to pharmacies for supply on prescription it is hardly possible that it could be regarded as a 'new drug' here.
Lessons to be Learnt
What lessons are to be learned from the tangled history of cannabis as a medicine? The first and most impressive is how sheer prejudice and superstition can lead to the total abandonment (as seen in the 1950s) of medicinal use and even of medical research into what was once a therapeutic substance of major importance. The second is how rapidly experience of its use even in the very recent past can be denied or forgotten; in the case of extract and tincture of cannabis in the UK this occurred while the substances were still available in pharmacies and listed in the pharmacopoeia and indeed after some of the new research results of the 1970s, such as those on glaucoma, were already available. The third, and in some ways the most interesting, lesson is how much modern researchers could learn from their nineteenth-century counterparts. Traditionally, before a researcher tested a drug on humans, he tried it on himself(102). This excellent tradition has quite recently been abandoned by those labouring under the illusion that subjective observations are 'unscientific' a view which has no support from any reasonable theory of scientific methodology. It is remarkably easy to distinguish between cannabis research done by those with personal experience of the drug and that done by those without, and to see how the first group have been assisted, at least to the point of knowing what are relevant questions to ask, while the second have been hindered by their ignorance. Insights derived in this way must of course be submitted to objective testing: but until the right questions are asked all the objective research in the world will produce no results of any value. A great deal of information on cannabis is available from the subjective experience of its users; it is tragic that so little use is made of it. This is particularly important now that the 'psychoactive' or intoxicant properties of cannabis are increasingly being seen by medical researchers as an undesirable side-effect. Cannabis 'intoxication' is, of course, a learned effect; the importance of this in the context of therapeutic use has been discussed in a characteristically discursive and insightful paper by Prof. N.E.Zinberg(83).
The modern pharmacologist's attitude has been expressed by Prof. R. Mechoulam in these words: "The main problem facing pharmaceutical research into cannabis is not the lack of activity but rather the wide spectrum of activity exhibited by the cannabinoids. In the clinic, one needs drugs which are specific for a certain condition and do not cause other effects."(103) While the process of torturing molecular configurations until they respond to human preconceptions about what a drug ought to do goes on apace, it may still be worth pleading for a little more investigation of the complex mixture of cannabinoids which nature has provided us with, in the form of a plant which has been associated with humanity since before the dawn of recorded history.
References.
1. T.H. Mikuriya: Marijuana: Medical Papers 1839-1972, MediComp Press, Berkeley, 1973.
2. A.D. McDonald: The Action and Uses of Hemp Drugs, Nature 1941 147 167
3. R.P. Walton: Marihuana: America's New Drug Problem, J.B. Lippincott. Philadelphia, 1938.
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V. Rubin (Ed.): Cannabis and Culture, Mouton, The Hague, 1975.
5. Dwarakanath, op. cit.
6. N Culpeper: The English Physician, or an Astrologophysical discourse of the vulgar herbs of this nation, London, 1652. J. Kabelik: Hanf in der Alt- und Volksmedizin, Pharmazie 1957 12 (7) 439; S. Benet: Early Diffusion and Folk Uses of Hemp, in V. Rubin (Ed.): Cannabis and Culture, Mouton, The Hague, 1975, p.39.
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12. J. Brown: Cannabis indica - a Valuable Remedy in Menorrhagia, Br. Med. J. 1883 i. 1002; S. Fraenkel: Chemie und Pharmakologie des Haschisch, Arch. Exp. Path. Pharmak. 1903 49 226
13. W M. Kelly: Cannabis indica, Br. Med. J. 1883 i. 1281.
14. H.L. Jones: Note on C. indica as a narcotic, Practitioner 1885 35 251; Fraenkel, op. cit.
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16. Berthier: Sommeil procure par le haschisch, Gaz. Hop. 1867 40 387: Reynolds: op. cit.
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23. U S. Dept. of Health, Education and Welfare: Marihuana and Health, 8th Annual Report, 1980.
24. S. Loewe: Studies on the pharmacology and acute toxicity of compounds with marihuana activity, J Pharmac. Exp. Ther. 1946 88 154.
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26. H.A. Hare: Clinical and physiological notes on the action of Cannabis indica, Therap. Gaz. 1887 11 225.
27. W. Osler and T. McCrae: Principles and Practice of Medicine, Appleton & Co., New York, 8th Ed., 1916, p.1089.
28. A.E. Fossier: The Marijuana Menace, New Orleans Med. Surg. J. 1931 84 247, is a typical early example. There is a great deal of such material, culminating in the classic: H.J. Anslinger & C.R. Cooper: Marijuana Assassin of Youth, American Magazine, July 1937 (also in Reader's Digest, Feb, 1938).
29. For Egypt see Proc. 2nd Internat. Opium Conference, Geneva, 1924 for the famous and much reprinted speech; "The countenance of the addict becomes gloomy, his eye is wild and the expression of his face is stupid." For India, W S.J Shaw: "Cannabis indica A "Dangerous Drug", Br Med. J. 1923 ii 586.
30. M. Sasman: Cannabis indica in pharmaceuticals, J. New Jersey Med. Soc. 1938 35 51.
31. T.H. Mikuriya: The History of Cannabis in American Medicine, presented at ICAR 1st Internat. Cannabis Legalisation Conference, Amsterdam, 1980.
32. J.P. Remington & H.C. Wood: Dispensatory of the USA, J B. Lippincott & Co., Philadelphia, 20th Ed., 1918, reprinted in T.H. Mikuriya: Marijuana: Medical Papers, 1973.
33. Report of the Committee on Legislative Activities, J. Am. Med. Ass. 1937 108 2214.
34. D.F. Musto: The 1937 Marijuana Tax Act, Arch. Gen. Psychiat. 1972 26 101. Reprinted in Mikuriya: Marijuana: Medical Papers, 1973.
35. L.S. Goodman & A. Gilman: The Pharmacological Basis of Therapeutics, 3rd Ed., New York, 1965, p.1725.
36. R. Adams: Marijuana, the Harvey Lecture 1941-2, Bull. N.Y. Acad. Med. 1942 18 705, and a series of more than thirty papers from R. Adams, M. Hunt & J.H. Clark: The Structure of Cannabidiol, Part 1, J. Am. Chem. Soc. 1940 62 196, to R. Adams, M. Harfenist & S. Loewe: New Analogs of THC, Part XIX, J Am. Chem. Soc. 1949 71 1624.
37. A.R. Todd: Hashish, Experienta, 1946 2 55; A.R. Todd: The Chemistry of Hashish, Scient. J Royal Coll. Sci. 1942 12 37.
38. The synthesis is in R. Adams, S. Mackenzie & S. Loewe: THC homologs with doubly branched alkyl groups in the 3-position, Part XVIII, J. Am. Chem. Soc. 1948 70 664. The pharmacological work is in S. Loewe: Toxicity of Marijuana-active Principles, Fedn. Proc. 1945 4 127; S. Loewe: Study on the Pharmacology and Acute Toxicology of Compounds with Marijuana Activity, J Pharmac. Exp. Ther. 1946 88 154; S. Loewe & R. Adams: Structure-Activity Relationship & Pharmacological Peculiarities of New Synthetic Congeners of THC, Fedn, Proc. 1947 6 352; S. Loewe: Cannabiswirkestoffe und Pharmakologie der Cannabinole, Arch. Exp Path. Pharmak. 1950 211 175. See also Refs. 41.
39. V M. Sim: personal communication to THM, 1967.
40. Arthur D. Little Co.: New Incapacitating Agents Quarterly Report 15116 Supplement. Preclinical Pharmacology & Toxicology of Candidate Agent 226, 169. (Papers on Tetrahydrocannabinols cleared for public release, National Technical Information Service, Dept. of Commerce, 1971.
41. H.F. Hardman, E.F. Domino & M.T. Seevers: General Pharmacological Actions of some Synthetic THC Derivatives, Pharmac. Rev. 1971 23 295. Oddly, Adams' most potent synthetic proved not to be psychoactive in humans; L. Lemberger et al.: Pharmacologic Effects and Physiologic Disposition of DMHP in Man, Clin. Pharmac.
Ther. 1974 15 380.
42. G.B. Wallace (Ed.) & the Mayor's Committee on Marihuana: The Marihuana Problem in the City of New York, Jaques Cattell, Lancaster, Pa., 1944. Psychiatric study also published as S. Allentuck & K.M. Bowman: The Psychiatric Aspects of Marihuana Intoxication, Am. J. Psychiat. 1942 99 248. Reprinted in D. Solomon: The Marijuana Papers, 1966.
43. G.E. Mitchell: Migraine associated with Menstruation, J. Am. Med. Ass. 1942 120 326, and editorial in same issue: Recent Investigations of Marihuana.
44. Editorial: Marihuana Problems, J Am. Med, Ass. 1945 127 1129. See also Editorial: The Marihuana Bugaboo, Milit. Surg. 1943 93, 94; H.J. Anslinger: Psychiatric Aspects of Marijuana Intoxication, J Am. Med. Ass. 1943 121 212; J. Bouquet: Marijuana Intoxication, J. Am. Med. Ass. 1944 124 1010; K.M. Bowman: (same title), J Am. Med. Ass. 1944 125 376; R.P. Walton: Marihuana Problems, J. Am. Med. Ass. 1945 128 383; K.M. Bowman: Marihuana Problems, J. Am. Med. Ass. 1945 128 899, Editorial: Sanity Concerning Marihuana, Milit. Surg. 1945 96 532; H.L. Kreschmer: The Marihuana Problem, J Am. Med. Ass. 1945 129 1108.
45. E.J. Rolls & D. Stafford-Clark: Depersonalisation treated by Cannabis indica and psychotherapy, Guy's Hosp. Rep. 1954 103 330.
46. Positive results were obtained in L.S. Kubie & S. Margolin: The Therapeutic Role of Drugs in the Process of Repression, Dissociation and Synthesis, Psychosom. Med. 1945 7 147; G.T Stockings: A New Euphoriant for Depressive Mental States, Br. Med. J 1947 i. 918; and M.H. De Groot: The Role of Hallucinogens in Depersonalisation and Allied Syndromes, in R. Crocket et al. (Eds.), Hallucinogenic Drugs and their Psychotherapeutic Use, H.K. Lewis, London, 1963. Negative results were found in D.A. Pond: Psychological Effects in Depressive Patients of the marijuana homolog Synhexyl, J. Neurol. Neurosurg. Psychiat. 1948 11 271 and in C.S. Parker & F. Wrigley: Synthetic Cannabis Preparations in Psychiatry: (1) Synhexyl, J Ment. Sci. 1950 96 176.
47. J. Kabelik et al.: Konopi jako lek (Hemp as a Remedy), Acta Univ. Palack. Olomuc. (Fac. Med.) 1955 6 27
48. McMeens: op. cit.; Lilly's Handbook of Pharmacy and Therapeutics, Eli Lilly & Co., Indianapolis, 1898, p.32.
49. Zd. Krejci, M. Horak & Fr. Santavy: Konstituce Kyseliny Kanabidiolove ... (Constitution of Cannabidiolic Acid ... ) Acta Univ. Palack. Olomuc. (Fac. Med.) 1958 16 9.
50. Kabelik: op. cit.
51. J. Jubacek: (A study of the effect of C. indica in oto-rhino-laryngology) (in Czech.), Acta Univ. Palack. Olomuc. (Fac. Med.) 1955 6 83; J. Hubacek: (A contribution to the treatment of Sinusitis Maxillaris) (in Czech), same journal, 1961 23 207.
52. JT Simek et al.: Uziti extraktu z C. indica v Konservacni Stomatologii (Application of C. indica extract in preserving stomatology), same journal, 1955 6 79; J Soldan: Therapeuticke vysledky aplikace latek z C. indica ve stomatologii (Therapeutic results in stomatology after application of substances derived from C. indica), same journal, 1955 6 73; J. Soldan: Fytoncidy ve stomatologii (Phytoncides in Stomatology), Cesk. Stomatol. 1953 53 23.
53. J Navratil: (Effectiveness of C. indica in chronic otitis media)(in Czech), Acta Univ. Palack. Olomuc. (Fac. Med.), 1955 687.
54. J, Procek: Predbezne sdeleni o lokalnim ucinku C. indica pri lecbe specifickych pisteli (Preliminary study on the local effects of C. indica as a remedy for specific fistulas), same journal, 6 91.
55. The material on specific applications has not been translated, although the originals have English summaries. Kabelik's interesting review of the history of hemp in European folk-medicine has appeared in German - J. Kabelik: Hanf (C. sativa) - Antibiotisches Heilmittel: 1. Mitteilung: Hanf in der Alt und Volksmedizin, Pharmazie 1957 12 (7) 439. The chemical and in vitro work is covered in Zd. Krejci: Hanf - Antibiotisches Heilmittel: 2. Pharmazie 1958 13 155 and Zd. Krejci: Hanf Antibiotisches Heilmittel: 3. Pharmazie 1959 14 349. A much-abbreviated English version appeared only in 1960 - J. Kabelik, Zd. Krejci & Fr. Santavy: Cannabis as a Medicament, Bull. Narcot. 1960 12 (3) 5.
56. Third Report of the Expert Committee on Addiction-Producing Drugs, WHO Tech. Rep. Ser, 1952 57 11.
57 Fifth Report of the Expert Committee . . ., WHO Tech. Rep. Ser. 1955 95 1.
58. Sixth Report of the Expert Committee . . ., WHO Tech. Rep, Ser. 1955 95.
59. UN Document E/CN.7/409 (E/CONF. 34/5) 1961: The merits of antibiotic substances obtainable from C. sativa.
60. Eleventh Report of the Expert Committee . . ., WHO Tech. Rep. Ser, 1961 211 11.
61. Zd. Krecji: Micro-method of thin layer chromatography adapted for the analysis of cannabis, UN Document ST/SOA/SER.S/16, 1967. The Czech work was followed up to some slight extent: L. Ferenczy: Antibacterial substances in seeds, Nature, 19S6 178 639; L. Ferenczy et al.: An antibacterial preparation from Hemp. Naturwiss. 1958 45 188; J. Martinec & M. Felklova: Einfluss verschiedener Dungung auf die antibakterielle Aktivitat des Hanfes (C. sativa L.), Pharmazie 1959 14 276; S.I. Zelepukha et al.: (Antibacterial properties of preparations from Hemp) (in Russian), Mikrobiol. Zh. Akad. Nauk. Ukr. RSR 1963 25 42. The final perversion was the use of the antibiotic effect for forensic purposes - A. Radosevic, M. Kupinic & L. Grlic: Antibiotic activity of various types of cannabis resin, Nature 1962 195 1007
62. Record of the 465th Meeting of the Commission on Narcotic Drugs (16th Session): UN Document E/CN.7/SR465, 1961.
63. United Nations: Single Convention on Narcotic Drugs 1961, New York, 1962.
64, Government of Egypt, Central Narcotics Intelligence Bureau: Annual Report. 1944, Chap. 8. Hashish.
65. Advisory Comnmittee on Drug Dependence: Cannabis, H.M. Stationery Office, 1968.
66. R.S. Hepler & I.M. Frank: Marihuana smoking and intraocular pressure, J. Am. Med. Ass. 1971 217 l392.
67 T.H. Mikuriya: The History of Cannabis in American Medicine, presented at ICAR 1st Internat. Cannabis Legalisation Conference, Amsterdam, 1980: U S. Dept. of Health. Education & Welfare: Marihuana and Health, 8th Annual Report, 1980.
68. S. Cohen: Marijuana as Medicine, Psychology Today, April 1978, p.60. R.A. Roffman: Using Marijuana in the reduction of nausea associated with chemotherapy, Murray, Seattle, 1979; R. Randall: Marijuana, Glaucoma and Public Policy, NORML, Washington, 1978: Editorial: Marijuana may lessen spasticity of MS, J. Am. Med. Ass, 1979 241 2476.
69. Reviewed in: S. Cohen: op. cit.; S. Cohen: Marijuana. J. Am. Med. Ass. 1978 240 1761; R. Mechoulam & N. Lander: Cannabis: a possible source of new drugs, Pharmacy Internat. 1980 1 19: N.E. Zinberg: On Cannabis and Health, J. Psychedelic Drugs 1979 11 135: A. O'Leary. The Present Status of Cannabis as Medicine in the USA, presented at 1st ICAR Cannabis Legalisation Conference, Amsterdam, 1980.
70. K. Green: The Occular Effects of Cannabinoids, in J.A. Zadunansky & H. Davson: Current Topics in Eye Research, Academic Press, 1979. Vol. I. p. 175; on the effect as applied to glaucoma patients see R.S. Hepler & R.J. Petrus: Experiences with Administration of Marihuana to Glaucoma Patients, in S. Cohen & R.C. Stillman: The Therapeutic Potential of Marihuana, Plenum, New York. 1976, p. 63 and W J. Crawford & J.C. Merritt: Effects of THC on arterial and intraoccular hypertension, Int. J. Clin. Pharmacol. Biopharm. 1979 17 191. On synthetics see D.M. Ebert & A.T. Dren: Intraoccular pressure lowering properties of Abbot-43981, a cannabinoid-derived heterocyclic benzopyran with minimum CNS activities, Pharmacologist 1977 19 230.
71. R. Randall: communication to ICAR 1st Internat. Cannabis Legalisation Conference, Amsterdam, 1980; US Dept. of HEW, Marihuana & Health, 8th Annual Report, 1980.
72. Randall: op. cit.; L. Tucker: Marijuana by Prescription, Am. Pharmacy. 1979 NS19 537
73. US Dept. of HEW, op. cit.
74. S.E. Sallan, N.E. Zinberg & E. Frei: Antiemetic effect of delta-9-THC in patients receiving cancer chemotherapy, New Eng. J. Med. 1975 293 795; S.E. Sallan et al.: Antiemetics in patients receiving chemotherapy for cancer, New Eng. J. Med. 1980 302 135; A.E. Chang et al.: Evaluation of antiemetic effects of delta-9-THC during adjuvant chemotherapy in patients receiving high-dose methotrexate, Ann. Intern. Med. 1979 91 825.
75. US Dept. of HEW: op. cit.
76. R.A. Roffman: Using Marijuana in the reduction of nausea associated with chemotherapy, Murray, Seattle, 1979.
77 D.J. Petro & C. Ellenberger: Treatment of Human Spasticity with delta-9-THC, presented at AAAS Annual Meeting, Houston, 1979; Editorial: Marijuana may lessen spasticity of MS, J. Am. Med. Ass. 1979 241 2476.
78. A.K. Nadkarni: Indian Materia Medica, Popular Books, Bombay 1954; E.J. Waring: Practical Therapeutics, Lindsay & Blakiston, Philadelphia, 1874.
79. J.P. Davis & H.H. Ramsey: Antiepileptic action of marihuana-active substances, Fedn. Proc. 1949 8 284.
80. R. Mechoulam & N. Lander: Cannabis: a possible source of new drugs. Pharmacy Internat. 1980 1 (1) 19.
81. D.M. Feeny, M. Spiker & G.K. Weiss: Marihuana and Epilepsy, in S. Cohen & R.C. Stillman (Eds.): The Therapeutic Potential of Marihuana, Plenum, New York, 1976.
82. Comprehensively reviewed in H.N. Bhargava: Potential Therapeutic Applications of naturally occurring and synthetic Cannabinoids, Gen. Pharmac. 1978 9 195.
83. N.E. Zinberg: On Cannabis and Health, J. Psychedelic Drugs 1979 11 139.
84. A.H. Douthwaite: Hashish, Guy's Hosp. Gaz 1948 62 138.
85. D.P. Tashkin et al.: Effects of smoked marihuana in experimentally induced asthma, Am. Rev. Resp. Dis. 1975 112 377. D.P Tashkin et al.: Respiratory status of 74 habitual marihuana smokers, presented at Annual Meeting, American Thoracic Society, Boston, 1978.
86. L.J. Thompson & R.C. Proctor: The use of pyrahexyl in the treatment of alcoholic and drug withdrawal conditions, N. Carol. Med. J. 1953 14 520.
87. I.J C. Dunbar: personal communication to DAA, 1969.
88. T.H. Mikuriya: Cannabis substitution: an adjunctive therapeutic tool in the treatment of alcoholism, Med. Times, 1970 98 187: J. Scher: Marihuana as an agent in rehabilitating alcoholics, Am. J Psychiat. 1971 127 147.
89. J. Kotin, R.M. Post & F.K. Goodwin: Delta-9-THC in depressed patients, Arch. Gen. Psychiat. 1973 28 345.
90. R. Gordon, R.J. Gordon & R.D. Sofia: Antitussive activity of some naturally occurring cannabinoids in anesthetized cats; Eur. J. Pharmac. 1976 35 309.
9l. E.C. Gaulden et al.: Menstrual Abnormalities associated with Heroin Addiction, Am. J. Obstet. Gynec. 1964 90 l55.
92. F.T. Ames: A Clinical and Metabolic Study . . . , J. Ment. Sci. 1958 104 972; J M. Watt & M. Breyer-Brandwijk: The Medicinal and Poisonous Plants of Southern and Eastern Africa, Livingstone, Edinburgh, 2nd Ed., 1962.
93. Anon.: Effects of cannabis and alcohol during labour, J. Am. Med. Ass. 1930 94 1165; L, T. Schlesinger: De l'action du chanvre indien sur l'accouchement, Sem. Hop. 1948 24 2929.
94. S. Cohen: Marijuana as Medicine, Psychol. Today, April 1978, p.60.
95. W.J. Crawford & J.C. Merritt: Effects of THC on arterial and intraoccular hypertension, Int. J. Clin. Pharmacol. Biopharm. 1979 17 191.
96. On the synthetics see R.K. Razdan et al.: Drugs derived from cannabinoids, published in six parts in J. Med. Chem. 1976 19 at pp. 445, 454, 549, 552, 461 and 719. Also see L. Lemberger & H. Rowe: Clinical pharmacology of nabilone, a cannabinol derivative, Clin. Pharmac. Ther. 1975 18 720; H. Kurth. U. Kraatz & F. Korte: Zur synthese thioanaloger Cannabis derivate, Chem. Ber. 1976 109 2164. The pitfalls of this approach were demonstrated when nabilone, regarded as the most successful of the synthetics, was withdrawn from human testing in 1979 as a result of chronic toxicity studies on dogs: Wall Street Journal, 18 January 1979.
97 For developments in this area, see the excellent newsletter and documentation produced by the Medical Reclassification Project, NORML, 2317 M Street NW, Washington DC, 20037.
98. U.S. Dept. of HEW: Marihuana and Health, 8th Annual Report 1980.
99. ISDD, Some Projects for the Future, London, 1978.
100 H.B. Spear: Personal Communication to DAA, 1980.
101. M. Rose: Cannabis: A Medical Question?, Lancet 1980 i. 703.
102. See Refs. 3, 8 & 9 and the following: C.R. Marshall: A contribution to the pharmacology of cannabis indica, J. Am. Med. Ass. 1898 31 882: H.C. Hamilton, A.W Lescohie & R.A. Perkins: The physiological activity of C. Sativa, J. Am. Pharm. Ass. 1913 2 22; V Robinson: An Essay on Hashish, Ringer, New York, 1912, reprinted in B. Caspari-Rosen (Ed.), Hashish, Ciba. Fdn. Symposium, 1946 and in D. Soloman, The Marijuana Papers, 1966. Also the papers by Parker and Stockings quoted in footnote 46.
103. R. Mechoulam & N. Lander: Cannabis: a possible source of new drugs, Pharmacy Internatl 1980 1 (1) 19 (note the title!)
by
Don Aitken and Tod Mikuriya M.D.
Medicine in the western world has forgotten almost all it once knew about the therapeutic properties of cannabis. As a result of cannabis prohibition we have lost not only a valuable agricultural crop but a valuable medicine also. The history of cannabis in western medicine lasted from the 1840s to the 1940s, during which period it was extensively used to treat a wide variety of diseases.(1) According to Prof. A.D.McDonald of Manchester University, writing as recently as 1941: "In the clinical experience of many alienists, a good preparation of hemp is incomparably the best drug for depressive mental conditions."(2) It was equally widely used in the treatment of physical conditions.
NIDA Official JointsThe western experience with cannabis as a therapeutic substance must be seen against a background of traditional use of the plant as a folk-medicine over many thousands of years. Although the details are obscure it seems that such use was established in China, India and the Middle East during the first millennium BC.(3) It continues today throughout South Asia, Southern and Eastern Africa, South America and the West Indies.(4) Cannabis is one of the mainstays of the Unani Tibbi and Ayurvedic systems of medicine which in 1965 were estimated to be the only form of medical care available to 80 per cent of the population of India.(5) It was from India that cannabis as a medicament was introduced to Europe and North America, although the plant has been cultivated in these areas for fibre production for many centuries. Surprisingly, it seems certain that neither its intoxicant nor its medicinal properties were generally known in the West at the beginning of the nineteenth century, although there are a number of earlier references in herbals, particularly Culpeper's of 1652.(6)
The therapeutic use of cannabis was introduced into Western medicine in 1839 through a forty-page article by W B. O'Shaughnessy, a thirty-year-old physician serving in Bengal.(7) His discussion of the history of the use of cannabis products in the East reveals an awareness that the drugs had not only been used in medicine for therapeutic purposes, but had also been used for recreational and religious purposes.
After studying the literature on cannabis and conferring with contemporary Hindu and Muslim scholars, O'Shaughnessy tested the effects of various hemp preparations on animals, before attempting to use them to treat humans. Satisfied that the drug was reasonably safe, he administered preparations of cannabis extract to patients, and discovered that it had analgesic and sedative properties. O'Shaughnessy successfully relieved the pain of rheumatism and stilled the convulsions of an infant with this strange new drug. His most spectacular success came, however, when he quelled the wrenching muscle spasms of tetanus and rabies with the fragrant resin. Psychic effects resembling a curious delirium, when an overdose was given, were treated with strong purgatives, emetics with a blister to the nape of the neck, and leeches on the temples.
O'Shaughnessy
W.B. O'Shaughnessy M.D. Professor of Chemistry and Natural Philosophy, Medical College, Calcutta.
"In 1839, W.B. O'Shaughnessy, MD., a thirty-year-old graduate of the medical school in Edinburgh, under service to the British East India Company, published his monograph 'On the Preparation of the Indian Hemp, or Gunjah.'
This marked the introduction of hemp into conventional 19th Century western medicine. O'Shaughnessy's monograph provided a summary of all the knowledge available to him and reviewed his experiments with animals before he performed human experiments with diseases, including rheumatism, cholera, rabies and tetanus.
Some seven years before, at the end of his medical training in Scotland, O'Shaughnessy invented intravenous fluid and electrolyte replacement therapy during a cholera epidemic. In the years following his hemp research, he went on to publish a pharmacopeia of Indian medicines. He then changed careers, becoming an engineer, and brought the telegraph to India, a service for which he was knighted. He then returned to England, changed his name, and was married three times before dying at the age of eighty-one." (The Marijuana Papers, ed. Mikuriya, 1973)
The use of cannabis derivatives for medicinal purposes spread rapidly throughout Western medicine, as is shown in the report of the Committee on Cannabis Indica of the Ohio State Medical Society, published in 1860. In that report physicians told of success in treating stomach pain, childbirth psychosis, chronic cough, and gonorrhea with hemp products.(8) A Dr Fronmueller, of Fuerth, Ohio, summarized his experiences with the drug as follows:
I have used hemp many hundred times to relieve local pains of an inflammatory as well as neuralgic nature, and judging from these experiments, I have to assign to the Indian hemp a place among the so-called hypnotic medicines next to opium; its effects are less intense, and the secretions are not so much suppressed by it. Digestion is not disturbed; the appetite rather increased; sickness of the stomach seldom induced; congestion never. Hemp may consequently be employed in inflammatory conditions. It disturbs the expectoration far less than opium; the nervous system is also not so much affected. The whole effect of hemp being less violent, and producing a more natural sleep without interfering with the actions of the internal organs, it is certainly often preferable to opium, although it is not equal to that drug in strength and reliability. An alternating course of opium and Indian hemp seems particularly adapted to those cases where opium alone fails in producing the desired effect.
It seems to have been assumed for some years that only Indian hemp (then known as Cannabis indica) was of medicinal value. The fact that American and European hemp (Cannabis sativa) were capable of producing the same effects was not established until 1869, when Wood tried the extract of 1.5 ounces of Kentucky-grown cannabis on himself and found the effects unmistakable (they lasted for 24 hours). About one per cent of this dose was found to be therapeutically effective in cases of neuralgia.(9) In spite of this clear demonstration that American cannabis could be as effective as the best Indian (also, incidentally, that the male plant is as active as the female), the pharmacopoeia specifications continued to require Indian hemp and the material used in the preparation of extracts and tinctures used in American and European medicine continued to be obtained from India.
Effective in Treating Many Illnesses
Cannabis was used during these years, with varying degrees of success in the treatment of dysmenorrhoea,(10) strychnine poisoning(11), menorrhagia(12), pericarditis following rheumatic fever(13), delirium tremens(14), chloral and opium addiction(15), insomnia(16), dyspepsia, indigestion and other stomach disorders(17), persecution mania(18), phthisis(19), migraine and other headaches(20). The purpose for which it chiefly established itself, however, was as a sedative and hypnotic, in which role its superiority to the opiates was established to the satisfaction of many physicians, notably Suckling(18) and Mattison(21). According to Suckling:
With a wish for speedy effect, it is so easy to use that modern mischief-maker, hypodermic morphia, that they (young physicians) are prone to forget remote results of incautious opiate giving.
Would that the wisdom which has come to their professional fathers through, it may be, a hapless experience, might serve them to steer clear of narcotic shoals on which many a patient has gone awreck.
Indian hemp is not here lauded as a specific. It will, at times, fail. So do other drugs. But the many cases in which it acts well, entitle it to a large and lasting confidence. My experience warrants this statement: cannabis indica is, often, a safe and successful anodyne and hypnotic.(18)
The most influential of the nineteenth-century reports on the therapeutic uses of cannabis was probably that of J. Russell Reynolds, published in 1890. The author's position as Physician in Ordinary to HM Queen Victoria and President of the Royal College of Physicians, in addition to his thirty years of clinical experience with the drug, all served to give credence to his emphatic statement that "Indian hemp, when pure and administered carefully, is one of the most valuable medicines we possess". Reynolds carefully listed both those conditions in which he had found cannabis useful and those which he had not. He recommended it in senile insomnia, neuralgia, migraine, gouty pains, epileptoid and other spasms and convulsions (as distinct from true epilepsy), spasmodic asthma and spasmodic dysmenorrhoea.
Advantages and Disadvantages
In their study of the medical applications of cannabis, physicians of the nineteenth century repeatedly encountered a number of difficulties. Recognizing the therapeutic potential of the drug, many experimenters sought ways of overcoming these drawbacks to its use in medicine, in particular the following:
* Cannabis products are insoluble in water.
* The onset of the effects of medicinal preparations of cannabis takes an hour or so; its action is therefore slower than that of many other drugs.
* Different batches of cannabis derivatives vary greatly in strength; moreover, the common procedure for standardization of cannabis samples, by administration to test animals, is subject to error owing to variability of reactions among the animals.
* There is wide variation among humans in their individual responses to cannabis.
Despite these problems regarding the uncertainty of potency and dosage and the difficulties in mode of administration, cannabis has several important advantages over other substances used as analgesics, sedatives, and hypnotics:
* The prolonged use of cannabis does not lead to the development of physical dependence. There is minimal development of tolerance to cannabis products(11,13,14,24)
* Cannabis products have exceedingly low toxicity(24,9,21,22,23) (The oral dose required to kill a mouse has been found to be about 40,000 times the dose required to produce typical symptoms of intoxication in man.)(21,24)
* Cannabis produces no disturbance of vegetative functioning, whereas the opiates inhibit the gastro-intestinal tract, the flow of bile and the cough reflex.(12,24,44,46,25)
Psychic Effects
Besides investigating the physical effects of medicinal preparations of cannabis, nineteenth-century physicians observed the psychic effects of the drug in its therapeutic applications. They found that cannabis first mildly stimulates and then sedates the higher centres of the brain. Hare suggested in 1887 a possible mechanism of cannabis' analgesic properties:
During the time that this remarkable drug is relieving pain a very curious psychical condition manifests itself; namely, that the diminution of the pain seems to be due to its fading away in the distance, so that the pain becomes less and less, just as the pain in a delicate ear would grow less and less as a beaten drum was carried farther and farther out of the range of hearing.
This condition is probably associated with the other well-known symptom produced by the drug; namely, the prolongation of time.(16,26)
Reynolds stressed the necessity of titrating the dose of each patient, increasing gradually every third or fourth day, to avoid 'toxic' effects:
The dose should be given in minimum quantity, repeated in not less than four or six hours, and gradually increased by one drop every third or fourth day, until either relief is or the drug is proved, in such case, to be useless. With these precautions I have never met with any toxic effects, and have rarely failed to find, after a comparatively short time, either the value or the uselessness of the drug.(22)
Synthetic Drugs Take Over
The unchallenged position of cannabis as the remedy of choice in cases of migraine was recognised in 1916 by its inclusion in Osler's standard textbook.(27) The flurry of papers in the medical journals, particularly notable in the 1880s and 1890s, died away as cannabis took its place as a routine prescription for many conditions. By this time, however, there was increasing competition from new synthetic drugs, and the extensive use of cannabis was coming to be the mark of a rather conservative, and probably elderly doctor. According to Walton:
This popularity of the hemp drugs can be attributed partly to the fact that they were introduced before the synthetic hypnotics and analgesics. Chloral hydrate was not introduced until 1869 and was followed in the next thirty years by paraldehyde, sulfonal and the barbitals. Antipyrine and acetanilide, the first of their particular group of analgesics, were introduced about 1884. For general sedative and analgesic purposes, the only drugs commonly used at this time were the morphine derivatives, and their disadvantages were very well known. In fact, the most attractive feature of the hemp narcotics was probably the fact that they did not exhibit certain of the notorious disadvantages of the opiates. The hemp narcotics do not constipate at all, they more often increase than decrease appetite, they do not particularly depress the respiratory center even in large doses, they rarely or never cause pruritis or cutaneous eruptions and, most important, the liability of developing addiction is very much less than with opiates.(44)
Cannabis Under Attack
The addiction liability of the opiates had been dramatically increased by the introduction in the 1850s of the hypodermic syringe, which enabled water-soluble drugs to be administered intravenously, with virtually instantaneous effect. The fact that cannabis, being non-soluble, could not be administered in this new, more 'scientific' way was doubtless held against it by some members of the medical profession, as indeed it still is today.
By the 1930s, when the scare campaigns against marihuana smoking by Mexicans in the New Orleans area and elsewhere were beginning to get under way,(28) cannabis was regarded among the medical profession as an obscure and unexciting traditional drug on which little original research had been done for more than thirty years and which was notoriously variable both in composition and in effect. Furthermore, the intoxication occasionally seen with medicinal doses, which was well recognised by the nineteenth century practitioners, who invariably pointed out that it was quite harmless(20,22), was now looked at in quite a different light in view of the increasingly lurid reputation attached to recreational cannabis use, which was being described at this time as the major cause of insanity in both India and Egypt.(29) However, when international control of the cannabis traffic was established under the terms of the Geneva Convention of 1925 the continuation of its medical use was provided for. During the 1930s cannabis continued to be found as a constituent of many proprietary medicines(30), of which Chlorodyne became the best known. However, cannabis was never a major source of income for the pharmaceutical companies; the semisynthetic derivatives, such as Cannabin, which was first marketed in the 1890s(31), never replaced the natural extract and tincture, on which profits were inevitably much lower than on synthetic drugs. American-grown cannabis was introduced onto the US pharmaceutical market in 1918 in competition with the Indian product, which was heavily taxed.(32) In spite of the enactment of prohibitory legislation in many states, the American Medical Association continued to defend the medicinal use of cannabis:
... there is positively no evidence to indicate the abuse of cannabis as a medicinal agent or to show that its medicinal use is leading to the development of cannabis addiction. Cannabis at the present time is slightly used for medicinal purposes, but it would seem worthwhile to maintain its status as a medicinal agent for such purposes as it now has. There is a possibility that a re-study of the drug by modern means may show other advantages to be derived from its medicinal use.(33)
The AMA vigorously opposed the passage of the Marihuana Tax Act of 1937(34), arguing that it would make the continued therapeutic use of cannabis impossibly difficult. Their forebodings soon proved correct. In 1941 cannabis was dropped from the US National Formulary: the Federal Bureau of Narcotics subsequently was able to eliminate therapeutic use by the simple expedient of refusing any licences for the manufacture of cannabis preparations, after which the only legal source of the drug for any purpose was the Bureau itself.(35)
The Chemistry of Cannabis
Outside the USA the medicinal use of cannabis continued to be legally possible, although increasingly rare. Surprisingly, the ten years following the Marihuana Tax Act saw an upsurge of cannabis research for the first time since the 1890s. Little of this was directed towards therapeutic uses, although the 1940s saw major advances in understanding the chemistry of cannabis as a result of the work of Adams in Chicago(36) and of Todd at Cambridge(37). Adams and his group proceeded to develop synthetic homologs and analogs of the natural cannabis constituents which were up to 500 times as strong, as measured by animal tests.(38) The subsequent history of research on these compounds is interesting. The last published paper, in 1950, was a brilliant study of 11 different THC homologs for potency, analgesia, anticonvulsant activity, and hypnotic qualities. More than twenty years of silence followed. In fact the work continued, under US Army auspices, at Edgewood Arsenal, Maryland and through sub-contractors Arthur D. Little and Co. and the University of Michigan, the purpose now being the production of effective 'incapacitating agents' for chemical warfare purposes. In the event, nothing of military interest resulted; the existence of this research was revealed in 1967(39) and the results were declassified in 1971(40). As well as confirming the anticonvulsant activity first reported by O'Shaughnessy, suggesting that cannabis might be a potent anti-epileptic, this research also showed THC homologs to be powerful hypothermogenic agents, producing a reduction in body temperature which could be valuable as an adjunct to surgery.(41)
Research in the Forties and Fifties
To return to the 1940s, the other main research effort of those years was commissioned by Mayor La Guardia of New York.(42) Publication of the results aroused much controversy, since the report dismissed many of the supposed ill-effects of marihuana smoking which had been generally accepted up to that time. The Journal of the AMA, which had always consistently supported the therapeutic use of cannabis(43), now reversed its position and, in the course of a violent attack on the report, supported such critics as Commissioner Anslinger by describing the treatment of opiate addiction with cannabis as 'the substitution of one addiction for another.'(44) The Journal has maintained a strongly anti-cannabis stance from that day to this.
Between 1945 and 1956 such therapeutic research as there was (which was very little) concentrated on psychiatric uses, primarily in the treatment of depression. Although some spectacular successes were seen(45), the results taken as a whole seemed unpromising(46). By this time research with cannabis in the USA was no longer encouraged, and all the American workers in this field used Adams' synthetics. Interestingly, it was the two programmes in which real cannabis was used (Rolls and De Groot) which produced some of the best results; but by this time it was of course LSD which was the favoured drug for work of this kind.
It seems quite likely that the work of Rolls and Stafford-Clarke in 1953 (with one patient) was the only use of the therapeutic potential of cannabis by the medical profession anywhere in the 'developed' world between 1942 and the 1960s. The low point was reached in 1956; in the same year as the US Congress passed the Boggs Act, introducing 20 year minimum sentences for cannabis offences, the United Nations decided to take the opportunity of the forthcoming conference to draft a 'single convention' on international drug control to recommend the complete abolition of the medical and quasi-medical use of cannabis throughout the world. No sooner had this decision been made than the bureaucrats were thrown into a flurry by the appearance of a very detailed report from Czechoslovakia which suggested that cannabis might have a completely new therapeutic application—as an antibiotic(47). This was entirely unexpected, although it is possible in retrospect to see that the nineteenth century reports of cannabis as a cure for gonorrhoea might not be so silly as they had seemed for so long.(48)
Antibiotic Effects Ignored
The Czech team established without any possibility of doubt that extracts of hemp grown in Czechoslovakia had bactericidal properties. They further succeeded in isolating the substance mainly responsible for this activity (cannabidiolic acid), although they also noted that the extract itself was more effective than any single constituent.(49) It was effective , against Staphylococcus, Streptococcus, Pneumococcus, and many other Gram positive bacteria. It was inactivated by blood serum and was therefore useful only for external use(50). It was, however, found superior to penicillin in the treatment of sinusitis(51), used successfully on a large scale in dentistry(52), applied in the treatment of ear infections(53), and used to achieve complete cure of an infected thumb which had been threatened with amputation after the failure of standard antibiotics(54). This work, however, was not too difficult to ignore, especially since most of it was never translated from the Czech.(55) The World Health Organisation had committed itself in 1952 to the flat statement that "there is no justification for the medical use of cannabis preparations."(56) In 1955 they recommended "extension of the effort towards the abolition of cannabis from all legitimate medical practice"(57), and in the same year was "pleased to note the decision . . . to place cannabis drugs . . . together with heroin and ketobemidone, in . . . Schedule IV . . . in the . . . Single Convention"(58) (which in the draft convention involved the prohibition of medical use.) It was not until 1961 that the Czech work was reviewed in detail.(59) The resulting report laid great stress on the fact that, six years after first publication, there was still no product on the market (although in view of the international legal climate this was hardly surprising), as well as on the existence of other antibiotics (particularly neomycin and bacitracin) which could duplicate the effects obtained with cannabis.
Although unbiased medical opinion might have take the view that a new antibiotic, even if limited in its applications, would be a useful thing to have, the WHO group "concluded that at present the case has not been proved in favour of making cannabis resin available for the extraction of drugs. The opinion expressed in our third report (in 1952) remains unchanged. Cannabis and its preparations are practically obsolete, and there is no justification for their medical use."(60) The Czechs seem to have accepted their defeat; a few years later their team's leading chemist turned to applying his talents to the development of new analytical techniques for use by law-enforcement agencies(61).
"A Thoroughly Vicious Drug"
In spite of having so easily disposed of the Czechs, the UN master plan for world-wide cannabis prohibition came to grief after all. It was defeated by the opposition of the British government, which had been defeated on this issue in 1956, to any attempt to prohibit the medical use of heroin, as well as the determined opposition of the governments of India and Pakistan to any measure which would deprive their people of the only type of medical care available to many of them. The Indian representative referred pointedly to the need for underdeveloped countries to make use of their natural resources (instead, presumably, of importing expensive pharmaceuticals from the West)(62). The result was a complicated compromise. The new convention(63), signed in 1961, provided that the prohibition of medical use of Schedule IV drugs (including cannabis and heroin) should be merely recommended, rather than obligatory. Extracts and tinctures of cannabis were placed in Schedule I, so that this recommendation did not apply to them, and the 'quasi-medical' or 'traditional' use of cannabis in India and Pakistan was to be phased out over 25 years.
In spite of the compromises they had had to make, the framers of the Single Convention could be reasonably sure that the medical use of cannabis was on its way out at last. The signatories of the Convention effectively endorsed the view of cannabis which had established itself since the 1930s; that "it is in fact a thoroughly vicious and dangerous thing of no value whatever to humanity, and deserving of nothing but the odium and contempt of civilised people."(64)
Influence of Increased Recreational Use
No sooner had this victory been won than the whole situation was radically changed by the explosive growth of recreational cannabis use throughout North America and western Europe, and soon all over the world. It should be remembered that up to this time cannabis smoking had, at least according to official figures, been on the decline for more than half a century and an early end to it was confidently looked forward to. In the new situation, in which the harmfulness or otherwise of cannabis had suddenly become a political issue, the possible medical uses began to be looked at again. In England, in the 1960s, extracts and tinctures of cannabis could still legally be prescribed, and some doctors began to show an interest in using them in the treatment of alcoholism and addiction, as they had been used in the nineteenth century. Some doctors, also, were inclined to regard relief of the paranoia induced by fear of being arrested as a reasonable ground for prescribing them to those who would otherwise smoke illegally obtained cannabis. The Wootton Committee, in the course of their study of the cannabis situation, were impressed by the therapeutic potential of the drug and recommended that the power of doctors to prescribe it in the ordinary way should be retained(65). In the event, it lasted only until 1973, when new legislation came into force which required medical use of any cannabis preparation to be licensed.
New Research
The increase of cannabis use was followed by an increase in cannabis research, the first result of which was the successful isolation of a considerable number of cannabis constituents. As in the 1940s the irrational belief that research on pure chemicals was somehow more 'scientific' immediately diverted most cannabis researchers to working with THC. As interest in Cannabis Plantpossible new pharmaceuticals derived from cannabinoids began hesitatingly to develop, the revival of medical use of cannabis itself seemed, in the late 1960s, to be more unlikely than ever. The discovery which was completely to change the situation was made, like many important scientific discoveries, entirely by accident. In 1971, in the course of a study of the effects of cannabis on driving, it was observed that the smoking of cannabis lowers intraocular pressure(66). The application of this effect to the treatment of glaucoma, which many sufferers from that condition had had to discover for themselves, was now something which medicine could no longer ignore.
The 1970s saw the discovery or rediscovery of a whole range of therapeutic possibilities for cannabis, hampered throughout by a bitterly fought rearguard action by those who clung to the received view that 'cannabis has no medical uses.' In the USA cannabis and its derivatives were officially classified as 'investigational new drugs', thus requiring the consent of a multitude of regulatory bodies to any research; this classification simply ignored the whole mass of scientific and medical data accumulated over more than a century and required researchers to begin again from the beginning as if it had never existed(67). The initiatives which led to the investigation of the therapeutic possibilities of cannabis in cases of glaucoma, cancer chemotherapy, epilepsy and spasticity in the 1970s came not from the government or the medical profession but from individual sufferers from these conditions who discovered beneficial effects for themselves.(68)
Current Therapeutic Uses(69): Glaucoma
There is now no doubt that the cannabinoids produce reduced intraocular pressure. This effect is seen with cannabis, with THC, with THC metabolites and with synthetic THC analogs, and with administration intravenously, topically, orally or by smoking.(70) It seems, however, that the THC eyedrop currently being tested is less effective than smoked cannabis.(71) The application of cannabis to the treatment of glaucoma was described in Hepler's original 1971 paper as 'obvious', and in view of the fact that this disease is responsible for 14 per cent of all cases of blindness its application might have been expected to be treated as a priority. Nothing of the sort occurred, and glaucoma patients were left, as they still are, to obtain supplies illicitly. In 1975 Bob Randall, who had been treating himself in this way for three years, was charged with unlawful possession of marihuana and acquitted on the basis of the common-law defence of 'necessity'. He was then allowed to enroll as a volunteer in a research programme, as 'a politically acceptable way of supplying me with marihuana,' as he put it. In 1978, after his supply was interrupted, he brought proceedings for an injunction against the federal government agencies concerned, which were settled on the basis that cannabis from government sources would in future be prescribed to him within the framework of the normal doctor-patient-pharmacist relationship. He remains the only person in the USA to be supplied cannabis legally other than for research purposes.(72) According to the National Institute on Drug Abuse 'the long-term safety and efficacy of marihuana-related drugs administered chronically to glaucoma patients has not been established, nor is there any data from long-term controlled studies to demonstrate whether these preparations can actually preserve visual function in such individuals.'(73)
Cancer Therapy
The second established modern therapeutic application for cannabis is as an adjunct to cancer chemotherapy. The drugs used in cancer, treatment produce severe nausea and vomiting; sometimes so severe that patients are unable to continue with the only treatment which may save their lives. Various anti-emetic drugs are commonly given in an attempt to control this reaction: it now seems that cannabis is successful in a substantial number of cases in which standard anti-emetics are ineffective.(74) According to NIDA this "is probably the single most promising application of these drugs."(75) Again, it is being used by many patients, often on medical recommendation(76), from illicit sources and illegally, while legal supplies are, confined to research purposes.
It also seems likely that cannabis may be effective in reducing muscular spasticity in cases of multiple sclerosis. Although formal research is at a very preliminary stage this again arises from reports from patients who have used it on a do-it-yourself basis and found it effective.(77)
Prospects and Possibilities
There are a number of other possible therapeutic applications, suggested by nineteenth-century uses, modern research on animals, or both. Some are currently receiving research attention, but a number unfortunately, are not.
1. Antiepileptic. This was an area of nineteenth century interest, although findings were never entirely consistent(7,18,22,78). A very brief research report of 1949 found a synthetic cannabinoid more effective than a standard anticonvulsant in a group of epileptic children.(79) Both THC and CBD (which is a natural cannabinoid without psychoactivity) have been shown to have anticonvulsant effects in animals, and favourable preliminary results have also been obtained in humans with CBD.(80) A study of social cannabis-smoking among epileptics failed to find any effect, whether adverse or beneficial.(81)
2. Gastrointestinal effects. Appetite stimulation is one of the best known effects of cannabis, and the drug was often prescribed for this purpose in the nineteenth century(7,8). One of the unsung research triumphs of the 1970s was solemnly to 'confirm' this piece of common knowledge by establishing that under controlled laboratory conditions "subjects given 0.5 mg./kg. orally drank a greater quantity of a chocolate milkshake preparation compared to those receiving placebo."(82) This effect has recently been applied in the treatment of anorexia nervosa, with some degree of success.(83) In addition to the now well-known antiemetic effect the cannabinoids have a antidiarrhoeal effect, at least in animals.(82) One or other of these effects, or both, may explain the success achieved in treating indigestion and dyspepsia in the 1890s(l7), as well as stomach ulcers, for which cannabis appears to have been given at Guy's Hospital during the 1940s.(84) After many years' neglect it has recently been shown that cannabis appears to produce significant lowering of stomach acidity; this has led to the suggestion that cannabis consumption may have been a major factor in the substantial reduction of the incidence of stomach ulcers which has been observed in a number of western countries in recent years. More work in this field seems overdue.
3. Anti-asthmatic. Cannabis smoking undoubtedly causes acute bronchodilation, with beneficial results in asthma attacks, although chronic heavy smoking can produce the opposite effect as a result of the irritant effect of the smoke.(82) Thus another traditional use, well-established in the nineteenth century(78), is confirmed by modern research. Work on aerosol preparations is under way.(85)
4. Sedative/Analgesic. The older work(7,8,18,21,22,26,78) suggests that cannabis, in addition to its sedative action, has a specific pain-relieving effect. This has been confirmed by modern research on animals, in which cannabinoids have produced effects comparable to morphine, and in cancer and surgery patients. It also seems that they have value in combatting fever and inflammation(82) as suggested by U.S. Defense Department studies.(40)
5. Treatment of Addiction. The older work on alcohol and opiate withdrawal and substitution(15,18,21,42) has been followed up to some slight extent. Although the history of substitution therapies in opiate addiction is not encouraging, recent animal work does suggest that THC can inhibit the morphine abstinence syndrome in animals(82). With alcoholics synthetic cannabinoids(86), cannabis tincture(87) and illicitly obtained cannabis(88) have all been used with some success.
6. Anti-depressant. Since the 1950s(45,46) there has been only one study using THC, which was not encouraging(89). More work in this area may still be justified(82).
7. Migraine/Headache/Neuralgia. In this area, where cannabis was once the standard treatment(27), there seems to have been no modern follow up at all.
8. Cough suppressant. The nineteenth century observations(8,26) have been confirmed in modern animal studies(90).
9. Menstrual Abnormalities. Confirmation of the once well-known results in this field(10,12) has been rendered impossible by the prohibition in the USA of all cannabis research on women of childbearing age. There is however one modern observation which confirms the effect to some extent; it seems that the menstrual irregularity induced by heroin use is less marked in women who also use cannabis(91). Recent, as yet unpublished, preliminary findings on a study of female cannabis users in New York indicate that cannabis does indeed affect the menstrual cycle, possibly producing a reduction in fertility. In accordance with the modern tradition of cannabis research this is now interpreted as an adverse effect on health rather than a possible therapeutic application.
10. Childbirth. The use of cannabis in childbirth is traditional in Southern Africa and elsewhere(92). The sedative and analgesic effects are clearly relevant; it has also been suggested that uterine contractions are directly stimulated(93).
11. Antibiotic. There has been no follow-up on the Czech results(49-61) since 1965(94).
12. Antihypertensive. The use of cannabis in treatment of high blood pressure has been suggested; the effect is related to that on intraoccular pressure(82,95).
13. Anaesthesia. Cannabis is a sedative and potentiates the action of a number of anaesthetics, suggesting a possible application in premedication(82).
14. Cancer treatment. Apart from the well-established use in connection with chemotherapy, and the possible use as an analgesic, both discussed above, there is a rather speculative possibility that the direct anti-tumour effect of some of the cannabinoids may be clinically useful(82).
Where do we go from here?
From the above description of the present state of knowledge a number of questions suggest themselves, namely:
* Why is there such determined resistance to the provision of cannabis drugs for therapeutic purposes?
* Why is there such pressure in favour of the use of synthetics or THC rather than natural cannabis, to the extent that researchers who wish to use the latter are forced to use the former instead?
* Why is nothing happening anywhere outside the USA?
In relation to the first two questions the fundamental problem is the irrational insistence that cannabis is a new drug in the same sense that a substance synthesised yesterday in the laboratory of a pharmaceutical company is a new drug. The only possible basis for this approach is that the legal classification of the drug as having no therapeutic use outweighs three thousand years of experience to the contrary. A great deal follows from this classification, for all countries require new drugs to undergo extensive tests before they are allowed to be put on the market; in the USA these tests are particularly stringent and invariably take several years and cost several million dollars.
There is nothing unreasonable about this in the case of a genuinely new drug; the pharmaceutical company which develops the drug will finance the tests and recoup the cost out of profits on subsequent sales. The synthetic cannabinoid analogs are certainly new drugs and no-one denies that this procedure should be applied to them; the delay before the drug is made available for therapeutic use is the price which must be paid for ensuring the safety of the product. In the case of cannabis itself, however, two factors completely change the situation; the first is that the drug has already been tested far more thoroughly than any pharmaceutical by several hundred million willing, indeed enthusiastic, volunteers; the second is that cannabis, being a natural product, is not patentable, and hence there is no incentive to any company to spend its funds on the necessary work.
In reality the 'new drug' classification of cannabis fulfils one purpose and one purpose only; protection for the pharmaceutical industry, which is devoting a great deal of effort to the synthetics, against the risk of having to compete with a natural product which could otherwise be on the therapeutic market before their own much more expensive and much more profitable preparations are ready(96). The other effect of this policy is that large numbers of cancer and glaucoma patients are left without legal access to a substance which can certainly benefit them and possibly save their eyesight or their lives and which is simultaneously being used by millions of people for pleasure and is available on any street corner. In these circumstances it is hardly surprising that a fair number of reputable physicians have felt that they had no alternative to advising their patients of the possible benefits and leaving them to obtain their own (illegal) supplies. Guides have even been published to how best to use material obtained in this way(76).
The lunacy of this situation has led to a widespread revolt against the official line, ably co-ordinated by the U S. National Organisation for Reform of Marihuana Laws. Twenty-four states have now passed special legislation to make cannabis available for therapeutic purposes, in disregard of the categories established by federal law, although difficulties are still encountered where supplies must be obtained from federal agencies(97).
The reason for the lack of action outside the USA has been simply that cannabis research of any kind is now almost entirely an American preserve. Therapeutic effects have been discovered or rediscovered entirely as an unintended (and to some unwelcome) spin-off of a 35 million dollar research programme designed primarily to identify the deleterious effects of recreational cannabis use(98), and which came into existence in response to public pressures for cannabis law reform. The extensive results of this programme are now, of course, available to be applied anywhere, although it is remarkable to see that in the UK even the basic research which is needed to allow the American information on cannabis and health to be applied to the British situation has not been done(99). The only British therapeutic research yet published consists of work on the use of THC as a sedative in lung cancer patients and a study of the bronchodilator effects of cannabis extract, both carried out at the Welsh National School of Medicine. There are currently seven researchers holding Home Office licenses in this field, of whom six are working on cancer chemotherapy and one on glaucoma(100). These research workers are apparently expected to maintain a low profile; their names and affiliations are not available. It does not seem that anyone wishes to be known to be working with such a disreputable substance and the less publicity these licenses get the less likely it is that more doctors will apply for them.
All these researchers are working with THC; there appears to he no official source of natural cannabis for therapeutic research in the UK. However, now that the therapeutic possibilities of cannabis have been forcibly placed before the British medical profession(101) it may be that action will follow. For the sake of the patients involved it is certainly to be hoped that it will. Since it is only seven years since a British pharmaceutical company was distributing extract and tincture of cannabis to pharmacies for supply on prescription it is hardly possible that it could be regarded as a 'new drug' here.
Lessons to be Learnt
What lessons are to be learned from the tangled history of cannabis as a medicine? The first and most impressive is how sheer prejudice and superstition can lead to the total abandonment (as seen in the 1950s) of medicinal use and even of medical research into what was once a therapeutic substance of major importance. The second is how rapidly experience of its use even in the very recent past can be denied or forgotten; in the case of extract and tincture of cannabis in the UK this occurred while the substances were still available in pharmacies and listed in the pharmacopoeia and indeed after some of the new research results of the 1970s, such as those on glaucoma, were already available. The third, and in some ways the most interesting, lesson is how much modern researchers could learn from their nineteenth-century counterparts. Traditionally, before a researcher tested a drug on humans, he tried it on himself(102). This excellent tradition has quite recently been abandoned by those labouring under the illusion that subjective observations are 'unscientific' a view which has no support from any reasonable theory of scientific methodology. It is remarkably easy to distinguish between cannabis research done by those with personal experience of the drug and that done by those without, and to see how the first group have been assisted, at least to the point of knowing what are relevant questions to ask, while the second have been hindered by their ignorance. Insights derived in this way must of course be submitted to objective testing: but until the right questions are asked all the objective research in the world will produce no results of any value. A great deal of information on cannabis is available from the subjective experience of its users; it is tragic that so little use is made of it. This is particularly important now that the 'psychoactive' or intoxicant properties of cannabis are increasingly being seen by medical researchers as an undesirable side-effect. Cannabis 'intoxication' is, of course, a learned effect; the importance of this in the context of therapeutic use has been discussed in a characteristically discursive and insightful paper by Prof. N.E.Zinberg(83).
The modern pharmacologist's attitude has been expressed by Prof. R. Mechoulam in these words: "The main problem facing pharmaceutical research into cannabis is not the lack of activity but rather the wide spectrum of activity exhibited by the cannabinoids. In the clinic, one needs drugs which are specific for a certain condition and do not cause other effects."(103) While the process of torturing molecular configurations until they respond to human preconceptions about what a drug ought to do goes on apace, it may still be worth pleading for a little more investigation of the complex mixture of cannabinoids which nature has provided us with, in the form of a plant which has been associated with humanity since before the dawn of recorded history.
References.
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5. Dwarakanath, op. cit.
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12. J. Brown: Cannabis indica - a Valuable Remedy in Menorrhagia, Br. Med. J. 1883 i. 1002; S. Fraenkel: Chemie und Pharmakologie des Haschisch, Arch. Exp. Path. Pharmak. 1903 49 226
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23. U S. Dept. of Health, Education and Welfare: Marihuana and Health, 8th Annual Report, 1980.
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26. H.A. Hare: Clinical and physiological notes on the action of Cannabis indica, Therap. Gaz. 1887 11 225.
27. W. Osler and T. McCrae: Principles and Practice of Medicine, Appleton & Co., New York, 8th Ed., 1916, p.1089.
28. A.E. Fossier: The Marijuana Menace, New Orleans Med. Surg. J. 1931 84 247, is a typical early example. There is a great deal of such material, culminating in the classic: H.J. Anslinger & C.R. Cooper: Marijuana Assassin of Youth, American Magazine, July 1937 (also in Reader's Digest, Feb, 1938).
29. For Egypt see Proc. 2nd Internat. Opium Conference, Geneva, 1924 for the famous and much reprinted speech; "The countenance of the addict becomes gloomy, his eye is wild and the expression of his face is stupid." For India, W S.J Shaw: "Cannabis indica A "Dangerous Drug", Br Med. J. 1923 ii 586.
30. M. Sasman: Cannabis indica in pharmaceuticals, J. New Jersey Med. Soc. 1938 35 51.
31. T.H. Mikuriya: The History of Cannabis in American Medicine, presented at ICAR 1st Internat. Cannabis Legalisation Conference, Amsterdam, 1980.
32. J.P. Remington & H.C. Wood: Dispensatory of the USA, J B. Lippincott & Co., Philadelphia, 20th Ed., 1918, reprinted in T.H. Mikuriya: Marijuana: Medical Papers, 1973.
33. Report of the Committee on Legislative Activities, J. Am. Med. Ass. 1937 108 2214.
34. D.F. Musto: The 1937 Marijuana Tax Act, Arch. Gen. Psychiat. 1972 26 101. Reprinted in Mikuriya: Marijuana: Medical Papers, 1973.
35. L.S. Goodman & A. Gilman: The Pharmacological Basis of Therapeutics, 3rd Ed., New York, 1965, p.1725.
36. R. Adams: Marijuana, the Harvey Lecture 1941-2, Bull. N.Y. Acad. Med. 1942 18 705, and a series of more than thirty papers from R. Adams, M. Hunt & J.H. Clark: The Structure of Cannabidiol, Part 1, J. Am. Chem. Soc. 1940 62 196, to R. Adams, M. Harfenist & S. Loewe: New Analogs of THC, Part XIX, J Am. Chem. Soc. 1949 71 1624.
37. A.R. Todd: Hashish, Experienta, 1946 2 55; A.R. Todd: The Chemistry of Hashish, Scient. J Royal Coll. Sci. 1942 12 37.
38. The synthesis is in R. Adams, S. Mackenzie & S. Loewe: THC homologs with doubly branched alkyl groups in the 3-position, Part XVIII, J. Am. Chem. Soc. 1948 70 664. The pharmacological work is in S. Loewe: Toxicity of Marijuana-active Principles, Fedn. Proc. 1945 4 127; S. Loewe: Study on the Pharmacology and Acute Toxicology of Compounds with Marijuana Activity, J Pharmac. Exp. Ther. 1946 88 154; S. Loewe & R. Adams: Structure-Activity Relationship & Pharmacological Peculiarities of New Synthetic Congeners of THC, Fedn, Proc. 1947 6 352; S. Loewe: Cannabiswirkestoffe und Pharmakologie der Cannabinole, Arch. Exp Path. Pharmak. 1950 211 175. See also Refs. 41.
39. V M. Sim: personal communication to THM, 1967.
40. Arthur D. Little Co.: New Incapacitating Agents Quarterly Report 15116 Supplement. Preclinical Pharmacology & Toxicology of Candidate Agent 226, 169. (Papers on Tetrahydrocannabinols cleared for public release, National Technical Information Service, Dept. of Commerce, 1971.
41. H.F. Hardman, E.F. Domino & M.T. Seevers: General Pharmacological Actions of some Synthetic THC Derivatives, Pharmac. Rev. 1971 23 295. Oddly, Adams' most potent synthetic proved not to be psychoactive in humans; L. Lemberger et al.: Pharmacologic Effects and Physiologic Disposition of DMHP in Man, Clin. Pharmac.
Ther. 1974 15 380.
42. G.B. Wallace (Ed.) & the Mayor's Committee on Marihuana: The Marihuana Problem in the City of New York, Jaques Cattell, Lancaster, Pa., 1944. Psychiatric study also published as S. Allentuck & K.M. Bowman: The Psychiatric Aspects of Marihuana Intoxication, Am. J. Psychiat. 1942 99 248. Reprinted in D. Solomon: The Marijuana Papers, 1966.
43. G.E. Mitchell: Migraine associated with Menstruation, J. Am. Med. Ass. 1942 120 326, and editorial in same issue: Recent Investigations of Marihuana.
44. Editorial: Marihuana Problems, J Am. Med, Ass. 1945 127 1129. See also Editorial: The Marihuana Bugaboo, Milit. Surg. 1943 93, 94; H.J. Anslinger: Psychiatric Aspects of Marijuana Intoxication, J Am. Med. Ass. 1943 121 212; J. Bouquet: Marijuana Intoxication, J. Am. Med. Ass. 1944 124 1010; K.M. Bowman: (same title), J Am. Med. Ass. 1944 125 376; R.P. Walton: Marihuana Problems, J. Am. Med. Ass. 1945 128 383; K.M. Bowman: Marihuana Problems, J. Am. Med. Ass. 1945 128 899, Editorial: Sanity Concerning Marihuana, Milit. Surg. 1945 96 532; H.L. Kreschmer: The Marihuana Problem, J Am. Med. Ass. 1945 129 1108.
45. E.J. Rolls & D. Stafford-Clark: Depersonalisation treated by Cannabis indica and psychotherapy, Guy's Hosp. Rep. 1954 103 330.
46. Positive results were obtained in L.S. Kubie & S. Margolin: The Therapeutic Role of Drugs in the Process of Repression, Dissociation and Synthesis, Psychosom. Med. 1945 7 147; G.T Stockings: A New Euphoriant for Depressive Mental States, Br. Med. J 1947 i. 918; and M.H. De Groot: The Role of Hallucinogens in Depersonalisation and Allied Syndromes, in R. Crocket et al. (Eds.), Hallucinogenic Drugs and their Psychotherapeutic Use, H.K. Lewis, London, 1963. Negative results were found in D.A. Pond: Psychological Effects in Depressive Patients of the marijuana homolog Synhexyl, J. Neurol. Neurosurg. Psychiat. 1948 11 271 and in C.S. Parker & F. Wrigley: Synthetic Cannabis Preparations in Psychiatry: (1) Synhexyl, J Ment. Sci. 1950 96 176.
47. J. Kabelik et al.: Konopi jako lek (Hemp as a Remedy), Acta Univ. Palack. Olomuc. (Fac. Med.) 1955 6 27
48. McMeens: op. cit.; Lilly's Handbook of Pharmacy and Therapeutics, Eli Lilly & Co., Indianapolis, 1898, p.32.
49. Zd. Krejci, M. Horak & Fr. Santavy: Konstituce Kyseliny Kanabidiolove ... (Constitution of Cannabidiolic Acid ... ) Acta Univ. Palack. Olomuc. (Fac. Med.) 1958 16 9.
50. Kabelik: op. cit.
51. J. Jubacek: (A study of the effect of C. indica in oto-rhino-laryngology) (in Czech.), Acta Univ. Palack. Olomuc. (Fac. Med.) 1955 6 83; J. Hubacek: (A contribution to the treatment of Sinusitis Maxillaris) (in Czech), same journal, 1961 23 207.
52. JT Simek et al.: Uziti extraktu z C. indica v Konservacni Stomatologii (Application of C. indica extract in preserving stomatology), same journal, 1955 6 79; J Soldan: Therapeuticke vysledky aplikace latek z C. indica ve stomatologii (Therapeutic results in stomatology after application of substances derived from C. indica), same journal, 1955 6 73; J. Soldan: Fytoncidy ve stomatologii (Phytoncides in Stomatology), Cesk. Stomatol. 1953 53 23.
53. J Navratil: (Effectiveness of C. indica in chronic otitis media)(in Czech), Acta Univ. Palack. Olomuc. (Fac. Med.), 1955 687.
54. J, Procek: Predbezne sdeleni o lokalnim ucinku C. indica pri lecbe specifickych pisteli (Preliminary study on the local effects of C. indica as a remedy for specific fistulas), same journal, 6 91.
55. The material on specific applications has not been translated, although the originals have English summaries. Kabelik's interesting review of the history of hemp in European folk-medicine has appeared in German - J. Kabelik: Hanf (C. sativa) - Antibiotisches Heilmittel: 1. Mitteilung: Hanf in der Alt und Volksmedizin, Pharmazie 1957 12 (7) 439. The chemical and in vitro work is covered in Zd. Krejci: Hanf - Antibiotisches Heilmittel: 2. Pharmazie 1958 13 155 and Zd. Krejci: Hanf Antibiotisches Heilmittel: 3. Pharmazie 1959 14 349. A much-abbreviated English version appeared only in 1960 - J. Kabelik, Zd. Krejci & Fr. Santavy: Cannabis as a Medicament, Bull. Narcot. 1960 12 (3) 5.
56. Third Report of the Expert Committee on Addiction-Producing Drugs, WHO Tech. Rep. Ser, 1952 57 11.
57 Fifth Report of the Expert Committee . . ., WHO Tech. Rep. Ser. 1955 95 1.
58. Sixth Report of the Expert Committee . . ., WHO Tech. Rep, Ser. 1955 95.
59. UN Document E/CN.7/409 (E/CONF. 34/5) 1961: The merits of antibiotic substances obtainable from C. sativa.
60. Eleventh Report of the Expert Committee . . ., WHO Tech. Rep. Ser, 1961 211 11.
61. Zd. Krecji: Micro-method of thin layer chromatography adapted for the analysis of cannabis, UN Document ST/SOA/SER.S/16, 1967. The Czech work was followed up to some slight extent: L. Ferenczy: Antibacterial substances in seeds, Nature, 19S6 178 639; L. Ferenczy et al.: An antibacterial preparation from Hemp. Naturwiss. 1958 45 188; J. Martinec & M. Felklova: Einfluss verschiedener Dungung auf die antibakterielle Aktivitat des Hanfes (C. sativa L.), Pharmazie 1959 14 276; S.I. Zelepukha et al.: (Antibacterial properties of preparations from Hemp) (in Russian), Mikrobiol. Zh. Akad. Nauk. Ukr. RSR 1963 25 42. The final perversion was the use of the antibiotic effect for forensic purposes - A. Radosevic, M. Kupinic & L. Grlic: Antibiotic activity of various types of cannabis resin, Nature 1962 195 1007
62. Record of the 465th Meeting of the Commission on Narcotic Drugs (16th Session): UN Document E/CN.7/SR465, 1961.
63. United Nations: Single Convention on Narcotic Drugs 1961, New York, 1962.
64, Government of Egypt, Central Narcotics Intelligence Bureau: Annual Report. 1944, Chap. 8. Hashish.
65. Advisory Comnmittee on Drug Dependence: Cannabis, H.M. Stationery Office, 1968.
66. R.S. Hepler & I.M. Frank: Marihuana smoking and intraocular pressure, J. Am. Med. Ass. 1971 217 l392.
67 T.H. Mikuriya: The History of Cannabis in American Medicine, presented at ICAR 1st Internat. Cannabis Legalisation Conference, Amsterdam, 1980: U S. Dept. of Health. Education & Welfare: Marihuana and Health, 8th Annual Report, 1980.
68. S. Cohen: Marijuana as Medicine, Psychology Today, April 1978, p.60. R.A. Roffman: Using Marijuana in the reduction of nausea associated with chemotherapy, Murray, Seattle, 1979; R. Randall: Marijuana, Glaucoma and Public Policy, NORML, Washington, 1978: Editorial: Marijuana may lessen spasticity of MS, J. Am. Med. Ass, 1979 241 2476.
69. Reviewed in: S. Cohen: op. cit.; S. Cohen: Marijuana. J. Am. Med. Ass. 1978 240 1761; R. Mechoulam & N. Lander: Cannabis: a possible source of new drugs, Pharmacy Internat. 1980 1 19: N.E. Zinberg: On Cannabis and Health, J. Psychedelic Drugs 1979 11 135: A. O'Leary. The Present Status of Cannabis as Medicine in the USA, presented at 1st ICAR Cannabis Legalisation Conference, Amsterdam, 1980.
70. K. Green: The Occular Effects of Cannabinoids, in J.A. Zadunansky & H. Davson: Current Topics in Eye Research, Academic Press, 1979. Vol. I. p. 175; on the effect as applied to glaucoma patients see R.S. Hepler & R.J. Petrus: Experiences with Administration of Marihuana to Glaucoma Patients, in S. Cohen & R.C. Stillman: The Therapeutic Potential of Marihuana, Plenum, New York. 1976, p. 63 and W J. Crawford & J.C. Merritt: Effects of THC on arterial and intraoccular hypertension, Int. J. Clin. Pharmacol. Biopharm. 1979 17 191. On synthetics see D.M. Ebert & A.T. Dren: Intraoccular pressure lowering properties of Abbot-43981, a cannabinoid-derived heterocyclic benzopyran with minimum CNS activities, Pharmacologist 1977 19 230.
71. R. Randall: communication to ICAR 1st Internat. Cannabis Legalisation Conference, Amsterdam, 1980; US Dept. of HEW, Marihuana & Health, 8th Annual Report, 1980.
72. Randall: op. cit.; L. Tucker: Marijuana by Prescription, Am. Pharmacy. 1979 NS19 537
73. US Dept. of HEW, op. cit.
74. S.E. Sallan, N.E. Zinberg & E. Frei: Antiemetic effect of delta-9-THC in patients receiving cancer chemotherapy, New Eng. J. Med. 1975 293 795; S.E. Sallan et al.: Antiemetics in patients receiving chemotherapy for cancer, New Eng. J. Med. 1980 302 135; A.E. Chang et al.: Evaluation of antiemetic effects of delta-9-THC during adjuvant chemotherapy in patients receiving high-dose methotrexate, Ann. Intern. Med. 1979 91 825.
75. US Dept. of HEW: op. cit.
76. R.A. Roffman: Using Marijuana in the reduction of nausea associated with chemotherapy, Murray, Seattle, 1979.
77 D.J. Petro & C. Ellenberger: Treatment of Human Spasticity with delta-9-THC, presented at AAAS Annual Meeting, Houston, 1979; Editorial: Marijuana may lessen spasticity of MS, J. Am. Med. Ass. 1979 241 2476.
78. A.K. Nadkarni: Indian Materia Medica, Popular Books, Bombay 1954; E.J. Waring: Practical Therapeutics, Lindsay & Blakiston, Philadelphia, 1874.
79. J.P. Davis & H.H. Ramsey: Antiepileptic action of marihuana-active substances, Fedn. Proc. 1949 8 284.
80. R. Mechoulam & N. Lander: Cannabis: a possible source of new drugs. Pharmacy Internat. 1980 1 (1) 19.
81. D.M. Feeny, M. Spiker & G.K. Weiss: Marihuana and Epilepsy, in S. Cohen & R.C. Stillman (Eds.): The Therapeutic Potential of Marihuana, Plenum, New York, 1976.
82. Comprehensively reviewed in H.N. Bhargava: Potential Therapeutic Applications of naturally occurring and synthetic Cannabinoids, Gen. Pharmac. 1978 9 195.
83. N.E. Zinberg: On Cannabis and Health, J. Psychedelic Drugs 1979 11 139.
84. A.H. Douthwaite: Hashish, Guy's Hosp. Gaz 1948 62 138.
85. D.P. Tashkin et al.: Effects of smoked marihuana in experimentally induced asthma, Am. Rev. Resp. Dis. 1975 112 377. D.P Tashkin et al.: Respiratory status of 74 habitual marihuana smokers, presented at Annual Meeting, American Thoracic Society, Boston, 1978.
86. L.J. Thompson & R.C. Proctor: The use of pyrahexyl in the treatment of alcoholic and drug withdrawal conditions, N. Carol. Med. J. 1953 14 520.
87. I.J C. Dunbar: personal communication to DAA, 1969.
88. T.H. Mikuriya: Cannabis substitution: an adjunctive therapeutic tool in the treatment of alcoholism, Med. Times, 1970 98 187: J. Scher: Marihuana as an agent in rehabilitating alcoholics, Am. J Psychiat. 1971 127 147.
89. J. Kotin, R.M. Post & F.K. Goodwin: Delta-9-THC in depressed patients, Arch. Gen. Psychiat. 1973 28 345.
90. R. Gordon, R.J. Gordon & R.D. Sofia: Antitussive activity of some naturally occurring cannabinoids in anesthetized cats; Eur. J. Pharmac. 1976 35 309.
9l. E.C. Gaulden et al.: Menstrual Abnormalities associated with Heroin Addiction, Am. J. Obstet. Gynec. 1964 90 l55.
92. F.T. Ames: A Clinical and Metabolic Study . . . , J. Ment. Sci. 1958 104 972; J M. Watt & M. Breyer-Brandwijk: The Medicinal and Poisonous Plants of Southern and Eastern Africa, Livingstone, Edinburgh, 2nd Ed., 1962.
93. Anon.: Effects of cannabis and alcohol during labour, J. Am. Med. Ass. 1930 94 1165; L, T. Schlesinger: De l'action du chanvre indien sur l'accouchement, Sem. Hop. 1948 24 2929.
94. S. Cohen: Marijuana as Medicine, Psychol. Today, April 1978, p.60.
95. W.J. Crawford & J.C. Merritt: Effects of THC on arterial and intraoccular hypertension, Int. J. Clin. Pharmacol. Biopharm. 1979 17 191.
96. On the synthetics see R.K. Razdan et al.: Drugs derived from cannabinoids, published in six parts in J. Med. Chem. 1976 19 at pp. 445, 454, 549, 552, 461 and 719. Also see L. Lemberger & H. Rowe: Clinical pharmacology of nabilone, a cannabinol derivative, Clin. Pharmac. Ther. 1975 18 720; H. Kurth. U. Kraatz & F. Korte: Zur synthese thioanaloger Cannabis derivate, Chem. Ber. 1976 109 2164. The pitfalls of this approach were demonstrated when nabilone, regarded as the most successful of the synthetics, was withdrawn from human testing in 1979 as a result of chronic toxicity studies on dogs: Wall Street Journal, 18 January 1979.
97 For developments in this area, see the excellent newsletter and documentation produced by the Medical Reclassification Project, NORML, 2317 M Street NW, Washington DC, 20037.
98. U.S. Dept. of HEW: Marihuana and Health, 8th Annual Report 1980.
99. ISDD, Some Projects for the Future, London, 1978.
100 H.B. Spear: Personal Communication to DAA, 1980.
101. M. Rose: Cannabis: A Medical Question?, Lancet 1980 i. 703.
102. See Refs. 3, 8 & 9 and the following: C.R. Marshall: A contribution to the pharmacology of cannabis indica, J. Am. Med. Ass. 1898 31 882: H.C. Hamilton, A.W Lescohie & R.A. Perkins: The physiological activity of C. Sativa, J. Am. Pharm. Ass. 1913 2 22; V Robinson: An Essay on Hashish, Ringer, New York, 1912, reprinted in B. Caspari-Rosen (Ed.), Hashish, Ciba. Fdn. Symposium, 1946 and in D. Soloman, The Marijuana Papers, 1966. Also the papers by Parker and Stockings quoted in footnote 46.
103. R. Mechoulam & N. Lander: Cannabis: a possible source of new drugs, Pharmacy Internatl 1980 1 (1) 19 (note the title!)
by
Don Aitken and Tod Mikuriya M.D.
