Poppy seeds: differences in morphine and codeine content and variation in inter- and intra-individual excretion
Poppy seeds from seven different origins (Dutch, Australian, Hungarian, Spanish, Czech, and two Turkish) were analyzed for the amount of opiates present. Four grams of each kind of seeds, equivalent to the amount of seeds on two bagels, were ingested by volunteers. One volunteer also ingested four times the same amount of poppy seeds from the same origin (Spanish). During 24 hours urine samples were obtained and screened for the presence of morphine and codeine using the FPIA technique (cut-off = 200 ng/mL) and a GC/MS confirmation with a limit of detection (LOD) of 25 ng/mL for codeine and morphine. Poppy seeds from different origins contain a wide variation of morphine (2-251 micro g/g) and codeine (0.4-57.1 micro g/g) content. No other opiate could be detected. After ingestion a large interindividual variation of excretion of opiates exists. The testing results from the same kind of seeds ingested four times with a one week interval by the same volunteer also show a poor reproduceability. Several kinds of poppy seeds can give positive testing results (Australian, Hungarian, Spanish and one kind of Turkish seeds). Within 24 hours all testing results became negative.
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The Opium Poppy
Until 1952, when morphine was synthetized (see Bulletin on Narcotics, Vol. IV, No. 2), the opium poppy was the only source of morphine and its derivatives.
The opium poppy has a number of uses of great economic importance:
Its seeds are edible, and are used, especially in Central Europe but also throughout the rest of the world (e.g., for the United States, see Bulletin on Narcotics, Vo l. II, No. 3), for the preparation of pastry, nougat; etc.;
The seeds provide a good-quality oil which is used for human consumption, especially in northern Europe;
In view of its high content of quick-drying substances, the first juice extracted is used to make oil varnishes, soap, greases, perfume, etc.;
The seeds are also used in pharmacy for making emulsions; 1
Oil-cake made from poppy-seeds is excellent. cattle feed and a first-class fertilize;
Lastly; because of the beauty of its flowers, the opium poppy is used throughout the world as an ornamental plant.
Accordingly, in addition to its use for opium production, the opium poppy has many important uses which give rise to extensive production and trade. 2
Whatever their garden names, all poppies of the species Papaver somniferum arecapable of producing morphine. When it is remembered that in 1926 a method of extracting morphine direct from the plant without passing through the intermediary stage of opium was discovered, it will be seen that the problem of the opium poppy is inherently complex, since the same plant can be used for entirely different purposes, some quite ordinary and legitimate and others coming within the province of the international control of narcotic drugs.
The opium poppy, Papaver somniferum L., belongs to the Papaveraceae family. The Papaveraceae are dicotyledonous, dialypetalous superovaried plants. Although the family itself is simple of classification, the same is not true of its internal classification: the number of genera and with it the number of species within each genus varies according to botanists. As this is a relatively secondary matter and of theoretical rather than practical importance, there is no need to go any further than the Bonnier classification. 3
1 See Bensussan, I., L’opium, Paris, Vigot, 1946, p. 11.
2 For example, in 1947 over 31,000 tons of poppy seed were produced in nine countries (Austria, Czechoslovakia, France, Germany, Hungary, Netherlands, Romania, Sweden and Switzerland). See document E/CONF.14/7.
Six genera: Papaver, meconopsis, glaucium, roemeria, chelidonium, hypecoum
Within the genus Papaver, six species: Somniferum, rhoeas, dubium, argemone, hybridum, alpinum.
For our purposes the essential question is which species or varieties contain the alkaloids governed by the international conventions on narcotic drugs. Much work has been done on this subject, and it may now be said that with the exception of protopine, cryptopine and thebaine, none of the opium alkaloids are found in any genus of the plant other than Papaver. As far as the species are concerned, the question is still an open one (1953). Without going into detail with regard to the number of species and their classification as species, sub-species or varieties, reference may be made to the work of C. G. Farmilo, H. L. J. Rhodes, H. R. L. Hart and H. Taylor, which is complementary to that of C. Fulton 4 and was published in the Bulletin on Narcotics, Vol V, No.1.
The above-mentioned four authors analysed twenty-five species (or sub-species or varieties) of poppies closely related to the opium poppy Papaver somniferum L. by a method of chemical analysis which they describe in detail in their paper. They discovered that the only one containing morphine, other than Papaver somniferum, was Papaver setigerum This provides a precise answer to the question of the number of species producing the alkaloids subject to international conventions on narcotic drugs.
Up to the time of the work done by C. Fulton and the other writers mentioned above, it was thought that Papaver setigerum, which grows wild in the Mediterranean region, especially southwestern Europe, was the “mother plant” from which Papaver somniferum was derived. But Papaver somniferum is diploid ( n = 11) and Papaver setigerum, which has twice as many chromosomes, tetraploid ( n = 22); and no other species of Papaver is known to have the number n=11, or a multiple of 11, which indicates that Papaver setigerum cannot be the ancestral species of Paper somniferum since a diploid would not be derived from a tetraploid plant.
3 See Bonnier, G., Tableau synoptique des plantes vasculaires de la flore de la France, Paris, Dupont, (n.d.), p. 12; for a detailed treatment see Fulton, C., The opium poppy and other poppies, United States Treasury Department, Bureau of Narcotics, Washington, D.C., 1944, p. 49.
4 See Fulton, C., The Opium Poppy and Other Poppies, United States Treasury Department, Bureau of Narcotics, Washington, D.C., 1944.9
It may therefore be concluded that for the purposes of narcotics control only Papaver somniferum and Papaver setigerum are of importance. However, it is impossible to give a description of the plant on the basis of its external characteristics, for the following reasons: firstly, Papaver somniferum is a cultivated plant and secondly, it is found over a large part of the earth’s surface. These two circumstances made it possible for a plant to produce almost infinite numbers of variations, according to the varied climatic, soil and other conditions in which it grows. Moreover, hybrids are developed by horticulturists; and in addition, the flower, while often self-pollinated, is sometimes cross-pollinated, with the result that in a single field spontaneous hybridization may occur; indeed, open and closed capsules have even been found together on the same plant.
It is not possible, therefore, to determine the ” theoretical” varieties of the plant.
Variation in the flower
The flower may be single or double, with considerable variation of shape, arrangement and colour of petals (white, pink, red, purple, crimson or variegated).
Variation in the seed
Here again contradictory assertions and classifications, attributing particular effects on the plant’s alkaloid content to certain colours of seed, are made. The fact is that there are white, yellow, coffee-coloured, black, grey, blue, etc., seeds, and there appears to be virtually no relationship between the colour of the flower and that of the seed.
Variation in the capsule
The capsules may be of different shapes (elongated, globular, oblate, etc.) and no relationship can be detected between the shape and the alkaloid content (on the other hand, some shapes are easier than others to incise for the collection of the latex). The capsules may also be closed or open, and there may be two, three or more capsules on each plant.
Lastly, the poppy may vary as to height (30 to 150 centimetres or more), stem appearance (glabrous or hairy), and leaf, which may be of many different shapes.
The practical conclusion is that it is impossible, from the botanical standpoint, to distinguish any precise varieties. That is a matter for the horticulturist (see, e.g., Vilmorin-Andreux et Cie, Fleurs de pleine terre, Paris, 1863, and Index Londinensis to illustrations of flowering plants, ferns and fern allies, Oxford 1931). The normal process is that poppies cultivated in a given region eventually acquire a number of common general characteristics and tend to form a local variety. Thus, for example, the so-called muhacirmali poppies, which were imported from Macedonia into European Turkey and after poppy-growing was prohibited there were sown in Asia Minor, soon acquired the characteristics of the local poppies (see “The Cultivation of the Opium Poppy in Turkey”, Bulletin of Narcotics, Vol. II, No. 1).
The last question arising in connexion with Papaver somniferum is the distribution of the alkaloids in the various parts of the plant. Generally speaking, there are two points to note:
most of the alkaloids found in opium are found in other parts of the plant as well as the seed;
the capsule and the latex it produces are by far the most important point of concentration of the alkaloids.
The fact that from the botanical point of view it is difficult to distinguish sub-species or varieties within the species Papaver somniferum is immaterial to the agriculturalist, whose concern, whether he is engaged in the production of seeds for food or industry or in opium production, is with yield. Agronomists have therefore studied the possibilities of developing “races” adapted to a particular climate or soil and, above all, to the particular type of production desired. For opium production the question is at present being studied at various agronomic research centres, in particular in the Turkish Soil Products Office, which is endeavouring to create types with a high alkaloid yield.
Since the poppy, as has been indicated, adapts itself easily to different soil and climatic conditions, horticulturists have succeeded by dint of time and care in developing “geographical races” which are relatively constant and well-adapted to the soil and climate of the given country. Thus efforts were made, with success, to develop closed-capsule species, and these are at present the predominating type, for instance, in Asia Minor: their capsules are larger and rounder, and consequently harvesting is easier; and in addition the morphine yield is generally two or three per cent higher than that of plants with dehiscent capsules.
The poppy is a hardy plant; it will grow in varying climates but cannot endure extreme cold. In a cold climate, its opium yield is greatly diminished: climatic conditions, particularly humidity, affect the yield more than any other factor.
In damp climates the poppy is attacked by the peronospora and other plant diseases. Moreover, if there is much rain, the plants grow very tall and may be beaten down when they are ripe. Heavy rain at the time of harvesting washes away some of the latex and may even wash it off completely. Thus the ideal conditions are snow in winter, rain in spring and dry weather while the plant is mature.
As the poppy cannot stand extreme cold, it cannot be cultivated in frosty climates unless there is a sufficient covering of snow in winter to protect the seed and the young plant.
The poppy is very sensitive to wind, particularly when it is maturing. The capsule is then comparatively heavy; it may be beaten down and the latex lost.
The poppy does not like either heavy, clayey soils or sandy soils. The ideal is an average soil treated with. manure or chemical fertilizers, for the poppy plant impoverishes the soil.
The poppy is an annual and may be sown in autumn or spring: the choice depends on the “race”, on economic conditions and, above all, on climate. The most important point is the alternation of rainy and dry seasons, which determines the opium yield. In poppy-growing areas, which are generally warm temperate zones, the sowing time may therefore begin in September and continue to as late as April.
Generally speaking, the autumn poppy is hardier and has a higher yield, but in regions where the winter is severe it naturally runs greater risks than the spring poppy.
Germination lasts two to three weeks; about a month later the first four leaves appear; and two or three weeks later the stem begins to form. The plant reaches full development in about two months. The flowering season varies according to climatic and other conditions and according to sowing date; the plant flowers by day and the flower lasts thirty to forty hours. After the petals fall the capsule continues to grow and is ripe in about two weeks.
Preparation of the soil
The poppy requires a rich soil and impoverishes it rapidly. A system of rotation must therefore be followed, or alternatively the plant must be sown on land that has lain fallow or on intensively fertilized land. The use of chemical fertilizers, which are very successful, is not very wide-spread in the poppy-growing regions. For that reason the Turkish peasant, for instance, usually has his poppy field near the village so that it may be fertilized by the natural manure of the herds. (Thirty to forty tons of manure per hectare are needed.)
The soil must be well worked and irrigated before sowing; for spring sowing it must be prepared during the previous autumn.
Generally speaking,agricultural machinery is practically unknown in the poppy-growing areas, and the seed is therefore generally sown broadcast, about 20 kilogrammes of seed per hectare being used instead of the three or four kilogrammes which would suffice with a mechanical sower.
Work to be done during growth
The main work is weeding, thinning out (the latter being done after the first four leaves have formed, leaving about 15 plants per square metre) and the nipping off of a number of capsules on each plant to allow the remaining three or four to develop better.
(e) The enemies of the poppy
These consist of:
Parasites which destroy the leaf and stem, such as, Perenospora arborescens , which gives the poppy mildew, and Orobanche papaveris , which attacks the roots;
Larvae of insects such as the beetle, locust, etc., which destroy roots, leaves and capsules.
As with other crops, the campaign against these parasites is a long and difficult task requiring constant attention.
Opium is harvested in two phases: the incision of the capsule and the collection of the latex. The period varies according to climatic conditions but is about two weeks after the petals fall. The capsule should be hard, but its colour depends on the local variety. The time for harvesting lasts about one week, after which the capsule dries. However, as not all the capsules ripen at the same time, even in any one field, harvesting may last over two weeks. The incision of the capsule is the vital operation and a highly skilled one: the latex is between the epicarp and the mesocarp, the juice channels running from below upwards. A great many channels must be made, but the wall of the capsule must not be cut right through or the latex will run down inside and be lost. Incisions are made at sunrise or sunset, and it takes from 8 to 14 hours for the latex to exude and solidify. The technique of incision is important, for the capsule must not be killed, and must therefore never be cut all round. Several incisions may be made in the same capsule, but in that case the percentage of morphine in the latex decreases (certain other alkaloids such as codeine, on the other hand, do not seem to vary). No definite conclusions have yet been reached on this point. 5
When the latex has caked, it is collected with a blunt-bladed instrument which scrapes the capsule without taking off the vegetable tissues and thus spoiling the purity of the opium. 6
The yield of opium per hectare is a very difficult question, depending on many factors: the nature of the soil, the climate and annual rainfall, the state of the seed, etc. That is why statistics show a variation of 1 to 6 between one year and another (with the same soil and “race”) and of 1 to 15 between different countries. The yield in Turkey averages about 10 kilogrammes of opium per hectare. The yield of Indian opium seems to be much higher, but it must be noted that in Turkey only one incision is usually made in each capsule, whereas in India incisions are repeated until all the latex has exuded, with the result that the quantitative yield is much higher.
In addition, as already indicated, the opium poppy is cultivated on a rotation system; in other words, the peasant actually grows opium in any one field only every third or even every fourth year. This also to some extent explains the differences in yield.
5. See Annett, H. E., Sen, H. D., and Singh, H. D., “Investigations on Indian opium , No. 1, Non-environmental factors influencing the alkaloidal content and yield of latex from the opium poppy ( Papaver somniferum)”, Memoirs of the Department of Agriculture in India , Vol. VI, No. 1, pp. 1-154.
6. For illustrations of the capsules and various instruments see, for example: Dr. Fethi Incekara, Turkiye Hashas Cesitleri , Ankara, 1949.
[History of opium poppy and morphine]
Opium has been known for millennia to relieve pain and its use for surgical analgesia has been recorded for several centuries. The Sumerian clay tablet (about 2100 BC) is considered to be the world’s oldest recorded list of medical prescriptions. It is believed by some scholars that the opium poppy is referred to on the tablet. Some objects from the ancient Greek Minoan culture may also suggest the knowledge of the poppy. A goddess from about 1500 BC shows her hair adorned probably with poppy-capsules and her closed eyes disclose sedation. Also juglets probably imitating the poppy-capsules were found in that period in both Cyprus and Egypt. The first authentic reference to the milky juice of the poppy we find by Theophrastus at the beginning of the third century BC. In the first century the opium poppy and opium was known by Dioscorides, Pliny and Celsus and later on by Galen. Celsus suggests the use of opium before surgery and Dioscorides recommended patients should take mandrake (contains scopolamine and atropine) mixed with wine, before limb amputation. The Arabic physicians used opium very extensively and about 1000 AD it was recommended by Avicenna especially in diarrhoea and diseases of the eye. Polypharmacy, including a mixture of nonsensical medications were often used. Fortunately for both patients and physicians many of the preparations contained opium. The goal was a panacea for all diseases. A famous and expensive panacea was theriaca containing up to sixty drugs including opium. Simplified preparations of opium such as tinctura opii were used up to about 2000 in Denmark. In the early 1800s sciences developed and Sertürner isolated morphine from opium and was the founder of alkaloid research. A more safe and standardized effect was obtained by the pure opium. Several morphine-like drugs have been synthesized to minimize adverse effects and abuse potential. Opioid receptors were identified and characterized in binding assays and their localization examined. However, the complexity of the system including interaction with several neurons and transmitters indicate the goal of nonaddictive opiates to be elusive. Combination therapy, innovative delivery systems and long-acting formulations may improve clinical utility.
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