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NARCOTICS AND MIND-MANIFESTING DRUGS (Hashish, Opium, Cocaine, Amphetamine, Khat, LSD, Mescaline, Psilocybin and Phencyclidine) By Dr. Kamal Eldin Hussein ElTahir Associate Professor of Pharmacology College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. (1990) 1 Causes for Intake of Narcotics and Mindmanifesting Drugs Scientific Prevention Strategies For thousands of years and in various parts of the World, human beings were stimulated by curiosity and boredom to experiment with the surrounding plants and mushrooms to relieve pain, tension or frustration. These trials led the primitive man to discover the ability of some plants to relieve pain, change the mood, alter perception or produce euphoria. Such plants included Opium in China and India, Mescal buttons in Mexico, Coca in Peru, Cannabis in China and Teonanctal mushroom in Mexico and South West USA. Furthermore some of these substances e.g. Mescal buttons, Teonanctal and Cannabis were used in religious ceremonies on the belief that the substances have the ability to enhance the religious emotional experience by clarifying the mind and detaching from the distracting surroundings leading to more concentration during worshipping of the God!! Use of some of these plants was confined to specific parts of the World for many centuries, however, in the early years of the 20th century use of these plants spread among the youth of many countries. The situation became worse when many synthetic compounds that have the ability to suppress pain, change the mood, induce visual hallucination or induce psychomotor stimulation were discovered. These synthetic compounds included heroin, a potent analgesic compound, amphetamine, a potent psychomotor stimulant and LSD, a potent hallucinogen. Most of these chemicals were misused throughout the World; however, chronic use of these substances led to emergence of various problems such as development of dependence and addiction to these substances and precipitation of psychotic diseases such as hallucinations, delirium or schizophrenia and mania. During this time many health authorities called for legislative measures to control and 2 prohibit the non-medical use of these substances. Indeed many countries were encouraged by WHO to control synthesis, distribution and sale of these dependence-inducing substances. However, the availability of these legislative measures and the severe penalties issued by many countries for breakers of these laws did not deter drug-pushers and illicit Narcotic Organizations from synthesizing and distributing many of the mind-manifesting drugs. Indeed, the job of these illicit drugpushers was facilitated by the inherent property of some of these drugs in inducing psychic dependence whereby the intake of the first dose compels and motivates the user to repeat the use of the drug. Indeed some of these drugs precipitate in the user a feeling of craving to the drug continuously to maintain his optimal state of wellbeing. Furthermore, some drugs have the ability to induce physical dependence which is characterized by appearance of troublesome symptoms (known as withdrawal symptoms) following abrupt discontinuation of drug intake. For these reasons illicit drug-pushers need only to introduce the drug for the potential user only once and the drug then completes their job by forcing the user to search for the drug among the illicit drug-pushers. Indeed, illicit drug-pushers sell the first dose very cheaply and sometimes distribute it without any charge!! Factors that predispose to drug misuse: There are many factors that facilitate or encourage individuals to use narcotics and mind-manifesting drugs. These factors may be divided into: A. Environmental Factors: The environmental factors that predispose to drug misuse include: 1. Ease of obtaining the drug or the plant. This may be due to widespread cultivation of the narcotic or mindmanifesting plant in the surrounding environment or due 3 2. 3. 4. to its wide availability and distribution by the illicit drugpushers and ease of its synthesis and smuggling from one country to another. Acceptance of drug use by the society e.g. mescaline and psilocybin by the Indians of Mexico and USA. Freedom of illicit drug dealers and pushers who are free to expose their wealth e.g. houses, cars ... etc. This will encourage poor individuals to indulge in that illicit trade and start selling and taking the drugs to become wealthy. Widespread of wrong deeds in the environment such as hate, cruelty, injustice, intolerance and dehumanization. B. Personal Factors: There are many personal factors that motivate many individuals to indulge in the use of narcotics and mindmanifesting drugs. These factors include: 1. Feelings of failure in education, job or familial life coupled with feelings of tension, shame and depression. 2. Curiosity to learn and experience new feelings. 3. Low ego strength and deviance from religion and disbelief in God and fate. 4. Lack of self worth and goals in life. 5. Dysphoria and psychological pain. 6. Boredom and desire to relieve monotony. 7. Availability of long periods of free time coupled with inadequate education and availability of passive forms of entertainment and excitment (e.g. videos) that don't exhaust youth energies. 8. Desire to facilitate social relationships, to gain status with peers and to show manliness and prestige. 9. Prevalence of some psychological diseases such as anxiety, depression, aphoria due to genetical or biochemical brain disorders that predispose to the feelings of grim future and bleak existence. 10. Prevalence of some organic diseases such as chronic pancreatitis, paraplegia, bone inflammations and cancer. 4 11. Search for self-transcendence and meaning of life. 12. The mistaken belief that mind-manifesting drugs increase creativity. 13. Decentralization of the family. 14. Decline in family nurturing or absence of one parent in the home. 15. Psychological alienation characterized by feelings of estrangement and separation from the society's established values and individual goals. 16. Unawareness about the adverse effects of narcotics and mind-manifesting drugs. 17. Feelings of failure to correct hate, cruelty intolerance and injustice in the society. 18. Indulgement in incest and crimes. 19. Feelings of neglect, exploitation and inconsistent treatment of children. Scientific solutions to deter youth from indulging in intake of Narcotics and Mind-manifesting drugs. The major scientific prevention approaches or strategies to deter youth from intake of narcotics and mind-manifesting drugs comprise the following steps: 1. 2. 3. Appropriate and correct education of children about the social norms and the correct deeds in life. Furthermore parents should be educated about better communication skills and understanding with their children. It should also be pointed that the free democratic family style with the decreased influence of parents over their children and lack of questioning and punishment about illegal acts motivate for drug-misusers. Youth should be advised about the correct and ideal criteria for selection of friends. Indeed, a drug-using friend is more likely to stimulate the non-user to start the drug. Isolation of drug misusers and establishment of rehabilitative units and clinics for treatment of drug 5 addicts. The aim should be to prevent drug misusers from infecting naive persons. 4. Trials should be made to identify the reasons of psychological stress and boredom that motivate drug misuse. Thus, we have to solve problems such as poverty, poor housing and racial discrimination in the society. 5. Government and businessmen should be encouraged to make the work more rewarding to the individual. Salaries should be adequate to cater for the needs and styles of life in the environment. 6. We have to aim to create an environment more conducive to meet the developmental needs of youth. 7. We have to promote those values, attitudes, satisfactions and skills that enhance youth ability to function in the society. We have to strengthen the capacity of the individual to deal with stress and resist attraction of narcotics and mind-manifesting drugs. 8. Families, schools, colleges and societies should aim to nurture the sense of trust, worth accomplishment and identity that will enable youth to face the uncertain future. Youth should be motivated to accomplish tasks of value to the individual and society. 9. Instruction of educational institutes to include in their curricula some psychosocial courses to help youth to understand human behaviour, to provide knowledge about adverse effects of drugs, to improve their abilities to communicate with others and deal with stress. Educational programmes should be aimed to provide youth with intellectual, social, cultural and recreational alternatives to drug abuse. 10. Public should be informed via broadcasting services, televisions, newspapers and dramatic acts in theatres and television programmes about the adverse effects and personal and social harms that can result from intake of narcotics and mind-manifesting or altering drugs. We 6 have to remember that any individual seeks good health and fears illness. 11. Government should be encouraged to pass laws with severe punishments to control narcotics and mindmanifesting drugs' distribution and use. Furthermore, information about penalties attached to promotion and use of narcotics and mind-manifesting drugs should be publicized. 12. Strong stress should be put to solve the causes that motivate for drug misuse. Such causes should be fulfilled by other alternatives. We have to note that people take drugs because drugs serve some function and give satisfaction in some area of their lives. We have to provide youth with alternatives to satisfy those motives and meet youth developmental needs. These alternatives should cover all aspects of life: emotional, intellectual, developmental, ethical or philosophical aspects. I believe that fulfillment of these strategies-with the help of God will pave the way towards drug-free societies. Lastly, we have to remember that great achievements are possible only by persistent and meaningful activity and work. 7 General References: 1. 2. 3. 4. 5. 6. 7. Burke, E.L. (1971). Drug Usage: reported effects in a select adloscent population. J. Psychedelic Drugs. 3, 5562. Chein, I., Gerard, D.L., Lee, R.S. and Rosenfeld, E.L. (1964). The Road to H. New York Basic Books Incorporation. DuPont, R. and Greene, M. (1973). The dynamics of a heroin addiction epidemic. Science. 181, 716-718. Isbell, H. and Chrusciel, T.L. (1970). Dependence liability of non-narcotic drugs. Bull. W.H.O. 43 (Suppl.) 5-15. Kandel, D. (1973). The role of parents and peers in adolescent marijuana use. Science. 181, 1067-1072. Nowlis, H. and Jackson, L.S. (1977). In: Drug Abuse. Clinical and Basic Aspects. (Eds. Pradhan, S.N. and Dutta, S.N.). Mosby Co. Saint. Louis pp. 535-543. WHO Expert Committee on Drug Dependence. 16th Report. WHO Technical Report. Serial No. 407, Geneva, 1969. 8 Introduction to the Author and the Book By Dr. Tahir Mohamed ElHassan. I have known Dr. Kamal Eldin Hussein ElTahir for several years especially during the period 1983-1985 when he as an active member in the Sudanese National Committee for Information about the Adverse Effects of Tobacco, the General Secretary for the Sudanese National Committee for Information and Enlightenment about the Adverse Effects of Alcoholic Drinks, a member of the Executive Committee of the Sudan Islamic Medical Association and an Editor of the Sudan Medical Journal. My contact with these committees and my close observations showed me the high activity and great contributions of Dr. Kamal in all these activities. He devoted much of his free time for these responsibilities besides his heavy teaching duties of Pharmacology for Pharmacy, Medical and Dental students at the Faculties of Pharmacy and Medicine and School of Dentistry, University of Khartoum, Sudan. In fact I was not astonished about Kamal's activities since he was one of the most brilliant pharmacy students during the years 19661971, Faculty of Pharmacy, University of Khartoum. As a student and besides his academic responsibilities, Kamal was an active football and basketball player in the first team of the University and the joint team for the Faculties of Medicine and Pharmacy. During his undergraduate studies he contributed greatly to the activities of the Students' Pharmaceutical Association and he was the Chief Editor for Sudan Pharmacy Journal in the year 1969/1970. Furthermore, when he was a student he established and edited the wall magazine "Al Amal" (i.e. The Hope). In this magazine he used to write scientific articles and short stories together with his meetings with foreign students studying in the Faculties of Pharmacy and Medicine. His aim was to introduce these students to his other colleagues to 9 strengthen the bonds of friendship and brotherhood. Indeed those years have shaped the character of Dr. Kamal whom we know today. Kamal contributed his academic success in his postgraduate studies for the MSc. in Pharmacology, Chelsea College, University of London and for his Ph.D. in Pharmacology at Bath University, England. During his studies he showed great interest in Pharmacology and Experimental Research which was culminated by awarding him Dr. Whittet Prize for the BEST Ph.D. student at Bath University in 1980 for his published work about the role prostacyclin in the reproductive system. Indeed, during those years the then Nobel Laureate Professor John Vane and his collaborators at Wellcome Laboratories, Beckenham, England, have newly discovered prostacyclin. Kamal's work was highly appreciated by the Scientific Media as reflected by the large number of reprint requests for his joint published work with his Supervisor Dr. Ivon Williams. Dr. Kamal extended his research activities at the Faculty of Pharmacy, University of Khartoum during the years 19811985 and thereafter at the College of Pharmacy, King Saud University, Riyadh. His contributions in the fields of prostacyclin, leukotrienes, calcium channel blockers, aminoacids and medicinal plants are very clear as reflected by the various research papers he has published in these fields. Dr. Kamal also supervised several MSc. Pharmacology students. This Book "Narcotics and Mind-manifesting Drugs" is an extension to his research activities. It is number 5 in the series of his published Books which included “Tobacco and Snuff: adverse effects"; "Medicinal Values of Bees, Honey, Onion and Garlic"; "The Pharmacology of Essential Drugs" and "The Medicinal Properties of Some Nutrients and Beverages: Dates, Banana, Pineapple, Honey, Garlic, Onion, Tea and Coffee". After reading this Book "Narcotics and Mind-manifesting Drugs" I felt and admired the enormous scientific effort which Dr. Kamal has put and spent in the preparation and writing it. These efforts really reflect the well-established and deep knowledge of Dr. 10 Kamal in Pharmacology in general and in the fields of narcotics and mind manifesting or psychedelic drugs in particular. Indeed, I believe any chapter in this Book will get greatly satiated from knowledge concerning the different aspects of the drug or plant under study regarding its historical background, chemical composition, pharmacological effects, pharmacokinetics, toxicity, tolerance, dependence on & addiction to. The Book is really an invaluable and interesting one. It is an accessible single-source guide to the pharmacology and toxicity of narcotics and mind-manifesting and hallucinogenic drugs. It is well written and provides a good overview for all that are interested to know about narcotics and psychedelic drugs. The compact presentation of narcotics and mind-changing drugs. I believe the Book will be of immense value to all those who are working hard to combat spread of narcotics and mind-altering drugs among youth and adults. Indeed the scientific strategies pointed by Dr. Kamal to deter youth from being addicted by narcotics and mind-manifesting drugs are well sound and if fulfilled or applied a near-eradication of these killing agents will be reached in the near future. I hope that this Book will reach the hands of every family in this World. Indeed, I was pleased when Dr. Kamal informed me that the Book will also be published in Arabic Language by Dar AL ILOOM, Riyadh so that the benefits of this Book will intend to all Arabic reading individuals. I really thank and congratulate Dr. Kamal for this great contribution and wealth of knowledge that will be highly appreciated by our descendents in the coming years. Lastly, I hope that Almighty God will accept this Book as "a good deed" which reward will continue forever. Dr. Tahir Mohamed ElHassam, Ph.D. Khartoum January, 1990 11 CANNABIS OR HASHISH Introduction Cannabis or hemp is an annual plant known by the name Cannabis sativa which belong to the botonical family Cannabaceae. It grows well in tropical and temperate zones. The height of the plant may vary from 1-4 meters. Generally two varieties are grown. The first variety is characterized by long stalks and little branching and is cultivated mainly for fibre production for manufacture of yarn, twine and tarpulins. The second variety indica is characterized by its short stalks and multi branches and is cultivated to provide the narcotic drug known by the names: marijuana (marihuana) or hashish. This review deals with this variety of the plant. The origin of Cannabis is believed to be Central Asia from where it spread to China, the Middle East, Europe and South and North America. The plant is believed to be known by the Chinese for almost fifty centuries ago. They used the plant (leaves, flowers or resin) for treatment of headache, migraine, malaria, asthma, pains, anorexia, anxiety, convulsions and gastrointestinal and eye diseases. In India the plant was used ritualistically in religious settings because it was believed to increase concentration!! Various parts of the plant have been used either by smoking as cigarettes or in pipes or by mixing it with foods or drinks as observed in some parts of India. The most used parts of the plant are the bracts, flowers, leaves and the resin which covers these parts [28]. During the last few decades millions of youth throughout the world have been attracted by the plant and indulged in its smoking to experience the psycho-activity and the brainchanging ability of the plant's active constituents to allow mind escape from the surrounding troubling environment. However, chronic use of the plant led to many psychological disturbances together with the development of both psychic and physical dependence on the plant. 12 The plant-induced psychological disturbances encouraged many countries to suggest means to control use of this plant. In fact many countries agreed to control the use of Cannabis in 1925 during the International Opium Convention. Following this, the USA passed the Federal Restrictions on Cannabis in 1937 and in 1968 the resitrictions were extended to Cannabis active substances. In 1969, the WHO labeled Cannabis as "a habit forming drug" and recommended all countries to control cultivation, trade, distribution and use of the plant or its active substances. Indeed, many countries passed rules in this regard and imposed severe penalties on possession, sale or use of Cannabis. Such penalties ranged from imprisonment for some years to death sentences. In this connection it should be recalled that the Prince Sodoun Al-Shikhoni who governed Egypt in 1341 G was the first governor to impose penalties on all those who smoke Cannabis. Indeed, the penalty was extrusion of some teeth of the smoker [47]. Although most countries passed rules to control the distribution and use of Cannabis, many illicit narcotic organizations still managed to promote its distribution and sale under many slang names, such as: Bhungo or Gobiraa (in some Arabian Countries), Bhang (in India), Kief or Takrouri (in Tunisia and some North African Countries), Habak (in Turkey) Djomba (in Central Africa), Liamba and Machona (in Brazil and some South American Countries), Ganga (in India and Jamica), Dogga (in South Africa), Ta-ma-jen (in China), Grifa in Spain and Mexico) and Anasha (in USSR). Furthermore, marijuana cigarette is known by numerous slang names as: Aunt Mary, Bush, Juanita, Hay, Grass, Yen-pop and Yerba. Similarly Cannabis resin (Hashish) is known by the slang names. Shishi, Half-Moon and Blue Cheese [15]. The English name Marijuana for Cannabis is believed to be derived from the Spanish name "Mary Jane" that refers to cheap tobacco. In this review the name "Hashish" will be used to indicate Cannabis leaves, flowers, bracts or Cannabis active constituents. 13 Chemical Composition of Cannabis: The first chemical studies on Cannabis plant started at the beginning of the twentieth century when Frankel succeeded in isolating Cannabinol from the plant and the Australian chemist Max Czerkis managed to study the chemical properties of this substance in 1907. Later on, in 1940 another constituent was isolated and named Cannabidiol [20]. However, both compounds failed to induce the same actions of Cannabis extract. This finding led to discovery of the active component tetrahydrocannabinol in 1960. Indeed, Cannabinol was not found in fresh Cannabis material and is believed to be a decomposition product of the active constituent tetrahydrocannabinol. Tetrahydrocannabinol was first decarboxylated to give tetrahydrocannabivarin that was converted by air oxidation to Cannabinol [28]. In 1964 Mechoulam and his associates succeeded in characterizing the active constituent of Cannabis as (-)-Δ9transtetrahydrocannabinol (Δ9THC) and managed to synthesize it chemically [28, 35]. This synthetic material is known in Trade as Hashish oil. Δ9-THC is also known as Δ1(2)-THC (due to a different chemical numbering system considering it as a monoterpene derivative). (-)-trans Δ9-THC is a resinous oil with pKa value of 10.6. It is very sensitive to heat and light and oxidizes rapidly to Cannabinol. It is adsorbed by glass or plastic surfaces. It can isomerize to Δ8-THC on exposure to air. It is very sensitive to acids since at pHs<4 it degrades to Cannabidiol and isocannabidiol due to ether cleavage. At pHs>4 but <7, it degrades to Δ8-THC and 9-hydroxyhexahydrocannabinol. The substance may be solubilized using ethanol, plasma, polyethylene glycol, sesame oil or olive oil [28]. Hashish active constituents can be easily extracted using petroleum ether, hexane or methanol and later purified using chromatography. The percentage of the active constituent (-)trans- Δ9-THC in cannabis varies depending upon the plant tested and the origin of the plant. Generally, the percentage of Δ9-THC varies 14 from 0.3-3.4% w/w in the flowers and 5-12% in the resin [28, 40]. The content of cannabinol and cannabidiol extracts are very low 0.15-0.17% w/w [28]. Besides Δ9-THC, cannabinol and cannabidiol, hashish contains various other cannabinoids and non-cannabinoid materials. These substances include: Cannabiglendol, Cannabiterol, Cannabivarin, Cannabidiolic acid, Cannabigerol, 3,5,4-trihydroxybibenzyl Canabioxoic acid [12, 33], Canabichromevarin and Cannabigerovarin and 3,4dihydroxy-5-methoxybibenzyl. Figure 1 shows the chemical structures of the most important cannabis or hashish constituents. Simple Chemical Tests for Detection of Cannabinoids: 1. Addition of 2% alcoholic KOH to cannabis extract gives a purple violet colour. 2. To cannabis material add vanillin in ethanol containing acetaldehyde. A blue-purple colour is produced. This is known as Duquenois-Levine Test. However, a positive test is given by some essential oils e.g. clove, spearmint, chenopodium, mentha arvensis and patchouli. 15 Figure 1. Major Cannabis Constituents: 16 Methods of Intake of Cannabis: The most famous method for intake of Cannabis is via pipes. Usually cannabis cigarettes containing 0.3-1g of cannabis material (dried bracts, flowers, leaves or resin) are smoked. Each cigarette contains approximately 8-30mg of Δ9THC (mean 20mg) together with small quantities of the other cannabinoids. However, cigarettes containing cannabis resin contain only 137-197 mg of the resin. It should be noted that the percentage of Δ9-THC that enters the body after smoking is only 18-23% of that contained in the cigarette since pyrolysis converts it to cannabinol (up to 36%) and Δ8-THC (28). The percentages of cannabidiol and cannabinol that enter the body after smoking are 10-40% and 38%, respectively [2]. None of these components undergoes pyrolysis. In some parts of the world e.g. India, cannabis is taken orally with foods or drinks. However, the onset of action is delayed for 1-2hr compared with 3-5min after smoking. Furthermore, after oral intake the acidic pH of the stomach converts Δ9-THC to the slightly less active isomer Δ8-THC (or Δ1(6)-THC). In addition cleavage of the pyran ring of Δ9-THC may occur. Exposure of non-cannabis smokers to subjects smoking cannabis results in inhalation of Δ9-THC by the non-smokers. Indeed, the level of Δ9-THC in the blood of these passive smokers may reach 13-20ng/ml. Following smoking of marijuana cigarettes containing 20mg Δ9-THC, the plasma level of this substance ranged from 45-233ng/ml 3-10 min after smoking. The duration of effects lasted 3-4h. PHARMACOLOGICAL ACTIONS OF HASHISH: A. Effects on the Brain: 3-5 minutes following cannabis smoking the smoker feels a state of euphoria and mood elevation. These are manifested as excitation, exaltation, extreme happiness, awareness and 17 increased friendliness. Following these0 effects depression of the central nervous system occurs as manifested by a decrease in motor activity and alertness. Hand steadiness and body equilibrium are disturbed. In some smokers, cannabis-induced sedation is preceded by anxiety, confusion and panic [17]. The smoker also experiences ataxia and disturbed time perception when time seemed to pass slowly. Furthermore, the discriminative ability and avoidance or escape responses are impaired. Such effects are similar to those observed following intake of alcohol [17]. Chronic intake of hashish leads to: 1. Impairment of learning, memory disturbance and decrease in intelligence. Indeed, cannabis smokers have low intelligence and memory quotients [44]. 2. Stimulation of appetite in humans; however in rats, chronic treatment with cannabis depressed the food appetite. 3. Decrease in body temperature in most mammals. The site of action seems to be the anterior hypothalamus, the third ventricle and the 4th ventricle. However, tolerance to this effect was observed. The induced hypothermia may be due to: a. Stimulation of 5-HT release. b. Decrease in PGE2 release. c. Increased release of endogenous opioids. These biochemical changes may decrease O2 consumption (or heat gain) and increase heat loss viainduced peripheral vasodilation. 18 4. Suppression of pain feelings (analgesia) [5, 41]. The induced analgesia is probably due to enhanced 5-HT release and release of endogenous opiates (enkephalins and endorphins) [5, 41]. Tolerance to this effect was observed. 5. Inhibition of the vomiting centre. Indeed administration of Δ9-THC to patients receiving anticancer drugs induced a clear antiemetic effect but was not superior to that of metoclopramide. 6. Decrease in tendency to aggressiveness and violence. 7. Decrease in REM-sleep and prolongation of stage IV sleep. Abrupt stoppage of cannabis led to an increase in REM-sleep. Chronic intake of hashish leads to precipitation of various psychotic reactions that include: paranoia, delusions, fear, mania, auditory and visual hallucinations, disorder of thought incoherences of speech, hysteria, apathy, lethargy, dizziness, amnesia, depression, disorientation, depersonalization and loss of identity [11, 31]. Furthermore, high resolution computerized tomographical scanning of brain of chronic marijuana users revealed atrophy of the caudate nucleus and the frontal portion of the brain. Similarly, there are disturbances in the electrical activity in the amygdala and hippocampus together with destruction of rough endopolasmic reticulum and changes in the synapses in the brain [16]. Sites and Mechanisms of Action of Δ9-THC: The major sites of action of Δ9-THC in the brain are the thalamus, cortex and the hypothalamus. Generally, the central depressant effects of Δ9-THC are believed to be due to: a. Interaction of Δ9-THC with cholesterol in the cellular membranes leading to membrane perturbation that results 19 in disordering of these membranes and increase in their fluidity resulting in alteration in ions permeability. b. Inhibition of some important enzymes such as: Na, K+ATPase, Mg-ATPase and Ca-ATPase. c. Elevation of brain cyclic AMP via desensitization of brain phosphodiesterase or release of central PGs. d. Inhibition of DNA, RNA and protein synthesis in the brain. e. Stimulation of release of some central neurotransmitters e.g. 5-HT, dopamine and noradrenaline and inhibition of their metabolism via inhibition of their reuptake back into their respective neurones [7]. f. Inhibition of ACh release and synthesis probably via inhibition of choline uptake by the cholinergic neurones. g. Inhibition of GABA metabolism via inhibition of its reuptake [7]. B. Effect of Hashish on the Cardiovascular System: Smoking hashish or administration of Δ9-THC to various mammals decreased the arterial blood pressure via: a. Central mechanisms located in the brain stem. b. Release of peripheral PGs that dilate blood vessels [8]. c. Direct peripheral vasodilation. The central component of the induced hypotension was clearly demonstrated by the failure of Δ9-THC to induce hypotension in spinal pithed animals. Furthermore, tolerance to the hypotensive effect was observed. Following smoking of hashish or administration of Δ9-THC to humans an increase in heart rate was observed. The induced increase may be >25% of the basal heart rate and is 20 probably due to inhibition of the vagal nuclei via the inhibitory of the baroreceptors on the nucleus tractus solitarius in the brain stem i.e. reflex tachycardia. However, administration of hashish or Δ9THC to various animals (rats, dogs) induced bradycardia that seemed to be mediated centrally since it was not observed in pithed animals or in those animals with transection of the spinal cord at C1-C2level. However, a direct effect on the heart cannot be ruled out since addition of Δ9-THC to the isolated rat heart decreased the heart rate. C. Effect on the Respiratory System: Smoking of hashish produced inconsistent effects on the respiratory function. In some smokers stimulation of respiratory function and bronchodilation were observed [38] whereas in others a depressant effect was observed. Furthermore, chronic cannabis smoking induced bronchial irritation cough, bronchitis and mucosal changes in the lungs [38]. On the other hand, exposure of animals to hashish smoke or administration of Δ9-THC depressed the respiration and increased tendency to pulmonary infection and pneumonitis [19]. The depressant effect seemed to be mediated centrally by antagonising the stimulating effect of CO2 on the medullary respiratory centre. D. Effect on Hormones: 1. Effect on gonadotrophins: Chronic smoking of hashish induced significant decrease in LH level without affecting FSH level. The effect is probably due to the ability of hashish to stimulate release of enkephalins that act on the hypothalamus to depress release of LH-RF. Furthermore, both THC and cannabidiol reduced the sensitivity of the pituitary gland to the stimulant effect of LH-RF [22]. Similarly, THC inhibited the binding of human chorionic gonadotrophin to the ovarian granulosa cells [25] and the testes. These changes resulted in decreased synthesis of testosterone and 21 impotence in males and to disturbances in ovulation and menstrual cycles and sub-fertility in females [14]. 2. Effect on Oestrogen and Progesterone: Addition of Δ9-THC to ovarian granulosa cells in vitro or addition of cannabinol, cannabigerol or cannabichromene inhibited FSH-induced release of oestrogen. In addition Δ9-THC decreased the level of hydroxysteroid dehydrogenase in the ovaries [25]. Similarly, Δ9-THC inhibited progesterone release and decreased serum progesterone level during the luteal phase. 3. Effect on Corticosteroids: Administration of Δ9-THC to rats but not mice or rabbits elevated plasma level of corticosterone. The release seemed to be due to stimulation of ACTH release from the hypothalamus [39, 46]. 4. Effects on other Hormones: Chronic administration of Δ9-THC to various mammals or smoking of hashish decreased plasma level of GH and prolactin. However, smoking of a single cigarette of hashish did not affect plasma prolactin level. Similarily, exposure of mammals to hashish smoke or administration of Δ9-THC decreased plasma level of both thyroxine and triiodothyronine. Studies on humans and animals revealed that smoking of hashish, systemic or topical application of Δ9THC induced significant decreases in intraocular pressure especially in patients suffering from glaucoma. There was also slight mydriasis, conjunctival reddening, corneal irritation, photophobia, cycloplegia and lachrimation [30]. 22 The decrease in intraocular pressure is probably due to: i) ii) Δ9-THC-induced increase of aqueous humor outflow resulting from vasodilation of the efferent blood vessels of the anterior uvea. Inhibition of ocular PGs synthesis. Reduction of aqueous humor formation due to activation of B-adrenoceptors in the eye. Besides the above changes in the eye hashish smoking induces alteration in visual perception since colours seem to be more vivid than usual [32]. F. Effect on the Ear: Chronic cannabis smoking alters auditory perception [32]. G. Effects on the Reproductive System: i) Effect on the Testis: Treatment of animals with Δ9-THC or exposure to the cannabis smoke or smoking of hashish induced: a. Depression of spermatogenesis. b. Depression of sperm metabolism and motility. c. Degeneration of the seminiferous tubules, prostate gland, epididymis and the testis. d. Increase in the percentage of abnormal sperms. e. Decrease in the enzymes involved in steroidogenesis and spermatogenesis. Furthermore, there was an increase in androgen binding protein inside the testis resulting in decrease in free testosterone level. ii) Effects on the Ovary: Treatment of various mammals with Δ9-THC or smoking of hashish resulted in inhibition of ovulation due 23 to inhibition of gonadotrophin release [4]. Furthermore, in those cases when ovulation occurred there was an increase in the number of the abnormal ova released. Indeed, chronic hashish smoking increased the interval between menstrual cycles to 3 months and increased the number of anovulatory menstrual cycles in women [4]. iii) Effects on the Uterus: Exposure of the mammalian uterus to cannabis extracts decreased the frequency and force of the contractions. Furthermore, treatment of mammals with hashish extracts exerted antioestrogenic activity as reflected by inhibition of oestrogen-induced increase in glycogen and water content, increases in phospholipids, alkaline phosphatase, acid mucopolysaccharides and hyaluronidase. These effects did not seem to be due to a direct effect on uterine oestrogen-receptors but are more likely due to suppression of gonadotrophins and LH release. On the other hand, hashish extracts are shown to contain apigenin and 3,4-dihydroxy-5-methoxybibenzyl that bind to oestrogen receptors in the uterine cytoplasm. iv) Effects on the Foetus: Administration of Δ9-THC or hashish extracts to pregnant mammals (rats, monkeys, hamsters, mice) during the embryogenesis period induced various teratogenic effects such as stunting, syndactyly, encephalocele, phocomelia, amelia, eventration of abdominal viscera, increased percentage of foetal resorption and cleft palate. Furthermore, administration of cannabis during pregnancy induced abortion and stillbirth together with acidosis, hypoxemia and hypercapnia in the foetus [1, 6, 36, 43]. In humans, cannabis smoking during pregnancy disturbed labour, shortened the gestation period, decreased foetal weight and induced foetal malformations. 24 Most of these disturbances are not due to a direct effect on the foetus because with the exception of sheep the cannabinoids do not pass the placental barrier. It is more likely that cannabis-induced teratogenic and embryotoxic effects were due to disturbances in the maternal hormones and gonadal function or due to induced decrease in plasma level of vitamin E in the mothers. H. Effects on Blood Constituents: Administration of hashish extracts or Δ9-THC to various mammals induced various changes in blood constituents. These include: i) ii) iii) iv) v) vi) vii) viii) ix) Elevation of blood glucose level. The increase may be due to 9-THC ability to antagonise insulin and/or stimulation of adrenaline release from the adrenal medulla [18]. Elevation of plasma level of non-esterified fatty acids i.e. enhancement of lipolysis. Elevation of plasma bilirubin level. Elevation of plasma cholesterol level. Elevation of plasma Ca2+ and decrease in plasma K+ levels. Decrease in number and disturbance in plasma membranes of RBC and decrease in haemoglobin content. Increase in blood carboxyhaemoglobin level. This effect may deteriorate the condition of patients with heart diseases. Degranulation and release of lysosomal enzymes from neutrophils together with reduction in phospholipid content and splitting of the nuclear membranes. Inhibition of platelet aggregation in small doses but complete aggregation and degranulation of the platelets with higher doses. 25 x) Stimulation of adenosine diphosphate release from RBC with concomitant aggregation of the platelets. xi) Disturbances in platelet membrane phospholipids. xii) Activation of phospholipase A2 enzyme with enhancement of arachidonic acid release concurrently with inhibition of PG cyclooxygenase and thromboxane synthetase and activation of lipoxygenase enzymes in platelets. I. Effects on Immune System: In vivo studies using different mammals (mice and rabbits) or in vitro studies clearly demonstrated the ability of Δ9-THC or Δ8-THC or hashish smoke to suppress both humoral and cellmediated immune responses [24]. These substances decreased antibody formation as a result of inhibition of lymphocytes' function e.g. inhibition of B-lymphocyte mitosis or due to decrease in number of helper T-lymphocytes together with suppression of thymus gland activity. This immunosuppressant activity may explain the decreased resistance of mammals to bacterial and viral infections. Thus cannabis smoking may suppress immunocompetence with the ultimate increase in susceptibility to cancer, bacterial and viral infections [9]. The biochemical mechanisms that underlie hashishinduced suppression of immunity may involve: i) Inhibition of lymphocytes' protein synthesis. ii) Inhibition of lymphocytes' ATPases that are essential for active transport of essential nutrients into cells [34]. iii) Inhibition of acyltransferases that are associated with activation of cell mediated immunity [45]. Generally, it should be pointed that the immunosuppressant effect of 9-THC or hashish will not be of any clinical value in humans with organ transplants due to the transient effects and high doses of Δ9-THC required. 26 J. Effects on the Gastrointestinal Tract: Administration of Δ9-THC or hashish smoking is consistently observed to decrease gastric acid and pepsin secretion and to suppress the development of stress-induced ulcers. Furthermore, hashish extracts exerted spasmolytic effects on the gastrointestinal tract due to both a direct effect and inhibition of ACh release from the intestine. However, the ability of hashish components to release PGs usually predisposes to diarrhoea. K. Effects on the Liver: Exposure of liver cells to hashish smoke or Δ9-THC in vivo resulted in: i) Inhibition of microsomal lipid peroxidation due to stabilization of the microsomal membranes. ii) Stimulation of glucose metabolism by increasing the activity of the enzymes UDP-G-dehydrogenase and fructose 1,6-diphosphate aldolase. iii) Stimulation of glycogenolysis. iv) Inhibition of hepatic oxidizing microsomal enzymes (mixed function oxidase system) but stimulation of hepatic heme oxygenase. L. Effects on the Kidney: Treatment of various mammals with Δ9-THC or hashish extracts induced diuresis due to inhibition of renal Na+, K+ATPase involved in active sodium reabsorption by the renal tubules or via inhibition of ADH release [37]. M. Effects on Microorganisms: In vitro studies revealed the ability of cannabidiol, cannabigerol, cannabidiolic acid and Δ9-THC to exert antibacterial activity against gram positive bacteria e.g. Staphylococci and Streptococci [13]. Furthermore, cannabichromene exerted both antifungal and antibacterial activity. In addition, Δ9-THC exerted an antiviral activity against 27 herpes simplex virus type 1 and type 2. However, it should be noted that the immuno-suppressant effect of Δ9-THC decreased host resistance to herpes simplex type 2 vaginal infection. In addition, the inhibitory concentration required for these effects on microorganisms cannot be attained in vivo by smoking hashish. N. Effects on Enzymes: Administration of Δ9-THC to animals or addition of the compound to organs in vitro revealed the ability of this substance to inhibit various enzymes e.g. MAO in platelets and brain, Na+, K+-ATPase and Mg-ATPase in brain, PG cyclooxygenase in platelets and Lysophosphatidyl acyltransferase in lymphocytes and brain. O. Effects on Cyclic Nucleotides: Studies in vitro revealed the ability of Δ9-THC to elevate the level of cyclic AMP in the brain and sperms but to decrease it in ovaries. The stimulant effect may be due to direct activation of adenylyl cyclase or inhibition of phosphodiesterase enzyme. P. Effects on PGs: The effect of Δ9-THC on PGs synthesis depends upon the organ tested. An increase in PGs was observed in the brain and lungs but a decrease was noted in platelets and mammary glands. Acute Hashish Intoxication: Acute intoxication with hashish either by vigrous smoking or by drinking hashish oil or accidental absorption of the oil via body orifices (anus or penis) during smuggling leads to: Lethargy, drowsiness, tachycardia, aniscoria, nausea, vomiting, dizziness, confusion, delusions, visual hallucinations, emotional ability, excitement, disorientation, panic, fear, loss of control and paranoia. Death may occur as a result of cerebral haemorrhage and circulatory failure [11, 31, 32, 36]. 28 Metabolism of Hashish Components: Metabolism of hashish active components usually occurs in the liver via the enzyme cytochrome P-450 [2]. The most 4important metabolites for Δ9-THC are: 1. 11-nor-Δ9-THC-9-carboxyl acid (Δ1THC-7-oic acid or Δ9THC-11-oic acid) and its O-ester glucuronide [23]. This metabolite is the most abundant metabolite in the plasma. It possesses an activity that is slightly less potent than Δ9-THC. It is excreted mainly in faeces (66%) and partly in urine. It undergoes enterohepatic cycling [2, 23]. However, the O-esterglucuronide derivative is mainly excreted in urine [23]. 2. 11-hydroxy Δ9-THC (or 7-hydroxy Δ1THC) This metabolite is excreted mainly in faeces. The major metabolites of Δ8-THC are: i) 11-hydroxy Δ8-THC (7-hydroxy Δ1THC). ii) 3 -hydroxy Δ8-THC. iii) 11-nor- Δ8-THC-9-carboxylic acid. 29 The major cannabidiol metabolites are: i) 11-hydroxy cannabidiol (or 7-hydroxy cannabidiol). ii) Cannabidiol-11-oic acid (or cannabidiol-7-oic acid). These metabolites are excreted mainly in faeces and partly in urine [2]. The major metabolites of cannabinol are: i) 11-hydroxy cannabinol (or 7-hydroxy cannabinol). ii) Cannabinol-11-oic acid (or cannabinol-7-oic acid). Both metabolites are excreted mainly in faeces and partly in urine. Hashish active constituents or their metabolites usually undergo enterohepatic circulation for several days in the body after intake that may enable their detection in blood or urine 512 days after intake [23]. These substances can be detected and assayed by: Enzyme immunoassay techniques, radioimmunoassays, HPLC, fluorometry, GC/Electron capture detection and GC/Flame ionization detection or spectrophotometry [42]. The terminal half-life of Δ9-THC usually ranges from 2057h. Tolerance to Hashish Effects: Studies in animals and humans clearly demonstrated the appearance of tolerance to various hashish effects. Tolerance may occur following a few days after repeated use. The type of tolerance is functional in nature. There was no increase in drug metabolism [10, 26]. Dependence on Hashish: Chronic hashish smoking leads to appearance of physical dependence on this substance with the characteristic appearance of withdrawal symptoms on abrupt stoppage of smoking. The symptoms of the abstinence syndrome usually start 8-12 h after the last cigarette and include: Irritability, salivation, tremors, sweating, nausea, vomiting, diarrhoea, 30 sleep disturbances, chills, restlessness, insomnia, abdominal distress, nasal stiffness, hiccups, dysphoria, dreams, anxiety, hostility, lacrimation, convulsions, hyperthermia, decrease in REM sleep and increase in intraocular pressure. These symptoms, if untreated, usually disappear after three days [21]. Withdrawal Symptoms in Animals: In rats chronically treated with Δ9-THC 2-6mg/kg/day for 5-10 days, withdrawal symptoms can be precipitated by i.p. or i.v. administration of some drugs e.g. chlorimipramine (15mg/kg, i.p.) or by naloxone. The withdrawal symptoms include: Writhing, backward kicking, jumping, head shaking, paw tremor whole body tremor. In monkeys the withdrawal symptoms include increase in movement, eye contact, and tooth baring. Δ9-THC Receptors: Specific binding sites (receptors) for Δ9-THC have been characterized in guinea pig brain and ileum. Cannabinoids Analogues: There are a few synthetic chemicals that are shown to mimic the effects of Δ9-THC. These include: 1. Nabilone. 31 2. (-)8 B-hydroxymethyl Δ9-THC. 3. Dimethylheptylpyran. 4. 05'-(1"-2"-dimethylheptyl) homolog of Δ9-THC. It is 15X more potent than Δ9-THC. References: 1. 2. 3. 4. 5. 6. 7. 8. 9. Abel, E.L. and Dintcheff, B.A. (1986). Alcohol Drug Res. 6, 277-80. Agurell, S., Halldin, M., Lindgren, J.E. and Hollister, L. (1986). Pharmacol. Reviews. 38, 21-43. Annis, H.M. and Smart, R.G. (1973). Br. J. Addict. 68, 315-321. Asch, R.H., Smith, C.G. and Siler-Khodor, T.M. (1981). J. Clin. Endocrinol. Metab. 52, 50-55. 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Tucker, R.B. and Graham, B.F. (1981). J. Canad. Soc. Forensic. Sci. 14, 41-45. 41. Tulunay, F.C., Ayhan, I.H., Portoghese, P.S. and Takemori, A. (1981). Eur. J. Pharmacol. 70, 219-224. 42. Turner, J.C. and Mahlberg, P.G. (1982). J. Chromatogr. 253, 295-303. 43. Vassiliades, N., Mourelatos, D. and Dozi-Vassiliades, J. (1986). Mutat. Res. 170, 125-127. 44. Wing, N.N. and Varma, V.K. (1977). Drug Alcohol. Depend. 2, 211-219. 45. Zimmerman, S., Zimmerman, A.M. and Laurence, H.L. (1977). Pharmacology. 15, 10-23. 46. Zuardi, A.W., Teixeira, N.A. and Karniol, I.C. (1984). Arch. Inter. Pharmacodyn. Ther. 269, 12-19. 1. AlZarkashi, BadrEldin (1987). In: Zahrat ElArish FiTahreem Elhashish (editor: Farah, Sayed Ahmed). Wafa for publication, Egypt. 34 OPIUM Introduction The name opium (which means juice in Greek) is given to the milky exudate obtained from the immature fruits of the plant: Papaver somniferum which belongs to the botonical family Papaveraceae. The plant is an annual bushy plant that varies in height from 0.5-1.5m and bears white or purple flowers. The plant is believed to be known to the Sumerians and Pharons for thousands of years before Christ birth. The plant was described by Theophrastus in the third century B.C. and by Dioscorides in his book "De Materia Medica" in the first century B.C. Opium was also described in Apres papers that have been discovered in 1873 by George Apres. These papers are believed to be written 1500 years before Christ birth. The plant is now grown licitly or illicitly in many countries which include: India, Turkey, Iran, Afghanistan, Laos, Thailand, Pakistan, Burma, Mexico, Equador, USSR and China. In the past centuries crude opium was used to relieve pain and to treat diarrhoea. However, in the 17th century and after discovery of tobacco and smoking, various traders from some European countries introduced the habit of opium smoking into China and later on into other Asian countries. This habit led to consumption of large quantities of opium in China and the demand was far greater than the amounts grown in this country. As a result large quantities of opium were imported from India. The great consumption of opium led to addiction to the drug and indeed the first cases of addiction were known in 1729. This problem forced Chinese Emperors such as Y Cheng (1723-1735) and Chia-Ching (1776) to issue rules to prohibit the importation, sale and smoking of opium. However, these rules were opposed by opium Foreign Traders (British, Portugese, French and Americans) and this opposition culminated in two Opium Wars. The first was between China and Britain during the period of 1839-1842 and the second between Britain and France against China in 1856-1860. China was defeated in the second war and accepted legalization of opium trade. However, 35 in 1907, China managed to sign an agreement with Britain and India to limit the export of Indian opium to China and controlled native cultivation and consumption of opium to date. Discovery of Morphine: The discovery of morphine returns back to 1803 when the German Pharmacist Feredrik Serturner succeeded in isolating an analgesic compound from opium and named it morphine after the name "Morpheus" the Greek god of dreams [15, 41]. Serturner published his first reports about the analgesic effects of morphine in 1817 and from that time on morphine became an important treatment for severe pain and diarrhoeas. The discovery of morphine encouraged various chemists to isolate other opium constituents. These efforts culminated in the isolation of codeine in 1832 and papaverine in 1848 and later on thebaine and noscapine. Codeine was found to possess good analgesic and antitussive activity whereas noscapine was found to be antitussive and papaverine spasmolytic. The mean percentage of morphine in opium ranged from 7-18%, for codeine 0.6-1.8%, for noscapine 1.46.4%, for papaverine 0.7-0.9% and for thebaine 0.3-2.6% [34]. The content of morphine and other constituents in opium can be easily estimated by colorimetry, fluorometry, radioimmunoassay and HPLC methods [24, 46]. Discovery of Heroin and other morphine analogues: The availability of pure morphine encouraged the wide use of this drug and led to appearance of serious side effects and addiction to the drug. These problems stimulated many chemists to synthesize some analogues with the hope of discovering potent compounds that lack addiction ability. These efforts resulted in synthesis of diacetyl morphine (Heroin) in 1874 by Wright of London and later on in 1890 by Dankwart in Germany. It was soon discovered that heroin was 3-times more potent than morphine as an analgesic compound but it was 36 more addicting than morphine. This disappointment led to synthesis of pethidine in 1939 by Eisleb and Schumann in Germany, methadone in 1948 by Bockmuhl and Ehrhart in Germany, Levorphanol in 1948 by Grewe and Mondon and Phenazocine and pentazocine in 1955 by May and Murphy. Pharmacological studies using these morphine analogues revealed that with regard to analgesia methadone was equipotent to morphine, levorphanol and phenazocine were equipotent to heroin whereas pethidine and pentazocine were 3 and 8 times less potent than morphine, respectively. The duration of action of all was in the range of 3-5 hours. Unfortunately these compounds were as effective as morphine in causing addiction. Thus, chemists continued to synthesize new analogues and this resulted in synthesis of etorphine which was found to be thousand times more potent than morphine and fentanyl which was found to be 80-l00 times more potent than morphine. Both compounds were very potent in inducing addiction and are very toxic. In 1974/1975 many pharmacologists in Britain, USA and Sweden started to search the human body for morphine like compounds. Indeed in 1975 J. Hughes succeeded in discovering and isolating two pentapeptides from the mammalian brain and named them metenkephalin and Leuenkephalin and later on the polypeptide endorphins were discovered in the mammalian pituitary and brain. These endogenous compounds are similar to morphine in their pharmacological actions as they combine with the same morphine receptors but they possess a short duration of action (<10min). The discovery of these compounds encouraged chemists to synthesize new analogues hoping for the discovery of new opiate compounds without any addiction ability. Unfortunately such hope was not fulfilled to date. Figure 1 shows the chemical structures of morphine and some of its analogues: 37 Figure 1. Morphine and some of its analogues: 38 Misuse of opiates: Most of these opiates are misused by many individuals throughout the world. The usual route of intake is the oral route but raw opium is mostly smoked via pipes. However, heat pyrolysis usually destroys 50% of morphine content, 20-40% of codeine and 100% of thebaine, noscapine and papaverine. The usual method for heroin intake is via intravenous route. Due to ease in chemical synthesis of heroin by acetylation of morphine and due to the high price of this substance in the illicit market, many illicit narcotics promotion organizations started to encourage youth in many countries to start taking this substance. Indeed they started to distribute the substance without charge to accustom youth for its use and get addicted to the substance when they start to sell it as expensive as possible. Indeed many youth become addicted to heroin at the turn of the century and many countries agreed to meet to discuss this problem. In fact the first conference about opiates' addiction was held in 1911 in the Hague in Holland. In this International Conference many countries agreed to control trade, distribution and use of opiates at both National and International levels. Following this the Government of USA passed the Harrison Narcotics Act in 1914 which controlled Narcotics use in USA. However, those laws did not deter opiate addicts and illicit Narcotics Organizations who continued to use and distribute opiates-especially heroin which constitutes >90% of the total misuse of opiates. Following the Hague Agreement many International Conferences and Agreements were made in 1925, 1931, 1936, 1946, 1961, 1964 and 1968 to control opiates trade and distribution. Indeed, the WHO encouraged many countries to issue laws to control opiates use. In fact most countries passed various National Laws to control opiates and imposed severe penalties against users and distributers of opiates that ranged from imprisonment for some years to death sentences. However, such rules did not deter illicit Narcotic Organizations from distribution of opiates due to the high revenues that they 39 gain from such trade. In fact many addicts obtain their usual opiate supplies from the illicit markets under various slang names. For instance heroin is known as: Balot, Boy, Dogie, Harry, Brown Rine, White Lady, Bolsa and Aunt Hazel. Morphine is known by the names Emsel, White Angel and Barnecide. Raw opium is known by the names: Chicory, Dream, Afuoon, Gum, Gee, Mashallah, Pen Yen and Skee. Pharmacological actions of opiates: Opiate users initially start to take small doses of raw opium (containing 10-20mg of morphine) orally or inject (i.v.) small doses of heroin (1-3mg) to experience the following effects: euphoria, elevation of mood, contentment, relief from environmental tension relief of pain and induction of sleep. Heroin is more potent than morphine and codeine in inducing the initial euphoria. Generally it should be noted that although opiates are sedatives in humans yet they induce stimulation in many mammals such as cats, dogs, tigers, rats, pigs, cows, bears, horses, mice, rats and hamsters [38]. A. Effects on the Central Nervous System: Administration of opiates (morphine, heroin, codeine, pethidine etc.) to humans and other mammals induced analgesia. This effect is mediated both in the brain and spinal cord to depress transmission of pain impulses from the nociceptors scattered on the skin to the pain centre in the thalamus via the dorsal horn of the spinal cord. In the brain, opiates combine with their specific receptors: µ (mu), (Delta) and (Kappa) located in the dorsal periaqueductal central grey region [5,12], on the nucleus reticulogiganto cellularis, on paramedial medulla oblongata and the raphe magnus in the medial medulla oblongata. Activation of these receptors stimulates the descending monoaminergic neurones reaching the dorsal horn of the spinal cord with concomitant activation of the substantia gelatinosa leading to inhibition of release of substance p at Laminae I and V in the dorsal part of the spinal cord. This inhibition suppresses 40 transmission of pain impulses from Laminae I and V to the pain centre in the thalamus [5, 12, 18, 20, 28]. Furthermore, the opiates combine with their specific receptors located on Laminae I and V in the dorsal horn resulting in suppression of substance p release and concomitant inhibition of transmission of pain impulses to the pain centre. Many drugs were observed to decrease opiates-induced analgesia. These include: -adrenoceptor blockers e.g. tolazoline and dibenzyline, serotonin synthesis inhibitors e.g. pchlorophenylanine and serotonin receptor blockers e.g. cinanserin [17]. On the other hand many drugs have been observed to potentiate opiates-induced analgesia such as monoamine oxidase inhibitors e.g. tranylcypromine, GABA, the GABA ergic agonist muscimol, dynorphin [1], caffeine, theophylline, glycine, B-alanine and amphetamine [32]. Beside being potent analgesic compounds, opiates produce various effects in the brain. These effects include: 1. Induction of hypothermia due to release of serotonin and noradrenaline. However, hyperthermia was noted in rats, and monkeys. 2. Stimulation of appetite due to activation of µ and receptors in the hypothalmus [39]. Indeed, destruction of the hypothalamic paraventricular nucleus in rats decreased morphine-induced hyperphagia. It is interesting to note that the level of -endorphin in the plasma increases just before feeding periods suggesting a physiological role for -endorphin in feeding. 3. Stimulation of water drinking due to activation of µ and receptors. 4. Suppression of cough by activating µ and receptors in the cough centre in the medulla oblongata [9]. 41 5. Activation of the vomiting centre on the chemoreceptor trigger zone in the medulla oblongata. Indeed opiate antagonists e.g. naloxone were found to be useful in suppressing the symptoms of motion sickness [2], suggesting the involvement of endogenous opiates in induction of motion sickness. 6. Suppression of seizures and convulsions due to activation of µ receptors. However, in rats morphine induced seizures. 7. Suppression of aggressiveness. 8. Enhancement of memory consolidation. This effect seemed to be mediated via activation of µ and receptors. 9. Enhancement of dopamine release in the caudate nucleus, substantia nigra and the hypothalamus [13]. 10. Enhancement of NA, 5-HT and GABA release in the striatum and substantia nigra. 11. Inhibition of ACh release in the cerebral cortex. However, in mice an elevation of ACh level was noted. 12. Inhibition of glutamate release in the cerebral cortex. 13. Stimulation of release of endogenous opiates. 14. Enhancement of adenosine release. 15. Enhancement of enkephalinase activity in the striatum and the dorsal part of the spinal cord. 42 16. Inhibition of the neurones of the reticular formation of the medulla and pons, and in the nucleus raphe magnus but stimulation of the neurones in the periaqueductal grey. 17. Inhibition of spontaneous discharge of the purkinje cells in the cerebellum and in the substantia nigra and the nucleus raphe magnus. B. Effects on the Respiratory System: Administration of opiates to humans or various mammals is consistently observed to depress both frequency and depth of respiration and to induce hypoxaemia, hypercapnia and acidosis [49]. These effects are due to direct effects of opiates on the respiratory centre in the medulla together with contraction of the expiratory muscles of the chest wall. Opiates were also observed to increase lung resistance. The depressant effects on respiration were effectively reversed by physostigmine or nikethamide. In experimental animals morphine was observed to suppress pulmonary oedema with concomitant decreases in pulmonary pressure and left atrial and ventricular end diastolic pressures [49]. The effect is probably due to peripheral vasodilation leading to reduction in venous return. C. Effects on the Cardiovascular System: Administration of opiates to humans or various mammals reduced both systolic and diastolic blood pressures and induced bradycardia. The effects seem to be due to a direct effect of the opiates on the dorsal midbrain and the nucleus locus ceruleus (site of NA, neurones cell bodies) and activation of the vagus nerve [l6]. Furthermore, morphine induced bradycardia in the isolated perfused rat heart. The ability of the opiates to activate both and K-receptors on blood vessels with concomitant decrease in NA release may contribute to the observed hypotension. 43 D. Effects on the Gastrointestinal Tract: Administration of various opiates to humans and animals induced various effects on the gastrointestinal tract. These effects include: 1. Stimulation of salivation due to central activation of the vagal nuclei. 2. Stimulation of the lower oesophageal sphincter circular muscle. 3. Inhibition of intestinal propulsive movements. The effect seemed to be mediated both peripherally and centrally via activation of µ receptors since it was antagonised by the highly selective µ antagonist funaltrexamine. 4. Reduction of blood flow to the duodenum. 5. Inhibition of ACh release and motilin from the intestine. These effects may explain the opiates-induced constipation [48]. 6. Enhancement of gastric mucous synthesis. 7. Inhibition of gastric acid secretion after i.v. or i.c.v. administration and suppression of cold- and restraintinduced ulcers together with inhibition of stressinduced gastric haemorrhage [3]. These effects are believed to be due to activation of µ, and opiate receptors resulting in inhibition of ACh release and stimulation of PG synthesis in the gastric mucosa. 8. Inhibition of pepsin secretion. 44 9. Inhibition of the spontaneous activity and relaxation of the internal anal sphincter probably via decrease in NA release. 10. Inhibition of the defecation reflex. E. Effects on the Gall Bladder and Bile Ducts: Administration of opiates to man and various mammals induced contraction and increase in pressure in the sphincter of Oddi and bile duct with concomitant decrease in bile flow [6]. In this respect morphine> pentazocine> pethidine> phenazocine. Furthermore, opiates antagonized the effect of cholecytokinin in inducing contraction and emptying of the gall bladder. F. Effects on the Liver: Acute or chronic intake of opiates has been observed to induce various effects on the liver. These effects include: 1. Accumulation of triglycerides due to enhancement in the synthesis of these substances following an increase in the activity of microsomal phosphatidate phosphohydrolase. 2. Inhibition of hepatic protein synthesis probably as a result of decreased ATP synthesis following opiates-induced depression of respiration and systemic hypoxaemia. 3. Inhibition of liver regeneration. 4. Decrease in cytochrome p-450 content. 5. Damage to liver cells with an increase in serum glutamate oxaloacetate transaminase (SGOT) and glutamic-pyruvic transminase (SGPT) [31]. 6. Decrease in glutathione content [19]. 45 7. Stimulation of K+ efflux from hepatic mitochondria and inhibition of adenine nucleotides transport across these structures. 8. Increase in the volume of the smooth endoplasmic reticulum of the hepatocytes. 9. Elevation of plasma level of -glutamyl transpeptidase (GGTP). G. Effects on Hormones: Intake of opiates was observed to induce various changes in the release of many hormones. These substances decreased release of: 1. LH and FSH due to inhibition of release of gonadotrophinreleasing factor(s) from the hypothalamus. As a result there is a decrease in synthesis of testosterone in the testes leading to impotence in males. In females ovulation and menstrual cycles are disturbed leading to infertility [27]. 2. Thyroxine due to inhibition of release of TSH via activation of serotoninergic mechanisms. 3. Somatostatin. However, opiates were observed to stimulate release of some hormones such as: 1. Corticosteroids via stimulation of release of ACTH. 2. Prolactin [22]. 3. GH. 4. ADH (vasopressin). 5. Insulin. 6. Aldosterone. 46 H. Effect on Blood Components: Chronic intake of opiates leads to the following changes on blood components: 1. Elevation of plasma glucose level probably due to stimulation of adrenaline release from the adrenal medulla. 2. Elevation of plasma triglycerides level [37]. 3. Decrease in free fatty acids [37] due to a depressive lipolytic activity. However, in rabbits morphine enhanced lipolysis. 4. Enhancement of blood clotting. I. Effects on the Eye: Administration of opiates to humans and rabbits induced miosis probably due to stimulation of ACh release since the effect was blocked by either naloxone or atropine [30]. However, in most other mammals e.g. mice, monkeys, cats, horses, mydriasis was observed. Furthermore, morphine increased retinal blood flow and decreased intra-ocular pressure. J. Effects on the Kidney: Administration of opiates to various mammals decreased renal blood flow, GFR and urine production. The effects did not seem to be due to stimulation of ADH since it was observed in mammals deficient in ADH. The inhibitory effect of opiates on PG synthesis may contribute to the observed effect. However, administration of the K-agonists e.g. ethylketazocine, ketazocine or bremazocine to rats enhanced urination. This is believed to be mediated centrally via activation of an (auto) presynaptic K-receptors in the neurohypophyses activation of which inhibited the co-release of ADH and dynorphin (Kagonist). 47 Opiates were also shown to suppress renal colic. However, chronic use of these substances caused lesions in the renal cortex, medulla and papilla. K. Effects on the Reproductive System: Chronic administration of opiates induced disturbances in ovarian function, suppressed ovulation and disturbed the menstrual cycle [33]. These changes may be due to opiatesinduced suppression of LH and FSH. Furthermore, opiates induced relaxation of the uterus; the only exception was pethidine which stimulated this organ. Studies in female rats demonstrated the ability of opiates to suppress the copulatory response (Lordosis). In males, opiates were observed to suppress penile erection [4], to decrease contractions of the vasodeferens and to diminish the sexual desire and precipitate impotence [4, 21]. Furthermore, opiates decreased sperms' respiration and glycolysis and inhibited their motilities. Intake of opiates during pregnancy especially during the critical period of embryogenesis induced teratogenic effects e.g. exencephaly and cryptorchid testes, decreased birth weight of offspring and increased infants' and mothers' mortality [11]. L. Effects on the Immune System: Chronic intake of opiates leads to decrease in spleen size, lymphocytes' number, inhibition of phagocytosis by leukocytes [42] and suppressed B- and T-lymphocytes activities. Thus, o`iates intake increases the susceptibility to both bacterial and viral infections. M. Effects on Chromosomes: Chronic administration of opiates induced chromosomal aberrations and damage [10, 45]. N. Effects on Cyclic Nucleotides: Treatment of mice or rats with morphine elevated the level of cyclic AMP in the plasma and prostate gland. However, 48 morphine antagonised PGE2-induced increase in cAMP in the striatum and isoprenaline-induced increase in the thalamus. Morphine also decreased the level of cGMP in the cerebellum of rats. O. Effect on Mast Cells: Exposure of rat mast cells to opiates stimulated histamine release. P. Effects on Muscles: 1. Administration of morphine to various mammals induced S-shaped tail (Straub Reaction) due to contraction of the sarcoccygeus muscle. It was prevented by section of the pelvic nerves or decapitation suggesting that it was mediated centrally and travels via the pelvic nerves. It was also prevented by pretreatment of the animals with central muscle relaxants such as baclofen and meprobamate. 2. Administration of morphine to rats induced catalepsy and rigidity due to activation of opiate receptors in the striatum. Opiates Intoxication: Intake of large doses of opiates during a short period results in acute intoxication and the appearance of the following symptoms: depression of respiration, miosis, pulmonary oedema, hypotension, anuria, convulsions and coma [29, 35]. These symptoms can be easily reversed by administration of specific opiate antagonists such as: Nalorphine, Levallorphan, Naloxone, Naltrexone, -funaltrexamine or cyclozocine. Naltrexone and cyclozocine are usually preferred due to their prolonged duration of action. 49 Metabolism of Opiates: Opiates metabolism usually occurs in the liver. However, heroin is initially deacetylated to its active metabolite 6monoacetyl morphine in the plasma by the enzyme choline esterase. Codeine was initially metabolized in the liver to morphine. Some of morphine metabolites are: morphine N-oxide, dihydromorphine, mono- and dihydroxy morphine. Methadone is metabolized by N-demethylation and cyclization. Pethidine is metabolized to meperidinic acid and normeperidinic acid. Pentazocine is oxidized and conjugated with glucuronic acid. All these metabolites are excreted in urine. Small quantities are excreted in milk and saliva [47]. Addiction and Tolerance to Opiates: One of the clear characteristics of Opiates in both humans and animals is their ability to stimulate drug-seeking behaviour and development of psychic dependence [40]. Continuous use of the drugs leads to development of physical dependence with the characteristic appearance of withdrawal symptoms on abrupt stoppage of drug intake. Furthermore, continuous intake of these substances leads to appearance of tolerance to most of their usual effects except for their ability to induce miosis, constipation and convulsions. In most cases tolerance occurs following daily intake for 3-14 days. However, in some cases tolerance was observed to occur following the first dose of the opiate [8]. Once tolerance occurred the user starts to increase his daily intake of the drug to obtain the previous effects induced by the previous small doses. Tolerance to opiates probably occurs due to one or all of the following effects: 1. Rebound increased synthesis of enzymes inhibited by the opiates. 50 2. Supersensitivity of the receptors neurotransmitters inhibited by opiates [7]. of those 3. Increased ability of the body to synthesize peptides having the ability to block opiate receptors. One of these peptides is Arg-Tyr-Gly-Phe-Met. 4. Increased synthesis and activity of aminopeptidases, dipeptidylcarboxypeptidases, and endopeptidase that metabolise endogenous enkephalins and endorphins [23, 43]. Decrease in brain level of these substances stimulates the opiate user to increase the usual dose to compensate for this decrease in endogenous opiates. Tolerance to opiates is enhanced by administration of tryptophan, cyclic AMP and GABA. However, tolerance to opiates can be suppressed by concurrent administration of some peptides such as: cyclo (Leucylglycine), propyl-Leucylglycinamide and N-carbobenzoxypropyl-D-Leucine, or by administration of tyrotropin-releasing hormone (TRH). Opiates Withdrawal Symptoms: Abrupt stoppage from intake of opiates in chronic users leads to precipitation of withdrawal symptoms (Abstinence syndrome). Some of these symptoms occur 12 hours after the last dose and include: lachrimation, rhinorrhea, yawning and sweating. Some symptoms occur during the second and third days of withdrawal and include: weakness, insomnia, chills, nausea, vomiting, anorexia, abdominal cramps, muscle spasms, kicking movements, tachycardia, respiratory stimulation craving for sweets, violent yawning, hyperthermia, piloerection, ejaculation in males and orgasms in females. If untreated, these symptoms disappear within 7-10 days. In animals the abstinence syndrome varies depending upon the species under study. For instance withdrawal symptoms in rats include: jumping, wet-dog shakes, teeth 51 chattering, weight loss, head shaking, hypothermia, diarrhoea, aggressiveness and crying. In gerbil: urination, teeth chattering, chewing, paw shakes, head shakes, wet dog shakes, yawning and writhing. Furthermore exposure of the ileum of a guinea pig chronically treated with morphine to naloxone induced contraction as an expression of the withdrawal sydrome. Withdrawal symptoms can be suppressed by readministration of the opioid previously used or any other one. However, experiments in animals revealed that withdrawal symptoms in rats can be suppressed by various agents such as: haloperidol, clonidine, flurazepam, mianserin, acupuncture, trifluperazine or chlorpromazine. In mice withdrawal symptoms can be suppressed by: the peptides: cyclo(Leucylglycine), propyl-leucylglycinamide or N-carbobenzoxy prolyl-D-leucine, by thyrotropin releasing hormone (TRH), by cyclo (His-pro) the metabolite of thyroliberin (TRH), by glycine or B-alanine, dynorphin, neurotensin or caffeine [1]. In monkeys the symptoms are suppressed by dynorphin. Similarly withdrawal symptoms in heroin addicts were suppressed by dynorphin. Quasi Abstinence Syndrome: Abstinence syndrome similar to true abstinence syndrome precipitated by naloxone in morphine dependent rats can be induced in naive rats by administration of the phosphodiesterase inhibitor 3-isobutyl-1-methyl xanthine (15mg/kg, i.p.) and a small dose of naloxone (0.03-1mg/kg, i.p. or s.c.). The symptoms were suppressed by pretreatment of the animals with clonidine (50µg/kg, i.p.). Similarly, quasi abstinence syndrome can be precipitated in naive rats by administration of dipropylacetate alone. The wet-dog shakings observed were suppressed by GABA transaminase inhibitors and by aminooxyacetic acid or with the alpha 2 agonists clonidine (30-40µg/kg, i.p.), guanfacine or azepexole and the effect of these agonists was blocked by the alpha 2 antagonists yohimbine and piperoxane. 52 Biochemical Changes Observed in the Brain During Opiate Withdrawal Symptoms: Animal studies revealed that opiate withdrawal symptoms are usually accompanied by some biochemical changes in the brain such as increase in NA and DA release in the midbrain, thalamus, cerebellum and striatum, decrease in GABA release in the striatum and decreased activity of ACh esterase [7]. Treatment of Opiates Addiction: Recent treatment of opiate addicts started in 1936 when the first hospital for rehabilitation of heroin addicts was opened in Lexington (Kentucky) and later on in 1938 followed by Fort Worth hospital in Texas. In the last years various treatments have been tried to treat opiate addiction. In one of these methods: treatment starts by withdrawal of the opiate from the addict followed by administration of methadone or alpha acetylmethadol (10-20mg/day orally) for 3 weeks. The drug is then substituted by Cyclozocine (4-6mg/day orally). Treatment is then continued for several weeks. Thereafter naltrexone is administered at a dose of 150mg orally every 3 days [14, 25, 26]. During treatment with methadone or L-alphaacetylmethadol, the drug dose should be reduced gradually to reach a drug free state within the 3 week-period of treatment. In some opiate addicts detoxification treatment may be started with precipitation of withdrawal symptoms by naloxone 0.8mg, i.m. every 3h on the first day, then 2mg, i.m. every 6h on the second day and 1.2mg, i.v. on the 3rd day. Thereafter naltrexone in a dose of 10-50mg/day is administered [36]. References 1. 2. Ahlijanian, M.K. and Takemori, A.E. (1986). Eur. J. Pharmacol. 120, 25-32. Allen, M.E., McKay, C., Evas, D.M. and Hamilton, D. 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Abuse. 1, 235-49. 56 COCAINE Introduction Cocaine is the active alkaloid present in the leaves of the plant Erythroxylon coca that belongs to the botanical family Erythroxylaceae. The plant is originally native to Peru and Bolivia. It is now grown in these countries and in some others in Africa and South East Asia at levels of 1500 meters above sea level. Two varieties are cultivated: ipadu and coca. The percentage of cocaine in these varieties ranges from 1-2%; however coca contains more cocaine than ipadu. Cocaine can be easily extracted from the leaves using the organic solvents such as alcohol and chloroform and chromatography. The cocaine content can be determined using HPLC or GC/MS. According to Schelenz, priority in the discovery of cocaine should be given to F. Gaedecke who first isolated the alkaloid and named it erythroxylin. The same alkaloid was later isolated by Rizzi and Niemann during 1857-1859 and gave it the name cocaine [25]. During the past centuries natives from Peru, Bolivia and Chilli used to chew coca leaves (locally known as Coquero) during their religious ceremonies because they believe that it allows them to concentrate during worshiping and for its ability to induce mediative trances. However, it was soon discovered that the plant has the ability to increase brain and muscular activity, suppress pain and hunger and alleviate fatigue especially when the leaves were mixed with lime or ashperhaps the alkalinity of these substances enhances the extraction of the non-ionised alkaloid from the leaves. To induce these effects the individual usually chews 50-500g of coca leaves per day. Those pharmacological investigations about cocaine started in the year 1884 when the Austrian physician Sigmund Freud started to investigate the pharmacological effects of cocaine on himself [13]. In that year he recommended the drug to his medical colleague Fleischl who was suffering from severe rheumatic pains. Fleischl started to use cocaine daily and 57 excessively since he found it effective in suppressing his pains. However, he soon became addicted to the drug and developed psychotic disturbances, abnormal behaviours and visual hallucinations sensed as crawling of snakes and mosquitos on his skin until he died [13]. During the same period (1884) the Austrian physicians Carl Koller, Sigmund Freud and Herman Knapp managed to discover the local anaesthetic activity of cocaine and advised its use in ophthalmological surgeries [7]. However, Siegel and Hirschman believe that the credit to the discovery of the local anaesthetic effect of cocaine should go to the Peruvian researcher Thomas Moreno Y Maiz [27, 31]. The stimulant effect of cocaine encouraged one of the Mineral Water companies in America to add coca leaves extracts to flavour one of its beverages named Coca-Cola but it was soon discovered that cocaine is a habit-forming drug and has the ability to precipitate paranoid psychosis. For this reason the American Government prohibited the addition of coca extract in beverages and new regulations for the use of cocaine as a drug were issued in 1906 in the Pure Food and Drug Act. Later on cocaine was classified as a narcotic in the 1914 Harrison Narcotic Act. Following this cocaine use was regulated and controlled in many countries. However, in the last decades simple methods have been discovered for isolation of cocaine and its conversion to its water-soluble powdered hydrochloride salt. The availability of these methods encouraged illicit Narcotic Organizations to synthesize the drug illicitly and to smuggle and distribute it among youth and adults in many countries. In the illicit-drug traffic the drug is sold under various slang names (nick-names) such as: Snow, Coke, Cholly, Ice, Girl, Gold, Dust, Happy dust, White girl, White mosquito, Coconut, Sugar, Cadillac, Flake...etc. [10]. Recently, and after discovery that alkalinization of urine increases renal reabsorption of cocaine and enhances its pharmacological effects, the Narcotic illicit Organizations started to mix cocaine with NaHCO3 powder and distribute it under the slang name Crack. 58 Methods for Intake of Cocaine: Initially drug abusers take cocaine by intranasal administration. However, this route of administration results in irritation and ulceration of nasal mucosa. Thus, nowadays drug abusers dissolve the cocaine powder in water and inject themselves intravenously with the substance. For this purpose they usually administer a dose of 100-250mg. Pharmacological Effects of Cocaine: A. Effects on the Brain: Following cocaine intake i.v. or intra-nasally in a dose of 2mg/kg the user experiences feelings of: euphoria, exhilaration, excitement, pleasant sensation of warmth all over the body, alertness, strength, cheerfulness and loss of fatigue. These effects last for two hours and are then followed by severe headache, discomfort, depression and fatigue together with a strong desire to take the drug again to overcome these bad feelings and hence the previous initial feelings were regained followed by the bad effects and the intake of the drug again and again resulting in cocaine addiction 24]. Cocaine is believed to induce its actions via stimulation of release of the neurotransmitters dopamine and noradrenaline in peripheral organs and brain [15, 19]. Cocaine also stimulates the synthesis of these neurotransmitters by activating the enzyme tyrosine hydroxylase. Furthermore, cocaine inhibits the metabolism of these neurotransmitters by inhibiting their reuptake back into their respective neurones after their release [15, 19]. It also partially activates the adrenergic and dopaminergic receptors. Besides these effects cocaine is shown to inhibit release of the central nervous system de`ressant GABA [12] probably as a result of increased dopaminergic activity in the striatum [21]. Besides the above mentioned effects administration of cocaine in the dose range of 2-4mg/kg, i.v. or intramuscularly has been observed to induce some effects that are mediated by its effect in the brain. These include: 59 1. Disturbance in the learning process and decreased accuracy in the performed work [23]. 2. Reduction in slow wave sleep and increase in wakefulness. 3. Increased predisposition to seizures and convulsions [29]. This is probably due to decrease in brain GABA level. 4. Decrease in body temperature due to excessive release of NA and DA [24]. However, in rabbit and guinea pigs it causes hyperthermia. 5. Depression of food appetite (anorexia) [23]. 6. Inhibition of water drinking [34]. 7. Induction of tremors. 8. Induction of analgesia. 9. Increase in striatal dopaminergic receptors. 10. Inhibition of aggressiveness. B. Effects on the Cardiovascular System: Administration of cocaine to humans and various mammals increased both the systolic and diastolic blood pressures and induced tachycardia [24] and potentiated adrenaline-induced arrhythmias. These changes are due to the ability of the drug to stimulate release of NA from the sympathetic neurones and slowing of its metabolism via reuptake. 60 C. Effects on the Respiratory System: Following administration of cocaine there was a clear stimulation of respiration in humans and various mammals. However, it should be noted that intoxication with cocaine leads to depression of respiration due to its local anaesthetic activity on the synapse between the phrenic nerve and the diaphragm and due to its central depressant effect on the respiratory centre in the medulla oblongata. D. Effects on the Gastrointestinal Tract: Administration of cocaine induced various effects in the gastrointestinal tract. These effects include: 1. Inhibition of gastric acid secretion probably via local release of NA. 2. Relaxation of intestinal smooth muscles. 3. Inhibition of amylase and protein secretion from the pancreas leading to disturbances in food digestion. 4. Stimulation of bile secretion into the intestine. E. Effects on Hormones: Administration of cocaine to various mammals suppressed LH release from the pituitary gland and suppressed testosterone synthesis in the testis [8]. It also disturbed the ovulation process. Cocaine also inhibited prolactin release but increased release of corticosteroids by stimulating release of ACTH from the hypothalamus. F. Effects on Blood Components: Continuous intake of cocaine was observed to induce the following changes in blood: 1. Elevation of glucose and non-esterified fatty acid levels [7]. 2. Increased efflux of K+ and Na+ from the RBC leading to haemolysis of these cells and appearance of anaemia. 61 3. Inhibition of 5-HT uptake by platelets leading to disturbance in platelet function and blood clotting and predisposition to haemorrhages. G. Effects on the Eye: Systemic or topical application of cocaine to eye resulted in local anaesthesia and mydriasis due to stimulation of noradrenaline release in the eye [24]. The induced mydriasis resulted in cycloplegia. H. Effects on the Liver: Chronic intake of cocaine induced adverse effects in the liver. These effects include: 1. Inhibition of synthesis of the microsomal enzymes e.g. cytochrome P-450 and FAD-containing monoxygenases [20]. 2. Destruction of hepatic cells and release of glutamine pyruvic transaminase [20]. 3. Stimulation of lipid peroxidation with the ultimate destruction and necrosis of hepatocytes and induction of liver cirrhosis [14]. It should be noted that these effects are potentiated by the cocaine metabolites norcocaine nitrooxide and N-hydroxy norcocaine and by alcohol intake [14, 22]. 4. Decrease in glutathione hepatic content resulting in an increased susceptibility of the hepatic cells to attack by lipid peroxides. The decrease is due to utilization of glutathione in cocaine metabolism. 5. Dilatation and swelling of the rough endoplasmic reticulum in centrilobular hepatocytes [9]. 62 6. Disruption of the mitochondria and changes in shapes and concentration of peroxisomes [9]. I. Effects on the Reproductive System: Studies in animals revealed the ability of cocaine to relax the uterus and to induce stimulation followed by inhibition of the fallopian tube. These effects may disturb the movement of the fertilized ovum in the tube and may seriously disturb the successful division and implantation of the ovum in the uterus. Cocaine is also shown to constrict the umbilical blood vessels and to inhibit uptake of amino acids by the placental villus [1]. These effects may explain the occurrence of ocular and skeletal teratogenic effects in foetuses of cocaine-treated mothers during early pregnancy. J. Effects on Sex Behaviour: In cocaine addicts, there is consistent increase in sexual perversion and aphrodisia. Metabolism of Cocaine: In the human body cocaine is extensively and rapidly metabolized mainly in the liver and partly in the plasma and brain. Complete metabolism occurs within one hour after administration of a single dose [26]. The most important metabolites are: norcocaine, benzoylecogonine, norcocaine nitrooxide and methyl esterecogonine. The enzymes involved in this metabolism are: Cytochrome P-450 and FADmonooxygenase and plasma cholinesterases. The metabolites are excreted in urine. The major urinary metabolite is 4'hydroxy-3'-methoxybenzoylecogonine methyl ester [11, 26, 28]. The major metabolites are shown in Figure 1 below: 63 Figure 1. Major metabolites of cocaine. The plasma half-life of cocaine is in the range of 1-2h after oral intake and is 41 min after i.v. injection. It should be noted that acidification of urine with NH4Cl (60mg/kg) decreases urinary pH and enhances ionization of the basic cocaine and its metabolites and enhances its excretion whereas alkalinizaion of urine inhibits ionization and stimulates reabsorption of the basic compounds back into the circulation. Acute Intoxication with Cocaine: Intake of a large dose (1-2g) of cocaine during a short period leads to acute intoxication with this substance and appearance of the following symptoms: seizures and convulsions, severe hypertension, tachycardia, arrhythmias, 64 hyperthermia, severe headache, mydriasis, sweating, twitches of face and hands, respiratory failure, cardiac failure and death. In some cases sudden death was observed after smuggling the substance by placing it into plastic bags and introducing it into body orifices or by smuggling it in condoms where large quantities of the substance are absorbed [4, 18, 30, 32]. Treatment of cocaine intoxication starts by performing artificial respiration, cardiac massage, intravenous diazepam to suppress convulsions (10mg, i.v.) and administration of chlorpromazine or prazosin to decrease the blood pressure and hyperthermia. Tolerance, Dependence and Addiction to Cocaine: A characteristic of cocaine is the development of rapid tolerance to its effects which compels the user to increase the dose to obtain the usual effects. The development of tolerance coupled with its ability to motivate the user to continue taking the substance (i.e. positive reinforcing property) leads to development of psychic dependence on the substance [6]. The development of tolerance is believed to result from decreased sensitivity of central dopamine and noradrenaline receptors. With regard to psychic dependence, it has been observed that administration of physostigmine decreases the stimulus for intake of cocaine [5] whereas administration of dopamine D1and D2receptor blockers e.g. haloperidol or the D2blocker pimozide increased the frequency of intake of cocaine. Similarly, administration of naloxone has been observed to enhance intake of cocaine [2] and this led to the suggestion that the higher the level of the endogenous opiates in the brain, the lower the motivation for continuous intake of cocaine. To date there are no reports about the development of physical dependence on cocaine since no withdrawal symptoms were observed on abrupt stoppage of drug intake [34]. One of the most dangerous things following use of cocaine is the development of anxiety, paranoid delusions, psychosis, mania, visual hallucinations, auditory hallucinations, 65 insomnia, impotence, schizophrenia and excessive sense of personal power that leads to aggressiveness and antisocial activities. Cocaine Antagonists: Animal studies revealed that the effects of cocaine can be antagonised by the use of dopamine receptor blockers e.g. chlorpromazine [15] or adrenoceptor blockers e.g. phenoxybenzamine [15] or prazosin (24) or via desensitization of the dopaminergic receptors with LiCl. Furthermore, cimetidine via its inhibitory effect on cytochrome P-450 was reported to protect against cocaine-induced hepatic toxicity. Amantadine was also reported to inhibit cocaine-induced effects probably by inhibiting binding and uptake of cocaine by the presynapic dopaminergic and adrenergic receptors. References 1. 2. 3. 4. 5. 6. 7. 8. Barnwell, S.L. and Sastry, B.V.R. (1984). Trophoblast. 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Abuse. 4, 936. 68 AMPHETAMINE (PHENAMINE) Amphetamine (phenylisopropylamine) Introduction: For thousands of years many medicinal plants have been used in China to alleviate various ailments. Records for such plants have been written upon strips of bamboo or palm leaves. Two collections of these records were written in 2700 B.C. and these are: Pen Tsao and is attributed to the second Chinese Emperor Shen-nung (the father of agriculture) and Nei-ching which is attributed to the Emperor Hant-ti. In 1923, the Chinese physician Ko-kui Chen of Peking Union Medical College explored the plants written in these two books. He observed that the plant Ma Huang (Ephedra vulgaris) was a consistent component in all treatments of asthma. Dr. Chen and his colleague C.F. Schmidt studied this plant chemically and pharmacologically and managed to isolate one of its alkaloids and named it ephedrine. They also synthesized the chemical and investigated its pharmacological effects. It was found to mimic adrenaline in inducing moderate bronchorelaxation. However, they later came to know that ephedrine had been already synthesized in Japan in 1887 by Yamanashi without studying its biological activity [47]. The discovery of the antiasthmatic effect of ephedrine stimulated many researchers to synthesize analogues of this chemical with the hope of obtaining a more potent antiasthmatic agent. These efforts culminated in the evaluation of amphetamine by Gordon Alles of San Francisco University in 1927 [1]. Initial pharmacological investigations revealed the poor bronchodilatory effect but the potent psychomotor stimulant effect of the compound. Indeed it was found to be 5 69 times more potent than ephedrine in prevention of narcolepsy [6, 34]. Amphetamine was synthesized in 1887 by Edeleano. The potent psychostimulant effect of amphetamine was misused during World War II when millions of tablets under the name "Benzedrine" were synthesized and distributed to the soldiers and pilots to alleviate fatigue and enhance performance. However, it was soon discovered that excessive use of the drug led to precipitation of violent and paranoid behaviours, visual hallucinations and schizophrenia. From that time various countries imposed rules to control synthesis, distribution and use of amphetamine. Indeed up to 1970 use of amphetamine was highly restricted in some medical uses which included: suppression of narcolepsy, suppression of appetite for management of obesity, to suppress hyperkinetic behaviours in children and to counteract the central depression by barbiturates and the like drugs. However, the potent psychostimulant effect of this drug encouraged illicit Narcotic Organizations to synthesize this chemical illicitly and distribute it in various countries for some non-medical uses that included: enhancement of physical performance in athletes during competitions, enhancement of mental performance of students during examination sessions, to prevent sleep and fatigue in truck drivers and even for some recreational purposes to elevate the mood and induce euphoria, confidence and decisive ability in those people with weak characters to face life complications [46]. During the last three decades the illicit Narcotic Organizations managed to synthesize and distribute huge quantities of amphetamine tablets throughout the world. This was facilitated by the discovery of simple methods for the chemical synthesis of the substance by reductive amination of phenylacetone [benzyl methyl ketone or phenyl 2-propanone (P2P)] under atmospheric pressure [40]. Due to the psychological disturbances induced by this chemical and its habit-forming property, the WHO encouraged many countries to control synthesis, distribution and use of amphetamine and its precursor chemicals. Indeed, to date 70 these chemicals are controlled in almost all countries and the penalties for disobeying these regulatory laws ranged from imprisonment for some years to death sentences. However, the huge revenues coming out from trade on amphetamine encouraged the illicit traders and organizations to synthesize and distribute amphetamine tablets by many means throughout the world. Indeed, for these purposes the drug is known by many slang names such as: Pep pills, Greenies, Oranges, Peaches, Bombita, Benz, Bombido, Dex, Crink, Speed, White cross, Congo tablets, Yellow Bams, Wake ups...etc. Besides the direct chemical synthesis of amphetamine, many pharmaceutical companies managed to synthesize chemicals that are biotransformed to amphetamine in the body. These chemicals included: a. Amphetaminil which is converted amphetamine + benzaldehyde. in the body to b. Prenylamine (amphetamine + diphenylpropanolamine). c. Furfenorex: 1-phenyl-2-(N-methyl-N-furfurylamino) propane that is biotransformed in the body to: amphetamine, methylamphetamine, furfurylamphetamine and 1-phenyl-2(N-methyl-N-valerolactonylamine) propane. d. Fenethylline [(+)amphetamine + theophylline)]. Also known as (Octagon). e. Fenproporex. Pharmacological Effects of Amphetamine: For the purpose of misuse of amphetamine drug misusers take it either orally in form of tablets containing dl-amphetamine (5-15mg) or in form of i.v. injections of methylamphetamine (1015mg). It should be noted that the d-isomer of amphetamine is more potent than the L-isomer [25]. Similarly d- 71 methylamphetamine (Dexedrine) is slightly more potent than damphetamine (Benzedrine). A. Effects on the Brain: After intake of amphetamine orally (5-15mg) the user experiences the following effects: Alertness, attentiveness, euphoria, hyperactivity, increased physical and mental power, hypervigilance, friendliness, loquaciousness (Logorrhea) and gregariousness [19, 20, 26]. However, when d-methylamphetamine is administered i.v. (10-15mg) the user experiences initial intense tingling sensation analogous to an electric shock (a buzz), followed by more tingling sensation, muscle contraction, extreme pleasure and all of the above mentioned effects [23]. The ability of amphetamine to produce the above effects is believed to depend upon the ability of this agent to induce the following biochemical effects: 1. Stimulation of domapine release from the dopaminergic neurones in the caudate nucleus, corpus striatum and misolimbic system [9, 41]. Amphetamine is believed to release newly synthesized dopamine in the cytoplasm before entrance into the synaptic vesicles for storage. 2. Stimulation of noradrenaline release from the adrenergic neurones in the hypothalamus, cerebral cortex, amygdala and the striatum [25, 41]. 3. Inhibition of dopamine and noradrenaline metabolism by inhibition of their reuptake back into their respective neurones [41, 42, 43]. As a result accumulation of these two neurotransmitters occurs outside the neurones with the resultant activation of their respective receptors. This effect is probably due to the ability of amphetamine to decrease the number of presynaptic receptors involved in the re-uptake process of these neurotransmitters [9, 43]. 72 4. Inhibition of the enzyme monoamine oxidase type A in the brain resulting in decreased metabolism of NA, DA and 5HT [33]. To date there is a general agreement that the major effects of amphetamine are due to the ability of this agent to release dopamine that activates its specific receptors located on the GABA-ergic neurones resulting in enhanced release of the central depressant neurotransmitter GABA. The released GABA then inhibits the inhibitory neurones reaching the substantia nigra and globus pallidus resulting in dis-inhibition of ventral thalamic motor centres and activation of the motor cortex. This suggestion is strengthened by the finding that administration of the GABA agonist muscimol into the substantia nigra of rats produced behavioural effects similar to those produced by amphetamine. It should be noted that although the general effect of amphetamine is psychomotor stimulation, yet this drug is observed to induce dysphoria in oestrogen-deficient females as in case of menopause [16]. Furthermore, administration of this drug to children before adolescence (prepuberty) leads to central nervous system depression and decrease in motor activity probably due to the abnormal stimulant effect of this drug on release of both serotonin and GABA that are known for their central depressant effects [37]. B. Other Effects on the Brain: Beside the above mentioned effects, administration of amphetamine induces some other effects on the brain which include: 1. Desynchronization of the electroencephatogram (EEG) or electrocorticogram (ECOG) and increase in the frequency of the wave rhythms especially of the low hippocampal theta rhythm [5]. 73 2. Decrease in sleeping time, reduction of the duration of REM sleep and slow wave sleep. 3. Improvement of auditory vigilance. 4. Enhancement of learning and memory [36]. It reversed the impairment in memory induced by electroconvulsive shock or by puromycin, cycloheximide, alpha-amanitin and anisomycin. It also enhanced retrieval of memories depressed by long time interval [36]. Generally, it should be noted that amphetamine-induced increase in mental performance is very weak in non-fatigued persons. Furthermore, it should be noted that although amphetamine stimulates the mind and prevents sleep, yet the fatigued stimulated mind can not learn or reason as well as the non-fatigued mind in absence of amphetamine treatment. The ability of amphetamine to reverse chemically induced amnesia is probably due to its ability to antagonize the chemical induced decrease in brain RNA synthesis and/or stimulation of Na+/K+-ATPase in the brain. Alternatively it may be due to amphetamineinduced heightened nervous system excitation. 5. Induction of anorexia and reduction of body weight. The induced anorexia seemed to be due to release of DA and NA from the catecholaminergic neurones that reach the caudal hypothalamus and the midlateral perifornical region of the hypothalamus [28]. Furthermore, the ability of amphetamine to stimulate corticosteroids secretion and enhancement of fat metabolism may contribute to amphetamine-induced weight reduction. 6. Inhibition of water intake. 7. Predisposition to aggressiveness even in ants (Formica pratensis) [7]. 74 8. Stimulation of tobacco smoking. 9. Induction of hyperthermia. The induced hyperthermia seems to be due to release of DA, NA, and serotonin. The effect seemed to be due to increased metabolic heat production and heat conservation together with cutaneous vasoconstriction. In this regard it should be noted that when amphetamine is used by athletes, severe hyperthermia may occur due to the direct effect of amphetamine coupled with exercise-induced hyperthermia or heat buildup. This may lead to circulatory collapse and death. Indeed, in Switzerland in 1980a cyclist died and another suffered a breakdown during a competition following an intake of 30mg of amphetamine before start of competition [3]. 10. Induction of analgesia. The effect seemed to be due to release of DA, 5-HT and endogenous opiate peptides [11]. 11. Inhibition of the vomiting centre. Indeed it was found to be effective in suppressing the symptoms of motion sickness. In fact combination of amphetamine with promethazine produced more suppression of motion sickness symptoms and antagonized the sedative effect of promethazine [45]. 12. Predisposition to convulsions and seizures [21]. 13. Enhancement consumption. of cerebral blood flow and oxygen 14. Stimulation of glucose utilization in cerebral cortex particularly in the extrapyramidal motor system and in the nucleus accumbens of the mesolimbic system. 75 15. Desensitization of B-adrenoceptors and increase in alpha 2-receptor density in the cortex and limbic forebrain. In this regard it potentiated the effect of desipramine. 16. Inhibition of the dopaminergic neurones in the caudate nucleus, in the substantia nigra and ventral segmental area. This effect is due to local release of DA. 17. Inhibition of the adrenergic neurones in the cerebellum and in the locus coeruleus. 18. Stimulation of the serotoninergic neurones in the mid raphe nuclei and in the caudal dorsal raphe nucleus. 19. Stimulation of the neurones in the brain stem reticular formation. 20. Stimulation of hypothalamus. the neurones in the ventro-medial 21. Inhibition of cerebral cortex neurones. 22. Stimulation of release and inhibition of reuptake of 5-HT in the cerebral cortex [41]. It also stimulated the synthesis of 5-HT in the cerebral cortex, in the brain stem and striatum. 23. Stimulation of substance P release in the striatum. 24. Stimulation of GABA release in the substantia nigra probably via activation of DA release. 25. Antagonism of GABA-induced inhibition of the neurones of the globus pallidus. 76 26. Stimulation of release of B-endorphin in the hypothalamus [16]. This effect may explain tolerance to amphetamineinduced anorexia. B-endorphin is an appetite stimulant. 27. Elevation of glutamate and aspartate level in the brain. 28. Inhibition of MAO enzyme [33]. 29. Inhibition of cholinesterase enzyme. 30. Decrease in the concentration of neuropeptide Y in the hypothalamus and caudate putamen. C. Effects on the Cardiovascular System: Intake of amphetamine leads to an increase in both systolic and diastolic blood pressure with concomittant tachycardia [27, 31]. These effects are due to enhancement of NA release from peripheral neurones and in the heart [27, 31] together with inhibition of NA reuptake and inhibition of cardiac MAO enzyme. D. Effects on the Gastrointestinal Tract: Intake of amphetamine induced suppression of gastric acid and pepsin secretion, delayed the rate of gastric emptying and stimulated healing of gastric ulcers. The drug inhibited ACh release from the intestine and relaxed intestinal smooth muscles. It thus predisposes to constipation. Furthermore, it decreased intestinal absorption of triglycerides. It stimulated bicarbonate secretion by the pancreas. E. Effects on the Liver: Amphetamine enhanced secretion of bile. It depressed hepatic lipogenesis and cholesterogenesis. Furthermore, it decreased the activity of cytochrome P-450 and alcohol dehydrogenase [29]. 77 F. Effects on Blood Components: Administration of amphetamine induced some effects on blood components. These included: 1. Inhibition of 5-HT uptake by the platelets. This effect may disturb platelet function and may interfere with blood clotting. 2. Elevation of blood glucose level. The effect seemed to involve release of catecholamines from the adrenal medulla [2]. 3. Decrease in free fatty acids and triglycerides. 4. Increase in globulin and decrease in albumin level. 5. Increase in phosphatidylserine. G. Effects on Hormones: Administration of amphetamine to humans and various mammals stimulated release of corticosteroids [8], GH, aldosterone and insulin but decreased release of prolactin [10] and ADH (vasopressin) [8, 10]. It should be noted that the ability of amphetamine to decrease ADH release may be expected to induce diuresis; however, the inherent property of amphetamine to relax the detrusor muscle and contract the trigone muscle and the sphincter of the urinary bladder opposes the effects following inhibition of ADH and in fact the net effect is a decrease in urine output. The effects are probably due to local release of catecholamines. Thus, these effects may explain the beneficial effects of amphetamine observed in treatment of enuresis and urinary incontinence. 78 H. Effects on the Respiratory System: Administration of amphetamine is followed by respiratory stimulation, decreased end tidal CO2, slight broncho-relaxation and elevation in pulmonary blood pressure [27]. I. Effects on the Eye: Intake of amphetamine produced mydriasis and produced variable effects on intraocular pressure [5]. J. Effects on the Reproductive System: Studies in mammals revealed the ability of amphetamine to enhance graffian follicle maturation and enhancement of ovulation. However, the drug passes the placental barrier and is observed to decrease foetal birth weight [17, 30]. K. Effects on Sexual Activity: In human continuous use of amphetamine increased hypersexuality [12], delayed male and female sexual orgasms and enhanced sexual pleasure and increased polymorphus sexual activity [13, 35]. In rats, amphetamine is consistently observed to inhibit sexual receptivity (Lordosis). The effect is probably mediated via activation of the serotoninergic mechanisms involving dopaminergic mechanisms. L. Effects on Cyclic Nucleotides: Administration of amphetamine to rats increased cerebellar cyclic GMP but did not affect cyclic AMP in the striatum. It increased cyclic AMP level in the spleen. Metabolism of Amphetamine: Amphetamine is mainly metabolised by hepatic microsomal enzymes-cytochrome P-450. Its major metabolites are: phenylacetone and p-hydroxy amphetamine [15]. It is also partly metabolized to norephedrine and p-hydroxy 79 norephedrine. It should be noted that the metabolite p-hydroxy amphetamine is an indirect sympathomimetic agent with a potency twice that of amphetamine. However, it is rapidly excreted in urine and thus it plays little role in amphetamine actions. Amphetamine and its metabolites are excreted mainly in urine [4] but some are secreted in saliva. The plasma half-life depends upon the urinary pH. In acidic urine the t1/2 ranged from 8-10.5h whereas in alkaline urine it was 16-31h. Urinary alkalinization increased the activity and duration of action of amphetamine [4]. The plasma level usually required to induce central stimulation is in the range of 5ng/ml whereas that for elevation of blood pressure is around 20ng/ml. However, in hyperkinetic children receiving the drug the plasma level is in the range of 60-65ng/ml. Amphetamine or its metabolites can be detected and estimated in plasma or urine by use of gas-liquidchromatography [4], GC/MS, spectroflurometry and HPLC, using UV detector or fluorescence detector. The compounds may also be detected in saliva using radioimmunoassay techniques. Intoxication with Amphetamine: Consumption of a large dose of amphetamine during a short period leads to acute toxicity characterized by: hyperthermia, tachycardia, hypertension, severe headache, tremors, abdominal cramps, convulsions, cranial haemorrhage, anginal pains, intracerebral hematomas, cardiovascular collapse and death [3, 14, 18, 21, 44]. Acute intoxication can be treated by cooling of the patient or placing him in a hypothermic blanket, administration of diazepam (5-10mg, i.v.) to suppress convulsions and administration of chlorpromazine (25-50mg, i.m.) or haloperidol (2.5-5mg, i.m.). Acidification of urine by administering NH4Cl (1/2g every 4h) may be useful to enhance excretion of amphetamine. 80 Tolerance to Amphetamine Effects: Various studies revealed the appearance of tolerance to some amphetamine effects such as its ability to induce anorexia or psychomotor stimulation. However, many reports described the appearance of an increase in sensitivity to amphetamineinduced behavioural effects after chronic use i.e. development of reverse tolerance [22, 38]. Tolerance to amphetamine is believed to be due to decrease in the sensitivity of postsynaptic receptors that are activated by DA and NA released by amphetamine. This suggestion is strengthened by the development of cross tolerance between cocaine and amphetamine. Tolerance has also been suggested to be due to accumulation of the amphetamine metabolite p-hydroxynorephedrine in the synaptic vesicles of dopaminergic and adrenergic neurones leading to dilution of neuronal stores of those neurotransmitters resulting in the usual effects produced by DA and NA. On the other hand, the appearance of reverse tolerance is explained by an increase in DA receptors in the striatum and decrease in the number of presynaptic dopaminergic receptors involved in DA reuptake [42, 43]. As a result DA accumulates postsynaptically. Dependence on Amphetamine: One of the characteristics of amphetamine is that intake of the first dose of this drug reinforces and compels the user to continue taking the drug. It causes psychic dependence. The cue produced by amphetamine for intake of the drug can be suppressed by administration of the selective alpha-1adrenoceptor blocker-prazosin but is slightly potentiated by the alpha-2-adrenoceptor blocker yohimbine [39]. Chronic use of amphetamine has been observed to produce several adverse effects which include: muscle tremors and pain, anxiety, dysphoria, repetitious bruxism, dyskinesia, rapid change in mood, irrationality, emotional ability, motor restlessness, abdominal pain, panic, fear, inability to 81 concentrate on any task or idea, visual and tactile illusions, visual hallucinations, hostility, aggressiveness, suspicion, depersonalization, illusions about the presence of insects, mosquitos and parasites over the body or in the surroundings so that continuous attempts are made to examine the body and environment to catch and kill these immaginary creatures!, fascination with details, shapes and textures of stones, papers, leaves ... etc. and attempts to gather these valuable materials and their storage in a bag which is continuously carried, feeling of paranoia, depression, appearance of facial tics, tendency to murder others and appearance of schizophrenia [24]. 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Depend. 9, 279-284. 44. Weiss, S.R., Raskind, R. and Morganstern, N. (1970). Int. Surg. 53, 123-130. 45. Wood, C.D., Manno, J.E, Manno, B.R. and Redetzki, H.M. (1984). Aviat. Space. Environ. Med. 55, 113-116. 46. Wrighton, J.D. (1975). Nursing Times 71, 35-36. In: History of Pharmacology. 47. Leake, C.D. (1975). An historical Account of Pharmacology to the 20th Century. Charles C. Thomas, Springfield, Illinois, USA, pp. 31-34. 85 KHAT Introduction: The khat tree is known by the name Catha edulis and belongs to the botonical family Celastraceae. The name is given to the plant by P. Farskal in 1775. The initial origin for this tree is believed to be the city of Kafa, province of Harar in Ethiopia. From this area it was introduced into Somalia, Djibouti, Yemen, Kenya, Madagascar, Tanzania, South Africa and some central Asian countries. In the different parts of Africa khat is known by different names. For instance in Ethiopia it is known by the names: Gofa, Khofta or Kiat; in Kenya it is known by the names: Mora, Kampa, Muongi or Olmera whereas in South Africa it is known by the names: Miraa, Moringo or Kikouomera [2]. The khat tree possesses no flowers or seeds. It is usually grown by grafting and grows best at altitudes of 4000-5000 feet above sea level. It usually reaches a height of 1-2 metres but it may grow to a height of 6 metres. It is allowed to grow for 3-4 years before cultivation of the leaves and young shoots. The leaves undergo colour changes during maturation. Initially the leaves are reddish-grey, then turn green and finally yellowishgreen. In Ethiopia the khat composed of the reddish-grey leaves is considered the best type and is known by the name: "Koda Khat". Green leaves provide a good type of khat known by the name "Orita Khat". A low grade type of khat is obtained from the yellowish-green leaves and is known by the name "Kirti Khat". Many varieties for khat are grown. For instance in Ethiopia we find the varieties Dima characterized by its red leaves; Dalota characterized by pale green leaves; Henricot characterized by reddish-green leaves and Mohdila characterized by olive-green leaves [3]. With regard to the methods for khat intake it has been reported that khat was initially used in form of a tea obtained by boiling the leaves in water [2]. To date the famous method for khat intake is chewing of the small leaves and the young shoots 86 of the plant. The normal chewer usually chews 50-100 g of khat per day whereas addicts may chew > 300 g/day. In Yemen the process of khat chewing is known as "Takhzeen" (storage) because the chewed material is allowed to stay in the mouth for several hours. The first mention of khat as a medicine was reported by the Arabian Physician Abou Al Rihan Bin Ahmed Albironi who lived during the years 973-1051 AD in his Book entitled "Pharmacy and Therapeutic Art" [2]. It is also mentioned by Nageeb El Din Al Samaragandi who died in the year 1230 AD in his Book entitled "Pharmacology" s a treatment for depression [2]. Furthermore in 1774 Carsten Nibuhres described the khat tree in his Book "Description of Arab Countries" who mentioned that khat is chewed by Arabs to facilitate food digestion and to strengthen the body. Its major effect is induction of insomnia [2]. In folk medicine khat is claimed to suppress cough, asthma, epidemic influenza, stomach ashes, diarrhea, urinary retention and malaria. However, khat is usually chewed to induce central stimulation, mental alertness, excitement and euphoria. Continuous use of the plant induces psychic dependence. Thus a lot of money is expended in buying the plant with ultimate neglect of work and family needs. For many years, khat chewing was confined to the areas in which it is grown but to date khat chewers are observed in Europe, USSR and USA among emigrants coming from khat cultivation areas. Indeed khat-induced psychotic diseases such as mania and schizophrenia have been observed among some emigrants in England [16] and USA [15]. Chemical Composition of Khat Leaves: The first attempts to isolate the active substances present in khat leaves started in 1887 when Flukinger and Gerock succeeded in isolating an alkaloid from the leaves and named it Katin [12]. In 1891, Mosso managed to isolate the alkaloid in form of its hydrochloride salt but named it celestrine. The same 87 substance was isolated by Beiter in 1900 [4]. In 1914, the British chemist Ralph Stockman managed to isolate three alkaloids from the leaves and named them: Cathine, Cathidine and Cathinine [39]. The chemical structure of cathine as (+)-dpseudoephedrine was discovered by Wolfes in 1930 [43]. From that time cathine was considered to be the active constituent of khat leaves until 1961. During this year the Sudanese Psychiatrist ElTigani ElMahi wrote a review about khat for WHO and pointed the low activity of dried khat leaves compared with fresh ones and speculated about the presence of another constituent in the fresh leaves [2]. Indeed this speculation was again raised in 1963 by the German scientist Friebel and Brilla who presented experimental evidence for the higher activity of freeze-dried fresh khat leaves compared with sun-dried leaves in inducing central nervous system stimulation in animals [14]. These observations aroused the interest of many researchers to look for a new constituent in fresh khat leaves. Indeed these efforts were culminated fruitfully in 1975 when researchers at the United Nation Narcotic Laboratory succeeded in isolating a new potent khat alkaloid from the fresh leaves and identified it chemically as (-) alpha-amino-propiophenone and assigned it the generic name (-) Cathinone [36, 37]. Thereafter many investigators managed to isolate the same substance [38]. It was soon discovered that (-)-Cathinone is an unstable alkaloid that can be easily converted by exposure to air or heat to the stable chemical (+)-Cathine [(+)norpseudoephedrine] [37]. It was also discovered that the percentage of cathinone is very high in fresh young leaves and is gradually converted to cathine during maturation of the leaves. The total percentage of these two substances in khat leaves ranges from 0.1 - 0.18% [1, 42]. 88 It should be pointed that, the mammalian body has the ability to convert cathine to the potent (-) cathinone via the enzyme dopamine B-hydroxylase, the enzyme involved in conversion of dopamine to noradrenaline in the adrenergic neurones and adrenal medulla [28]. Besides (+) cathine and (-) cathinone khat leaves were reported to contain many other constituents. These include: Tannins (14-14.5%) [1], the falvonoids (kaempferol, quercetin and myricetin) [5, 39], cathedulins: cathedulin-2, cathedulin-8, cathedulin [10], vitamin C (0.3%), niacin, sugars (glucose, fructose, rhamnose, galactose, xylose), B-sitosterol and its glycoside friedelin [10], volatile oil [39] and cathidines. Many of khat active constituents can be extracted by acidification and alcoholic or chloroform extraction and by the help of chromatography [8]. The constituents can be estimated using gas chromatography or HPLC [8, 11]. Pharmacological Actions of Khat: The major actions of khat are mainly attributed to the active alkaloids: (+) cathine [(+) norpseudoephed-rine] and (-) cathinone [(-) alpha-aminopropiophenone]. Generally, the potency of (-) cathinone is 4-10 times that of (+) cathine [44]. However, the duration of action of (+) cathine is longer than that of (-) cathinone but its onset of action is slower than that of (-) cathinone [36]. The delay in onset of action is probably due to the time required for conversion of (+) cathine to (-) cathinone in the body [28]. Similarly, the effects of the natural (-) cathinone are 3 times more greater than those of the synthetic (+) cathinone. The general pharmacological effects of (-) cathinone are closely similar to those of (+) amphetamine. (+) cathinone is 30-50% as potent as amphetamine [29]. A. Effects of Khat on the Brain: Following chewing of 50-100 g of fresh khat leaves (containing 100 - 180 mg of (+) cathine and (-) cathinone) the chewer experiences the following effects: central stimulation, 89 mental alertness, excitement, euphoria and increased muscular activity [7, 15, 19]. The duration of action ranged from 3 - 5 hours [19, 33]. For induction of these effects central dopaminergic and adrenergic neurones in the regions of nucleus accumbens, caudate nucleus and corpus striatum uptake (-) cathinone into their cytoplasms where cathinone enters the synaptic vesicles at the terminals of the neurones and stimulates release of DA and NA. The latter neurotransmitters combine with their respective postsynaptic receptors to induce the observed central stimulation [22, 23, 41, 45]. Indeed, administration of dopaminergic and 1 adrenoceptor blockers such as haloperidol and chlorpromazine antagonised khat or (-) cathinone-induced effects [41]. Similarly, administration of drugs that inhibit dopamine or (-) cathinone uptake such as nomifensine or benztropine or mazindol antagonised the observed khat or (-) cathinone effects [41]. Beside the above mechanisms of action (-) cathinone is reported to inhibit the enzyme MAO resulting in accumulation of DA and NA in the brain and other organs [44]. In addition to the central nervous system stimulation and euphoria, khat is also observed to induce many other effects by acting in the brain. These effects include: 1. Induction of anorexia with the resultant decrease in body weight probably due to release of DA [13, 26]. 2. Induction of hyperthermia [40]. 3. Induction of analgesia [32]. Suppression of pain may result from the ability of (+) cathine and/or (-) cathinone to stimulate release of serotonin or activation of its receptors in the brain and spinal cord [16, 17]. In addition, the ability of cathinone to enhance release of enkephalins or endorphins or direct activation of the central opiate receptors may contribute to the observed analgesia [32]. 90 4. Administration of (+) cathinone or (-) cathi-none to rats or mice was consistently observed to induce: increase in motor activity [19, 41], tremors in the head and neck [4, 7], pilo erection sniffing, biting and licking. B. Effects on the Cardiovascular System: Intake of khat or administration of (-) cathinone to humans and animals is shown to increase the arterial blood pressure, heart rate and force of contraction of the heart [19, 25, 42, 44]. The effects are due to the ability of khat constituents to stimulate release of NA from the peripheral adrenergic neurones and those in the heart together with simultaneous inhibition of its metabolism via the enzyme MAO [19]. C. Effects on the Gastrointestinal Tract: Following intake of khat, relaxation of intestinal muscles was observed leading to predisposition to constipation [40]. This effect is probably due to presence of tannins [1] in the leaves. Furthermore, khat administration decreased gastric acid secretion and enhanced healing of gastric ulcers [6]. These beneficial effects may be due to the presence of flavonoids such as kaempferol and quercetin in the leaves [6]. D. Effects on Blood Components Pressure: Administration of khat or (-) cathinone was observed to elevate the levels of glucose and free fatty acids in the plasma [31]. Similarly, administration of (+) cathine to animals reduced body lipid content. The lipolytic effect of khat constituents is probably due to stimulation of adrenaline release from the adrenal medulla since it was not observed in isolated fat cells in in vitro experiments [31]. E. Effects on the Eye: Khat is observed to induce mydriasis and to impair visual perception and discrimination. The latter effects are probably due to activation of the serotoninergic system [27]. 91 F. Effects on the Respiratory System: Administration of khat or cathine to experimental animals stimulated the respiration, elevated the pulmonary blood pressure and induced slight relaxation in the trachea. G. Effects on the Renal System: Khat is reported to constrict renal blood vessels and to potentiate adrenaline-induced vasoconstriction and decreased glomerular filtration rate with consequent decrease in urine output. H. Effects on Testes: Khat is shown to depress spermatogenesis Metabolism of Khat Active Constituents: In the body most of the absorbed (+) cathine is converted to (-) cathinone and the remainder is excreted in urine. Cathinone is metabolized to (-) norephedrine which is excreted in urine [9, 18, 34]. Tolerance to Khat Actions: Several reports revealed the appearance of tolerance to khat actions after continuous use [35]. As a result consumers tend to increase their usual intake of this substance. Dependence on Khat: Intake of khat usually results in development of psychic dependence [30]. It does not induce physical dependence. However, continuous intake of this substance predisposes to the appearance of schizophrenia, mania [15, 16], convulsions [4] and tremors of the head [7]. 92 Khat Antagonists: Various khat actions can be antagonised by administration of dopamine receptor blockers e.g. Haloperidol, pimozide, spiroperidol or chlorpromazine [41] or by drugs that inhibit DA and NA synthesis e.g. alpha-methyltyrosine or diethylthiocarbamate [41] Similarly, dopamine uptake inhibitors or NA uptake inhibitors such as nomifensine, mazindol and desipramine were reported to antagonise khat or (-) cathinone actions [24, 41]. Depletion of body cathecholamines by reserpine is reported to prevent khat or (-) cathinone effects [41]. References: 1. Alles, G.A., Fairchild, M.D. and Jensen, M. (1961). J. Med. Pharm. Chem. 3, 323-52. 2. AlMahy, E. (1987). Selected Essays. (Edited by ElSafi, A. and Bassher, T.) Khartoum University Press, Sudan. 3. AlMarzoogi, H. and AbuKhatwa (1987). Khat. Tihama Publications. Jeddah, Saudi Arabia. 4. Al-Meshal, I.A., Ageel, A.M., Parmar, N.S. and Tariq, M. (1985). Fitoterapia. 56, 131-52. 5. Al-Meshal, I.A., Hifnawy, M.S. and Nasir, M. (1986). J. Nat. Prod. 49, 172. 6. Al-Meshal, I.A., Ageel, A.M., Tariq, M. and Parmar, N.S. (1983). Res. Commun. Substance Abuse. 4, 143-150. 7. Berardelli, A., Capocaccia, L., Pacitti, C., Tancredi, V., Quinteri, F. and Elmi, A.S. (1980). Pharmacol. Res. Commun. 12, 959-64. 8. Brenneisen, R. and Geisshusler, S. (1985). Pharm. Acta. Helv. 60, 290-301. 9. Brenneisen, R., Geisshuesler, S. and Schorno, X. (1986). J. Pharm. Pharmacol. 38, 298-300. 10. Crombie, L. (1980). Bull. Narcotics. 32, 37-50. 11. Doyle, T.D., Adams, W.M., Fry, F.S. Jr., and Wainer, I.W. (1986). J. Liq. Chromatogr. 9, 455-71. 93 12. Fluckiger, F. and Gerock, J. (1887). Pharmaceutical J. Transactions. 18, 221-24. 13. Foltin, R.W. and Schuster, C.R. (1983). J. Pharmacol. Exp. Ther. 226, 405-10. 14. Friebel, H. and Brilla, R. (1963). Naturwissenschaften,50, 354-5. 15. Giannini, A. and Castellani, S. (1982). J. Toxicol. Chem. Toxicol. 19, 455-59. 16. Gough, S. and Cookson, I. (1984). Lancet, 1, 455. 17. Glennon, R.A. and Liebowitz, S.M. (1982). J. Med. Chem. 25, 393-7. 18. Guantai, A.N. and Maitai, C.K. (1983). J. Pharm. Sci. 72, 1217-18. 19. Gugelmann, R., VonAllmen, M., Brenneisen, R. and Porzig, H. (1985). Experientia, 41, 1568-71. 20. Hammouda, E.S.M. (1978). Bull. Fac. Sci. K.A.U. Jeddah. 2, 17-22. 21. Huang, D. and Wilson, M.C. (1983). Res. Commun. Subst. Abuse. 4, 215-25. 22. Kalix, P. and Glennon, R.A. (1986). Biochem. Pharmacol. 35, 3015-19. 23. Alix, P. (1986). Neuropharmacology 25, 499-501. 24. Kalix, P. (1983). Life Sci. 32, 801-7. 25. Kohli, J.D. and Goldberg, L.I. (1982). J. Pharmac. Pharmacol. 34, 338-40. 26. Luqman, W. and Danovski, L.S. (1976). Ann. Intern. Med. 82, 216-219. 27. Machula, A.I., Barkov, N.K., Fisenko, V.P. (1980). Farmakol. Toksikol (Moscow) 43, 16-19. 28. May, S.W., Phillips, R.S., Herman, H.H. and Mueller, P.W. (1982). Biochem. Biophys. Res. Commun. 104, 38-44. 29. Mereu, G.P., Pacitti, C. and Argiolas, A. (1983). Life Sci. 32, 1383-9. 30. Nahas, G.G. (1981). Bull. Narcotics. 33, 1-19. 31. Nencini, P. (1980). Pharmacol. Res. Commun. 12, 855-61. 32. Nencini, P. and Ahmed, A.M. (1982). Pharmacol. Res. Commun. 14, 759-70. 94 33. Nielsen, J.A. and Schechter, M.D. (1985). Prog. Neuropsychopharmacol. Biol. Psychiatry. 9, 739-43. 34. Rutter, E.R. (1972). Clin. Chem. 18, 616-20. 35. Schechter, M.D. (1986). Pharmacol. Biochem. Behav. 25, 13-16. 36. Schechter, M.D. (1986). Pharmacol. Biochem. Behav. 24, 1161-5. 37. Schorno, X., Brenneisen, R. and Steinegger, E. (1982). Pharmaceutica. Acta. Helveticae. 57, 68-176. 38. Schorno, X. and Steinegger, E. (1979). Experientia. 35, 572-4. 39. Stockman, R. (1914). Pharm. J. 89, 676-8 and 685-7. 40. Tariq, M., Ageel, A.M., Parmar, N.S. and Al-Meshal, I. (1984). Fitotherapia. 4, 195-199. 41. Valterio, C. and Kalix, P. (1982). Arch. Inter. Pharmacodyn. Ther. 255, 196-203. 42. WHO Advisory Group (1980). Bulletin Narcotics. 32, 83-93. 43. Wolfes, O. (1930). Arch. Pharm. 268, 81-3. 44. Zelger, J.L. and Carlini, E.A. (1981). Neuropharmacology. 20, 839-43. 95 HALLUCINOGENIC AGENTS Introduction: During the primitive man search for food or means to alleviate pain, his serendipity led him to discover many plants and mushrooms that have the power to alleviate pain, spasm, convulsions or to change the mood. Some of these substances were found to alter visual and auditory perceptions and cognitive powers without affecting consciousness. Indeed, some of the plants and mushrooms were found to induce hallucination i.e. perception or sensation of external objects in their absence or to induce illusions i.e. distortion or false interpretation of objects sensed or perceived. Some of these plants included hemp (Cannabis sativa), peyote (mescal buttons known as Lophophora williamsii), morning glory seeds (Ipomea violacea), Tabernanthe iboga and the muschroom teonanactal (Psilocybe mexicana). Most of these substances were used by primitive tribes to induce hallucinations and illusions during their religious ceremonies to enhance their religious experience. It was also believed that these plants purify the self, eliminate hostilities and anxieties and enhance intimate friendship between worshippers participating in the religious ceremonies. During the early years of the 20th century health authorities in many countries realized the dangers and hazards that follow chronic use of these hallucinogenic substances. As a result many regulations were issued to control the plantation, distribution, sale and use of these substances. However, these regulations were opposed by the users of those plants. Some of the famous opposers of these rules were the Indian cults of USA and Canada who venerate the hallucinogenic plant peyote (mescal buttons) very highly. Indeed, they believe that use of this plant leads to revelation of hidden knowledge and incurs protection and healing from diseases and motivates for doing good deeds. They usually use it during their worshipping ceremonies as they name it "the gift of God". For these reasons they fought against all laws that prohibit use of peyote 96 and to strengthen their opposition they united to form The Native American Church to defend them and upheld their right for the use of peyote. However, it was only recently that the USA Government legalised the use of peyote for individuals incorporated in the Native American Church and only during religious ceremonies. In the last few decade chemical researchers directed their attention to investigate the chemical constituents of these hallucinogenic plants and mushrooms and they succeeded in discovering the active compounds of some of the hallucinogenic plants and mushrooms. These active constituents are shown in Table 1. Table 1. Active Constituents of Some hallucinogenic Plants and Mushrooms Materials Active Constituents Peyote (mescal buttons) Mescaline Psilocybe mexicana (teonanctal) Psilocibin and Psilocin Peptadenia peregrina Dimethyltryptamine Banisteriopsis cappi Haramine Morning glory seeds (Ipomea violacea) Lysergic acid amide and DLysergamide Amanita muscaria Muscarine Besides these natural hallucinogenic substances, many new synthetic hallucinogenic compounds have been introduced. Some of these are: Lysergic acid diethylamide (LSD-25), 97 dimethyltryptamine (DMT), 2,5-dimethyoxy, 4-methyl amphetamine (DOM), (or STP - Serenity, Tranquility and peace), phencyclidine (or PCP). The availability of these synthetic materials and discovery of simple methods for their synthesis encouraged illicit Narcotic Organizations to synthesize and distribute these substances illicitly in many countries. In the following pages, the pharmacological effects of some natural and synthetic hallucinogens will be discussed. 98 LSD-25 Introduction: LSD-25 is chemically known as: d-Lysergic acid diethylamide (or Lysergide). It was first synthesized in 1943 in Sandoz Chemical Laboratory, Basel Switzerland by Arthur Stoll and Albert Hofmann. The method of synthesis was patented during the years 1946-1948 in Switzerland, England and USA [35]. The No. 25 that follows the abbreviation LSD refers to the No. of experiments performed to reach the successful synthesis of the chemical. Two major findings before 1943 paved the way for Stoll and Hofmann to synthesize LSD. One of these was the discovery of Lysergic acid as a product of the alkaline alcoholic degradation of the ergot alkaloid ergotinine (ergometrine) in 1934 by Walter A. Jacobs and Lyman C. Craig. The second finding was the discovery of the chemical structure of the ergot compound ergine as lysergic acid amide in 1934 by Sydney Smith and Geoffrey Timmis [32]. In fact LSD was synthesized during the preparation of derivatives of ergine. Interest in LSD was aroused following the years 1947 and 1948 after publication of Hofmann's experience of intake of 0.25 mg of LSD. Indeed this small dose produced various behavioural changes that included: feelings of distortion in shapes of objects and subjects, excessive dreaming, visual hallucinations of fantastic pictures and colours of various creatures [14, 15]. To date LSD is considered as the potent hallucinogenic agent since a dose of 1-2µg/kg orally is sufficient to induce severe hallucination. During the 1950s many individuals used LSD to experience the induced hallucination and this was facilitated by the illicit synthesis of the substance and distribution of the substance by illicit Narcotic Organizations. However by the year 1965 many adverse effects were reported following chronic use of LSD. From that time many countries issued laws to prohibit the manufacture, possession, sale, transfer and use of LSD. However illicit synthesis and distribution of LSD continued in 99 various countries under many slang names such as: Flash, Blue Chairs, Pure Love, The Ghost, Deeda, The Hawk, The Animal, The Beast, Mind Detergent, Brown Dots, Sacrament, California Sun Shine and Zen. Pharmacological Effects of LSD: 9,10-didehydro-N,N-diethyl-6-methyl(8)-ergoline-8carboxamide. A. General Actions of LSD: Following intake of 0.1 mg of LSD orally or (1-2µg/kg), the user experiences the following effects: Excitation, euphoria, laughing, crying or screaming for no obvious reason, visual hallucinations and changes in perception felt as continuous change of colours and shapes of objects, feeling of intense colouration of objects, appearance of rainbowlike halos around lights, movements and flying of fixed objects, appearance of depths in flat surfaces and development of synesthesia (crossing of senses) i.e. sounds seem to accompany seeing of coloured pictures. A period of illusion then starts when scratches and spots on walls appear to be human faces, disturbed estimation of object sizes, loss of time and space perception, disturbance of logical thinking and judgements, feeling of anxiety, tension or panic and elation. These phases are then followed by a period of quietness when 100 the user sits or lays with closed eyes and then disrobing to nudity [10, 33, 41]. The above sequence of events usually starts one hour after intake of LSD and reach their maximum 2-3 hours later and continues for a duration of 6-8 hours. Detailed pharmacological analysis revealed that the major brain sites affected by LSD are: the cerebral cortex, brain stem, the limbic system, diencephalon, temporal lobe, hippocampus, amygdala and hypothalamus [10]. The major mechanisms of action of LSD are believed to consist of: 1. Inhibition of the serotoninergic neurones leading to decreased release of serotonin in the brain [1, 4, 6, 27, 36, 40]. To induce this effect LSD combines with and activates presynaptic 5-HT in serotoninergic receptors [6] that control release of serotonin (5-HT) [1, 25, 27, 28]. A clear decrease was noted in the nucleus accumbens and in the hypothalamus [27]. 2. Stimulation of synthesis and release of the neurotransmitter dopamine (DA) especially in the area of the nucleus accumbens [13, 17, 26, 39]. 3. Activation of postsynaptic dopaminergic receptors in the striatum, cortex, and substantia nigra [22]. The above mechanism of action concerning 5-HT is strengthened by the findings that agents that elevate 5-HT level in the brain e.g. nilamide suppresses LSD effects whereas depletion of brain 5-HT e.g. by reserpine potentiates the effects of LSD. Similarly, administration of DA receptor blockers e.g. haloperidol decreased the effects of LSD [18, 39]. In addition to the above mechanisms, the ability of LSD to block central serotoninergic receptors may contribute to the actions of LSD. 101 It is believed that the inhibitory effects of LSD on the serotoninergic nerurones in the cerebral cortex (visual cortex) and the limbic system relieve the inhibitory effect exerted by the serotoninergic neurones in these areas [1, 25]. As a result excitation of these areas occur with the ultimate precipitation of hallucination. B. Other Effects on the Brain: Beside the above effects, administration of LSD was observed to cause: 1. Inhibition of the vomiting centre in the chemoreceptor trigger zone in the medulla. 2. Induction of insomnia. 3. Inhibition of learning and impairment of intellectual processes [34]. 4. Induction of anorexia [38]. 5. Elevation of body temperature. 6. Suppression of pain and enhancement of acupunctureinduced analgesia. 7. Enhancement of aggression. 8. Suppression of seizures. 9. Suppression of memory [34]. 10. Inhibition of protein synthesis. C. Effects on Eye and Vision: Following intake of LSD, mydriasis occurs due to activation of ocular sympathetic neurones and release of NA [19]. The drug also causes disturbances in dark adaptation and the electroretinogram. It increases the amplitude of the waves and decreases their latency. It activates the lachrimal glands. Furthemore, LSD was observed to enhance the neuronal activity of the visual cortex following optical stimulation [9]. This enhancement is probably due to inhibition of central serotoninergic neurons which normally inhibit the visual cortex and forebrain areas of the visual system. These changes may 102 explain the perceptual disturbances and distortion of visual perception caused by LSD. D. Effects on the Cardiovascular System: Intake of LSD by humans or administration of the substance to various mammals induced a very brief rise in arterial blood pressure followed by a prolonged decrease and significant tachycardia [19, 2]. The brief rise in blood pressure is probably due to a direct vasoconstricting effect on the blood vessels whereas the hypotensive effect seemed to be due to a central effect on the medulla oblongata [2]. E. Effects on Hormones: Administration of LSD is reported to decrease thyroxine, prolactin [18] and testosterone plasma levels but stimulated MSH release. F. Effects on Blood Components: Administration of LSD is shown to increase blood glucose level by enhancing glycogenolysis in the liver following stimulation of adrenaline release from the adrenal medulla. It also elevates blood free fatty acid level and enhances blood coagulation [8]. G. Effects on the Gastrointestinal Tract: Following intake of LSD there is an increase in salivation and nausea. It is also reported to decrease release of ACh from the intestine and thus predisposes to constipation. H. Effects on the Skin: After administration of LSD to humans, there was tingling in the hands and feet i.e. numbness, facial flushing and piloerection. Sweating is sometimes observed. 103 I. Effects on the Kidney: Intake of LSD is accompanied by decrease in urine excretion and an increase in urine osmolality. J. Effects on Enzymes: Administration of LSD to rats inhibited the enzymes MAO and ACh esterase. It also decreased alkaline phosphatase level in the leukocytes. K. Effects on Cyclic Nucleotides: LSD is reported to elevate the level of cyclic AMP in the hippocampus, the corpus striatum [39] and in the retina. L. Effects on the Immune System: Chronic intake of LSD decreased the size of the thymus gland and suppressed its functions. It also decreased leukocytes' mitosis and cell division. It induced severe chromosomal breaks in the lymphocytes and leukocytes. M. Effects on the Reproductive System: When LSD is taken by pregnant females the drug crosses the placental barrier, constricts the placental and umbilical blood vessels, decreases blood flow to the foetus and induces foetal hypoxia [3]. It also induces abortion, foetal abnormalities and death of offsprings. The foetal abnormalities may be related to the ability of this drug to induce chromosomal break. The LSD-induced abortion may be related to the oxytocic effect of this agent. N. Effects on Sex Behaviour: Administration of LSD to females suppressed sexual receptivity and in males induced initial sexual excitation followed by prolonged inhibition [31]. 104 Acute Intoxication with LSD: Intake of a large dose of LSD (>1mg) in a single dose induces acute toxicity characterized by: Hyperthermia, severe sweating, depression of respiration, screaming, terror, hyperkinesis, amnesin, severe hallucinations, catatonia, gastrointestinal tract bleeding, hematuria and coma [5]. The panic is accompanied by loss of self control and judgement, loss of logical reasoning, severe violence, and sudden upsurge of memories that are normally repressed. During this phase a strong feeling of suspicion on the surrounding peoples emerges and the patient feels that all people are plotting against him and thus tries to protect himself by killing them [5, 20]. To treat such patients, the patient should be moved to a calm place and injected with diazepam (15mg, i.v.) or chlorpromazine (50mg, i.m.) [7]. Tolerance, Dependence and Addiction to LSD: Generally, intake of the first dose of LSD does not motivate or inforce the user to administer other doses i.e. it does not induce psychic dependence [20]. However, continuous use of this drug precipitates tolerance to its effects. Tolerance usually occurs following a few days of use of the drug [37]. However, in some people the drug induces psychic dependence without any tendency to stimulate development of physical dependence. It should be noted that chronic use of this drug is consistently observed to induce chronic psychosis [12], neurosis and schizophrenia [20]. It also produces paranoia, continuous hallucination and depression with great tendency for homicidal and suicidal action [12]. Furthermore, chronic use of LSD enhances the development of solar retinopathy with its characteristic decrease in visual acuity, central scotoma and chromatopsia [29]. These effects are due to the ability of the drug to induce mydriasis compled with the attraction of the user to the sun to enjoy the imaginary beautiful halos around it. 105 One of the characteristics of LSD addiction is that chronic users may experience the usual LSD effects without taking the drug. This is known as "flash-back" phenomenon. To enjoy these free LSD trips, the addict creates the same environment that surrounded him in his previous drug taking period. After few minutes of concentration, the addict experiences most of the known LSD effects with their characteristic hallucination and emotional disturbances [20, 30]. Indeed such flash-backs can occur several months after the last dose of LSD. However, the occurrence of these flash backs is enhanced by intake of alcohol, cannabis, barbiturates or antihistamines [30]. Metabolism of LSD: LSD is mainly metabolised in the liver by microsomal enzymes. Its major metabolite is 2-oxy LSD, lysergic acid ethylamide, nor LSD, lysergic acid [16, 23]. Both LSD and its metabolites undergo enterohepatic cycling [24]. The plasma half-life of LSD is 175 min. The metabolites are excreted both in faeces and urine. The level of LSD or its metabolites in the plasma and urine can be estimated using spectrophotometry, gas-chromatography, radioimmunoassay and HPLC methods [42]. LSD in powder form can be easily identified by adding the powder to a test tube containing a mixture of FeCl3, acetic acid and H2SO4. A violet or lilac-coloured ring can be observed at the solution interface. References 1. 2. 3. Aghajanian, G.K. and Lakoski, J.M. (1984). Brain Res. 305, 181-185. Angus, J.A. and Black, J.W. (1980. Circ. Res. Suppl. 46, 64-69. Back, D.J. and Singh, J.K.G. (1977). Experientia. 33, 501502. 106 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. Chase, T.N., Breese, G.R. and Kopin, I.J. (1967). Science. 257, 1461-1464. Cohen, S. (1967). Annu. Rev. Pharmacol. 7, 301-311. Devivo, M. and Maayani, S. (1986). J. Pharmacol. Expt. Ther. 238, 248-253. Dhawan, B.N., Mathur, G.B. and Rajvanshi, V.S. (1968). Jap. J. Pharmacol. 18, 445-453. Dray, A., Fox, P.C., Hilmy, M. and Somjen, G.G. (1980). Brain. Res. 200, 105-121. Freedman, D.X. (1969). Annu. Rev. Med. 20, 409-419. Gant, D.W. and Dyer, D.C. (1971). Life Sci. 10, (part 1), 235-240. Hatrick, J.A. and DeWhurst, K. (1970). Lancet. 2, 742-744. Hetey, L., Schwitzkowsky, R. and Oelssner, W. (1983). Eur. J. Pharmacol. 93, 213-220. Hofmann, A. (1959). Acta. Physiol. Pharmacol. 8, 240-244. Hofmann, A. (1979). J. Psychedelic Drugs. 11(1-2), 53-60. Inoue, T., Tiwaguchi, T. and Murata, T. (1980). Xenobiotica. 10, 343-348. Jacobs, B.L. (1983). Psychopharmacology (Amsterdam) 1, 344-376. Lamberts, S.W.J. and McLeod, R.M. (1979). Proc. Soc. Exp. Biol. Med. 162, 75-79. Martin, W.R. and Sloan, J.W. (1986). Pharmacol. Biochem. Behav. 24, 393-399. McGlothlin, W.H. and Arnold, D.O. (1971). Arch. Gen. Psychiat. 24, 35-49. Meltzer, H.Y., Boutros, N.N., Simonovic, M., Gudelsky, G.A. and Fang, V.S. (1983). Dev. Neurosci. (Amsterdam) 16, 463-477. Mokler, D.J. and Rech, R.H. (1984). Pharmacol. Biochem. Behav. 21, 281-287. Moorthy, A.S. and Mitra, J. (1978). Nucleus (Calcutta) 21, 206-211. Parker, R.J., Hirom, P.C. and Milburn, P. (1980). Xenobiotica. 10, 689-703. 107 24. Penington, N.J. and Reiffenstein, R.J. (1986). Can. J. Physiol. Pharmacol. 64, 1413-1418. 25. Persson, S.A. (1978). Psychopharmacologia. 59, 113-117. 26. Pettibone, D.J. and Pflueger, A.B. (1984). J. Neurochem. 43, 83-90. 27. Rusmussen, K. and Aghajanian, G.K. (1986). Brain. Res. 385, 395-400. 28. Schatz, H. and Mendelblatt, F. (1973). Br. J. Ophthalmol. 57, 270-274. 29. Shick, J.F.E. and Smith, D.E. (1970). J. Psyched. Drugs. 3, 82-90. 30. Sietnieks, A. and Meyerson, B.J. (1980). Eur. J. Pharmacol. 63, 57-64. 31. Smith, S. and Timmis, G.M. (1934). Nature, 133, 579. 32. Smith, D.E. (1969). Clin. Toxicol. 2, 69-74. 33. Stasik, J.H. and Kidwell, J.F. (1969). Nature (London) 224, 1224-1225. 34. Stoll, A. and Hofmann, A. (1943). Helvetica Chin. Acta. 26, 944-947. 35. Trulson, M.E., Heym, J. and Jacob, B.L. (1981). Brain Res. 215, 275-293. 36. Trulson, M.E. and Crisp, T. (1983). Eur. J. Pharmacol. 96, 317-320. 37. Vaupel, D.B., Nozaki, M., Martin, W.R., Bright, L.D. and Morton, E.C. (1979). Life Sci. 24, 2427-2431. 38. Von Hungen, K., Roberts, S. and Hill, D.R. (1975). Brain Res. 95, 57-61. 39. White, F.J. (1986). Pharmacol. Biochem. Behav. 24, 365739. 40. Wolbach, A.B. Jr., Miner, E.J. and Isbell, H. (1962). Psychopharmacologia. 3, 219-223. 41. Zorz, M., Culig, J., Kopitar, Z., Milivojevic, D., Marusic, A. and Bano, M. (1985). Hum. Toxicol. 4, 601-607. 108 MESCALINE AND PEYOTI PLANT Mescal Buttons Introduction Peyoti plant is known by the name Lophophora williamsii (Lemaire) and belongs to the botonical family Cactaceae. It is also known as the cactus plant, peyotl or mescal buttons. It is believed to be indigenous to North Mexico and the South West parts of USA. For many centuries the Indians of these parts of the World used to chew the flowering heads of this plant during their religious ceremonies and rituals. They believe that the drug enriches their religious experiences, frees their souls from the surrounding environment and helps them to concentrate in their worshipping and contact with their god!! Indeed, a few years ago a prehistoric specimen of Lophophora williamsii has been discovered in a burial cave in west central Coahuila in Mexico. It was associated with radiocarbon dates of 810-1070 AD [5]. The major active substance in the flowering heads of this plant is the viscous alkaline colourless alkaloid mescaline. It was first isolated by the German chemist A. Heffter in 1896 and its chemical structure was elucidated by the Austrian chemist Ernst Spath in 1918 [39] and was characterized as 3,4,5-trimethoxyphenylethylamine. Till the beginning of the 20th century use of peyote was confined to the Indian tribes of Mexico and South West USA. However, thereafter the hallucinogenic effect of the plant attracted many peoples in the USA who indulged in consuming high quantities of it with the resultant appearance of various psychological disturbances and adverse effects in the users of 109 the plant. For these reasons the USA Congress passed laws in 1918 to prohibit distribution, sale or intake of peyote plant or its active constituent mescaline. These rules were opposed by the American Indians and united to form the Indians Native American Church which strongly opposed and rejected the control of peyote use on the grounds that peyote is an important sacrament in their religious rites. The position of this Church was strengthened in 1955 after the joining of the Canadian Indians to the Church. The latter then fought vigorously to legalize use of peyote in their religious ceremonies. At last in 1965 the USA Congress agreed to make some amendments on restriction of peyote use. In these amendments peyote and mescaline use is prohibited for all Americans except those joining the Native American Church with the restrictions that peyote should be used inside the Church only during worshipping and should be obtained from authorized suppliers only. To take peyote during worshipping, the Indian inside the Church sit in a circle round a fire during the evening and start to chew or suck the brown dried crowns of peyote plant (mescal buttons). They start their worshipping with chanting and meditation till the next morning when a communal meal is taken and the ceremony ended [21, 29]. During this session every worshipper consumes approximately 15-30g of peyote plant. This quantity is estimated to supply the worshipper with 300600mg of the active substance mescaline [21]. Since 1918 and after publication of the first method for the chemical synthesis of mescaline by Ernst Spath [32], several simple methods have been published for the synthesis of mescaline from gallic acid or pyrogallol and its conversion to the soluble hydrochloride salts [3]. It was also discovered that the mammalian body can easily convert the endogenous substances N-acetyl-4-hydroxy, 3,4-dimethoxy phenylethylamine (resulting from catecholamines metabolism) to the active substance mescaline in presence of S-adenosyl methionine [13]. 110 The availability of simple methods for mescaline synthesis stimulated many illicit Narcotic Organizations to synthesize and distribute mescaline among the youth in many countries. However, many governments passed rules that control synthesis, distribution and use of mescaline and its salts with severe penalties for those who outbreak these rules. However, these controls did not stop the illicit Narcotic Organizations from distributing mescaline under many misleading and slang names such as: Mesc, Dry Whisky, Dry Dokkar [16]. Similarly, peyote plant is distributed under the slang names: Full Moon, Big Chief, Huatari, Tops, Hikori, Wokowi and the Button [16]. Chemical Composition of Peyote Flowering Heads: The most important constituent of peyote flowering heads is the alkaloid mescaline which is synthesized from the precursors tyrosine and dopamine. The percentage of this substance ranges from 1.1 - 2.7% w/w [31]. Other alkaloids detected in this plant are: anhaline hordenine), anhalonidine, anhalonine, anhalamine, lophophorine and pellotine [1]. These alkaloids produce effects that are qualitatively similar to mescaline. Recent phytochemical investigations revealed the presence of mescaline in many other plants such as: Gymnocalycium gibbosum, Anhalonium Lewinii, Opuntia cylindrica [23], Stetsonia coryne, Trichocereus pachanoi, Pelecyphora aselliformis [25], Peyotl zacatensis, and Trichocereus cuzcoensis. Thus, use of any of these plants produces effects similar to those of peyote. 111 Pharmacological Effects of Peyote and Mescaline: A. General Effects: Two hours following consumption of 15-30g of peyote flowering heads or intake of mescaline 5mg/kg body weight orally, the user feels contentment, hypersensitivity, nervous calm, brilliant flushes of colour followed by extensive visual hallucinations comprised of seeing bright coloured lights, geometric figures, familiar and unfamiliar scenes of animals and peoples, severe illusions and experience of synesthesia when musical sounds seem to accompany the coloured vision. These effects continue for 8-12 hours and thereafter the user returns back to normal [7, 14, 35, 37]. Administration of mescaline to animals induced head twitches [9, 26], limb-flicking [35], increased locomotor activity, and catatonia [12]. Detailed analysis of the mechanisms of action of mescaline revealed that mescaline-induced effects are probably due to: 1. Activation of postsynaptic 5-HT2 serotoninergic receptors [2, 8, 9, 26, 34]. 2. Activation of postsynaptic dopaminergic receptors [2, 8, 9, 38]. 3. Release of 5-HT (serotonin) [27, 34, 38]. 4. Release of NA. Beside the above named effects, administration of mescaline produced various effects by acting on different brain regions such as the hypothalamus, pons, medulla oblongata, the thalamus, tegmentum, hippocampus and cerebellum [30]. Some of these effects include: 1. Disturbance in the EEG such as decrease in the amplitude of alpha-waves, disappearance of the hippocampal (theta) rhythm. 2. Decrease in body temperature [33]. 112 3. 4. 5. 6. 7. 8. Induction of analgesia [12]. Increase in reactivity (tactile startle responding). Induction of anxiety. Suppression of seizures. Induction of anorexia [33]. Depression of learning and consolidation processes [6]. B. Effects on the Eye: Following intake of mescaline there is mydriasis [12] and lachrimation [12], inability to discriminate between light intensities and disturbance in light-conditioned reflexes [12]. C. Effects on the Cardiovascular System: Administration of mescaline causes rise in arterial blood pressure and tachycardia probably due to central sympathetic stimulation [7]. However in rats and mice bradycardia was observed [24, 28]. D. Effects on the Gastrointestinal Tract: Intake of mescaline induces salivation [7, 12], nausea and vomiting [7] and relaxation of intestinal muscles. E. Effects on the Liver: Administration of mescaline is shown to depress the liver conjugating enzymes [15] and to deplete the SH groups in the hepatocytes [4] and thus increased the susceptibility of the liver cells to damage. F. Effects on the Respiratory System: Mescaline is shown to constrict the bronchi and to induce tachypnea [12]. G. Effects on Hormones: Administration of mescaline stimulates release of prolactin and GH [36]. These effects are probably due to activation of central serotoninergic receptors. 113 H. Effects on Blood Components: Continuous administration of mescaline is reported to elevate blood level of free fatty acids, to decrease total leukocyte count and to depress the activity of lymphocytes by incorporating into their proteins [20]. I. Effects on the Kidney: Intake of mescaline is shown to decrease urine output and to increase urine osmolarity. The effects did not seem to involve inhibition of renal vasodilator prostaglandins (PGS). J. Effects on Cyclic Nucleotides: Addition of mescaline to homogenates of monkey anterior limbic cortex or the auditory cortex enhanced cyclic AMP accumulation due to activation of DA receptors. K. Effects on the Reproductive System: Intake of mescaline by females is shown to increase uterine muscle contractility and to induce menstruation in women with amenorrhea [24]. However, the drug is shown to pass the placental barrier and to accumulate in foetal organs resulting in various teratogenic effects in the foetus. These included malformations in the brain, spinal cord, liver, skull, sternum and metatarsals. It also decreased foetal weight and enhanced foetal resorption [19]. Intoxication with Mescaline: Intake of a large dose of mescaline (>2g) in a single dose induces acute toxicity having the following symptoms: excessive visual hallucination, thought disorder, nausea, vomiting, sweating, diarrhoea, abdominal cramps & hypertension [17]. These symptoms can be easily suppressed by administration of mescaline antagonists such as: chlorpromazine (25-50mg 0i.m.), haloperidol (2.5-5mg, i.m.), 114 perphenazine or methysergide [22]. by ketanserin [26], pirenperone or Metabolism of Mescaline: Mescaline is partially metabolised in the body approximately 50%) in the liver and lungs via the enzyme MAO [18]. Its major metabolites are: 3,4,5-trimethoxy-phenylacetic acid and 3,4,5-trimethoxybenzoic acid. Both metabolites and unchanged mescaline are excreted in urine [11, 18]. These substances can be easily detected and estimated in blood or urine via use of colorimetry, GC/MS, and HPLC methods [10]. The plasma half-life of mescaline is 6 hours [7]. Tolerance to and Dependence on Mescaline: Continuous intake of mescaline results in development of tolerance to its various actions in the body [29]. Indeed, tolerance has been observed after 5 days treatment with mescaline [12]. Once tolerance to this drug occurs, there is also cross-tolerance to other hallucinogenic agents e.g. LSD and psilocybin. Chronic use of this drug induces psychological dependence without any tendency for physical dependence [29]. Chronic intake of this drug is consistently reported to induce: schizophrenia, catatonia, panic reactions and flashbacks. However, the most dangerous thing following chronic use of mescaline or consumption of mescal buttons is that users of these substances undergo changes in personality and lose ambitious and become more compliant than normal people. Furthermore, male users of these substances tend to feel more feminine than others [17]. 115 References: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. Anon. (1959). Bull. Narcotics. U.N. Dept. Social Affairs. 11 (2) 16-29. Arrigo, R.R., Scoto, G., Spadaro, C., Spampinato, S. and Braga, P.C. (1978). IRCS Med. Sci. Libr. Compend. 6, 9. Benington, F. and Morin, R.D. (1951). J. Am. Chem. Soc. 73, 1353. Bradley, C.A., Miya, T.S. and Yim, G.K.W. (1961). J. Neuropsychiatry. 2, 175-177. Bruhn, J.G., Lindgren, J.E., Holmstedt, B. and Adovasio, J. (1978). Science. 199, 1437-1438. Castellano, C. (1979). Psychopharmacology (Berlin) 62, 35-40. Cohen, S. (1967). Ann. Rev. Pharmacol. 7, 301-311. Commissaris, R.L., Lyness, W.H., Moore, K.E. and Rech, R.H. (1981). J. Pharmacol. Expt. Ther. 219, 170-174. Corne, S.J. and Pickering, R.W. (1967). Psychopharmacologia. 11, 65-78. Daldrup, T., Michalke, P. and Boehme, W. (1982). Chromatogr. Newsl. 10, 1-7. Demisch, L., Kaczmarczyk, P. and Seiler, N. (1978). Drug Metab. Dispos. 6, 507-509. Ferri, S. and Braga, P. (1976). Probl. Drug Depend. 966977. Friedhoff, A.J., Schweitzer, J.W. and Miller, J. (1972). Nature (London) 237, 454-455. Fundaro, A., Molinengo, L., Cassone, M.C. and Orsetti, M. (1986). Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 10, 41-48. Fischer, F.G.R. and Weber, R. (1949). Excerpta Med. Sect. 8, 2, 951. Hardy, R.E. and Cull, J.G. (1975). Drug Language and Lore. Springfield, III., Charles C. Thomas Pub. Hell, D., Baumann, U. and Angst, J. (1971). Deut. Med. J. 20, 511-514. Hilliker, K.S. and Roth, R.A. (1980). Biochem. Pharmacol. 29, 253-255. 116 19. Hirsch, K.S. and Fritz, H.I. (1981). Teratology. 23, 287289. 20. Holsapple, M.P. and Munson, A.E. (1985). Immunotoxicol. Immunophrmacol. 381-392. 21. Lerner, M. and Katsaficas, M.D. (1969). Bull. Narcotics. 21, 47-51. 22. Maffii, G. and Soncin, E. (1958). J. Pharm. Pharmacol. 10, 541-552. 23. Meyer, B.N., Mohamed, Y.A.H. and McLaughlin, J.L. (1980). Phytochemistry. 19, 719-720. 24. Morton, J.J.P. and Malone, M.H. (1969). J. Pharm. Sci. 58, 1169-1170. 25. Neal, J.M., Sato, P.T., Howald, W.N. and McLaughlin, J. (1972). Science. 176, 1131-1133. 26. Niemegeers, C.J.E., Colpaeret, F.C., Leysen, J.E., Awouters, F. and Janssen, P.A. (1983). Drug Dev. Res. 3, 123-135. 27. Penington, N.J. and Reffenstein, R.J. (1986). Eur. J. Pharmacol. 122, 373-377. 28. Raymond, H. (1931). Bull. Acad. Med. 105, 46-54. 29. Schultes, R.E. (1969). Bull. Narcotics. 21, 3-16. 30. Shah, N.S., Gulati, O.D., Powell, D.A. and Kleinburd, V. (1977). Neurochem. Res, 2, 265-279. 31. Siniscalo, G.G. (1983). Boll. Chim. Farm. 122, 499-504. 32. Spath, E. (1919). Monatsch. 40, 129-154. 33. Sykes, E.A. (1986). Life Sci. 39, 1051-1058. 34. Trulson, M.E., Crisp, T. and Henderson, L.J. (1983). Eur. J. Pharmacol. 96, 151-154. 35. Trulson, M.E., Preussler, D.W. and Trulson, V.M. (1984). J. Pharmacol. Expt. Ther. 228, 94-102. 36. Weltman, A.S., Sackler, A.M. and Schwartz, R. (1968). Exp. Med. Surg. 26, 187-197. 37. 1Wolbach, A.B. Jr., Miner, E.J. and Isbell, H. (1962). Psychopharmacologia. 3, 219-224. 38. Yamamoto, T. and Ueki, S. (1981). Pharmacol. Biochem. Behav. 14, 89-95. 117 TEONANCTAL MUSHROOM AND PSILOCYBIN Introduction: Teonanctal mushroom is known as Psilocybe mexicana (Heim). It has been known and used by the Indians of Mexico and Central America for many centuries. These Indians eat the flowering tops and fruits (Carpophores) of the mushroom during their religious ceremonies to induce visual hallucination which are believed to enhance the religious experience and enhance concentration during worshipping by detaching them from the distracting surroundings!! During these ceremonies each individual consumes 2.5-5gm of the mushroom to experience the psychic effects that last for 4 hours [10]. Scientific interest in this mushroom started in 1958 when Albert Hofmann, Roger Heim and Hans Kobel of Sandoz Laboratories, Basel Switzerland succeeded in extracting and elucidating the chemical structure of the active constituent of this mushroom [10, 12, 13]. The active constituent was found to be an alkaloid which they named Psilocybin and characterized it chemically as O-phosphoryl-4-hydroxy, N, N-dimethyl tryptamine [11, 12]. They also managed to isolate a second alkaloid which they named Psilocin and characterized it as the dephosphorylated product of psilocybin: 4-hydroxy, N,Ndimethyl tryptamine [11]. The percentage of psilocybin was found to be 0.3-0.4% whereas that of psilocin was 0.01% of the fruits weight [3, 10, 11]. The discovery of psilocybin and psilocin in Psilocybe mexicana encouraged many chemists to investigate various other mushrooms for the presence of these compounds. Indeed these efforts culminated in the discovery of psilocybin and psilocin in many mushrooms such as: Psilocybe semperviva (0.4 and 0.03%, respectively) [27]; Psilocybe semilanceata (0.25% - 1.3% of psilocybin) [7, 21, 29]; Psilocybe cubensis (0.5 - 1% of psilocybin); Psilocybe subaeruginosa (0.45% of psilocybin) [20]; Agrocybe farinacea (0.2 - 0.4% of psilocybin) [20]; Copelandia cyanescens; Panaeolus 118 subbalteatus; Inocybe aeruginascens [28]; and Psathyrella candolleana [20]. In these mushrooms both psilocybin and psilocin are biosynthesized from the precursors tryptophan and tryptamine [1]. The alkaloids can be easily extracted with methanol and separated by chromatography [10]. The percentage content can be estimated using spectrophotometry, gaschromatography and HPLC methods [30, 37]. The chemical structures of psilocybin and psilocin are shown below: The availability of simple extracting procedures and the ease of chemical synthesis of psilocybin stimulated many illicit Narcotic Organizations to synthesize and distribute these substances among drug misusers in many countries for recreational purposes and phantazia. However, the psycological disturbances caused by these substances forced the USA government in 1960 to impose control measures for synthesis, distribution, sale and use of psilocybin, psilocin and the mushrooms. These control measures were issued in The Drug Abuse Control Amendments to the Federal Food, Drug and Cosmetic Act. Many other countries also passed rules to control these substances. However, illicit Narcotic Organizations continued to synthesize and distribute these materials under the slang names: Silly Putty and Sacred Mushroom. 119 Pharmacological s of Psilocybin: A. General Effects: The major motive that encourages some people to take teonanctal mushroom or synthetic psilocybin is to enjoy the visual hallucinations induced by the drug. For this purpose a total of 2.5-5gm of the flowering tops and fruits of the mushroom (equivalent to 10-20mg of Psilocybin) are eaten or a single tablet of Psilocybin (10-15mg or 0.15-0.2mg/kg body weight) is sucked under the tongue or dissolved in water and drunk. One hour after intake of these substances the user experiences: initial euphoria, coldness of extremities, numbness of the lips, disturbed perception, sweating, yawning, weeping, facial flushings, visual hallucinations which comprise seeing of brighter colours, coloured objects, animals and humans and severe illusions. In addition the user experiences tremulous speech, disturbed concentration and attention, dreams which may be fearful, impaired coordination, impairment of reality appraisal (as in drunkness), loss of time perception, feeling of objects movement, closure of the eyes and sleep-like state with intense visual hallucinations [5, 15, 26]. All of these effects wane off 3-4 hours after intake of the substance. Experiments in animals revealed that administration of psilocybin produces head twitches, hind leg ataxia [16], limb flicks, decreased locomotion and piloerection [16]. The above effects are believed to be due to psilocybin itself and to its active metabolite psilocin produced by the enzyme alkaline phosphatase present in the intestinal mucosa, liver, kidney and plasma [16, 17]. The biochemical mechanisms that underlie psilocybininduced action seem to involve: 1. Stimulation of 5-HT (serotonin) release from central serotoninergic neurones [6]. 2. Activation of 5-HT receptors located in the raphe nuclei with the consequent depression of raphe unit activity [31]. 120 3. Suppression of 5-HT metabolism by inhibition of its reuptake by the serotoninergic neurones in the area of the hippocampus and caudate nucleus [19, 22, 35]. 4. Sensitization of postsynaptic serotoninergic receptors in the brain [2]. 5. Elevation of brain DA level by inhibiting its reuptake by the central dopaminergic neurones [19, 22, 35]. 6. Sensitization of central noradrenergic receptors [2]. 7. Inhibition of MAO enzyme in the brain leading to decreased metabolism of 5-HT, DA and NA [6]. Beside the above named effects, psilocybin or psilocin administration induced many effects in the brain. These include: 1. EEG disturbances such as disappearance of the spindle activity, disappearance of hippocampal theta rhythm, decrease in theta and alpha-frequencies and an increase in number of slow waves [33]. 2. Suppression of appetite [9]. 3. Elevation of body temperature [2]. 4. Disruption of learning and memory processes [32]. 5. Inhibition of aggressiveness [25]. 6. Stimulation of the respiratory centre and appearance of tachypnea [34]. 7. Stimulation of prolactin release [23]. B. Effects on the Eye and Vision: Following intake of psilocybin a clear mydriasis is observed [36] and the effect seemed to be due to activation of dopamine receptors in the eye. It also increased the frequency and amplitude of succades (-involuntary ocular muscles movement) and induced contraction of nearby visual space [14]. 121 C. Effects on the Cardiovascular System: Following intake of psilocybin both rises and falls in arterial blood pressure were observed [8, 34]. Similarly, both tachycardia and bradycardia were observed [36]. D. Effects on the Gastrointestinal Tract: Administration of psilocybin caused nausea [14, 26], contracted the stomach and did not affect basal intestinal activity. E. Effects on Blood Constituents: Psilocybin is consistently observed to elevate glucose [34] and free fatty acid level in the blood. It also decreases the number of circulating leukocytes specially the eosinophils [14]. F. Effect on Cyclic Nucleotides: Addition of psilocybin to human platelets increases cyclic AMP level. G. Effects on the Reproductive System: Intake of psilocybin by pregnant females resulted in uterine stimulation, constriction of umbilical blood vessels [5, 24] due to activation of serotoninergic receptors [5, 24]. Intoxication with Psilocybin: Intake of a large dose of psilocybin (>50mg) or consumption of large quantity of teonanctal mushroom during a single setting causes acute intoxication having the symptoms of hyperthermia and convulsions [23]. These symptoms can be suppressed by administration of serotonin antagonists such as: cinanserine, cyproheptadine or methysergide [5] or by administration of DA antagonists e.g. chlorpromazine or haloperidol. 122 Metabolism of Psilocybin: After intake of psilocybin the compound is rapidly metabolised in the intestine, liver, kidney and plasma by the enzyme alkaline phosphatase to its major metabolite psilocin (dephosphorylated psilocybin) [16, 17]. The activity of psilocin is approximately 70% that of psilocybin [4]. Psilocin is further oxidized to quinone derivatives and excreted in urine [16, 17]. A bluish colouration is imparted to urine [17]. Tolerance to and Dependence on Psilocybin: Continuous intake of teonanctal mushroom or psilocybin or psilocin for 7-13 days induced tolerance to the various effects of these substances [18]. Cross-tolerance was also observed between psilocybin, LSD and mescaline [15, 18]. These substances have the ability to induce psychic dependence only. 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Chromatogr. 286, 229-35. 125 PHENCYCLIDINE Introduction: Phencyclidine [(1-phenylcyclohexyl) piperidine] was first synthesized in 1957 by the chemists Harold Maddox and Erik Godefroi of Parke Davis Company and was introduced into the medical field under the Trade Name "Sernyl" as an injectable human general anaesthetic and under the name "Sernylan" as an injectable animal general anaesthetic in a dose of 0.25 mg/kg [23, 24]. However, it was soon discovered that the drug induces adverse side effects in the post anaesthetic period. These included: excitement, visual disturbances and delirium. For this reason the drug was withdrawn from human use and confined to animals only. Generally, phencyclidine causes alcohol-like central nervous system depression with ataxia and numbness of extremities. This property was realized by illicit drug users and pushers and they started to use and promote the drug as a "pence pill" in subanaesthetic doses of 0.1 mg/kg orally or by smoking. The alcohol-like effects of this drug attracted many youth who used this drug chronically specially during the years 19671969 in USA. Chronic intake of this drug resulted in precipitation of paranoia, schizophrenia and hallucinations, amnesia and difficulty in speech. For these reasons the USA Government issued rules to control synthesis, distribution and use of phencyclidine. These controls were published in 1969 under the United States Federal Food, Drug and Cosmetic Act. The control also was extended to the precursors of the drug e.g., piperidine and cyclohexanone. Many countries followed the USA in controlling phencyclidine and its precursors. 126 However, these regulatory controls did not stop illicit Narcotic Organizations from synthesizing and distributing this substance in many countries under misleading slang names such as Angel Dust, Elephant, Scuffle, DOA, and Monkey Dust. Pharmacological Effects of Phencyclidine: A. General Effects: Drug seekers and misusers usually take phencyclidine in form of tablets 5-10 mg orally or smoke a similar dose to experience the following effects: Ataxia, dizziness, disorientation, impairment of attention and induction of visual and auditory hallucinations [7, 8, 29, 31]. In addition the drug is observed to produce disturbance in speech, disorganization of thought, numbness of extremities, severe sweating, facial flushing, impairment of motor skills, depersonalization and bizarre behavior such as nudity in public [8, 31]. These effects continue for 4-6 hours after which the user returns to the normal condition. Administration of phencyclidine to animals was observed to induce: ataxia [31, 40], catalepsy, head shaking [16, 35], increase in locomotor activity [16], sniffing, horizontal locomotion [16] and back pedaling [32]. Detailed studies about the biochemical mechanisms that underlie phencyclidine-induced effects revealed that, the above effects are mediated by: 1. Activation of its specific receptors located in the cortex and hippocampus [15, 37]. Indeed, more recently an endogenous peptide named alpha-endopsychosin that selectively activates phencyclidine receptors in the brain has been discovered [19]. Both phencyclidine and alphaendopsychosin receptors are selectively blocked by metaphit [9]. 2. Stimulation of release of the opiate peptides enkephalins and endorphins in the corpus striatum region [14, 16, 30, 37]. 127 3. Direct activation of the opiate receptors: u (mu) and (Sigma) [14, 16, 41, 37]. This proposal is strengthened by the ability of the opiate antagonist naloxone to antagonise phencyclidine-induced ataxia [16]. 4. Stimulation of serotonin receptors [35]. The stimulation may be partially due to release of 5-HT from the serotoninergic neurones [32]. 5. Stimulation of DA release from the striatum and the ventral tegmental area [13, 43]. 6. Inhibition of DA reuptake by the dopaminergic neurones [44] and activation of DA receptors. 7. Release of NA in the area of the nucleus coeruleus in the cerebellum. 8. Inhibition of ACH release in the striatum. 9. Inhibition of MAO enzyme leading to decreased metabolism of 5-HT, DA and NA. Beside the above named effects, phencyclidine actson the brain to produce some other actions which include: 1. Suppression of food intake (anorexia) [17]. However, a stimulant effect on food intake due to activation of opiate receptors is also noted [16]. 2. Induction of general anaesthesia [6]. 3. Elevation of body temperature [17]. 4. Suppression of aggression. 5. Induction of disorientation and unawareness of the environment. 6. Suppression of convulsions. 7. Depression of EEG rhythm. 8. Blockade of K channels in brain nerve terminals [5]. 9. Constriction of cerebral blood vessels [1]. 10. Stimulation of histamine release. 11. Increase in brain GABA receptors. 12. Suppression of memory i.e. induction of amnesia [28]. The induced effect may be due to blockade of central muscarinic receptors, inhibition of protein synthesis and activation of alpha-adrenoceptors. 128 13. Progressive degeneration of brain neurones [2]. B. Effects on the Respiratory System: Administration of phencyclidine depresses the respiration and induces apnea [20]. The effect seems to be due to decrease in arterial CO2 tension and direct inhibition of the respiratory centre in the medulla. Partial activation of the muscarinic receptors in the area of the respiratory centre may also be involved since atropine but not methyl atropine decreased the induced apnea. The major cause of death during phencyclidine intoxication is respiratory depression. C. Effects on the Cardiovascular System: Administration of phencyclidine to humans or other mammals elevates the arterial blood pressure [3, 9, 45]. The effect seems to be due to direct activation of a adrenoceptors located on the blood vessels and stimulation of NA release from sympathetic neurones. The effect does not seem to be mediated centrally since it was observed in spinal pithed animals. In humans, the rise in blood pressure is usually accompanied by tachycardia; however, in many mammals reflex bradycardia was noted [25]. In the isolated hearts the drug usually increases the force of contraction [42]. This effect is probably due to phencyclidine-induced activation of Ca2+ influx into the heart [42]. D. Effects on the Kidney: Following intake of phencyclidine, an increase in urine flow was noted [45] without any increase in cations excretion suggesting a decrease in ADH secretion. Indeed the effect was antagonised by administration of vasopressin [45]. E. Effects on the Eye: Administration of phencyclidine is accompanied by mydriasis, nystagmus, diplopia and ptosis [8]. 129 F. Effects on the Gastrointestinal Tract: Intake of phencyclidine is shown to induce salivation [31] and to relax the intestinal smooth muscle. G. Effects on the Liver: Administration of phencyclidine is shown to induce swelling in hepatic mitochondria without affecting mixed function oxidase microsomal enzymes [4]. H. Effects on Hormones: Following intake of phencyclidine there are decreases in release of prolactin [3, 36] and LH [38] but there is an increase in corticosteroids release [36] due to stimulation of ACTH release. I. Effects on Cyclic Nucleotides: Administration of phencyclidine to mammals elevates the level of cyclic AMP in the cerebellum. Similarly, addition of phencyclidine to brain, liver, lung, ileum and kidney tissues in vitro stimulates the enzyme guanylate cyclase and elevates the level of cyclic GMP. J. Effects on the Nicotinic Receptors: Experiments in vitro revealed the ability of phencyclidine to interact with and block nicotinic receptors. K. Effects on the Reproductive System: Administration of phencyclidine to pregnant animals revealed the ability of this compound to pass the placental barrier and to reduce fetal nutrition leading to decrease in fetal growth, increased resorption and fetal malformations [19]. Intoxication with Phencyclidine: Acute intake of large doses of phencyclidine or chronic intake of this drug is shown to induce hypertensive 130 encephalopathy, intracerebral haemorrhage, cerebral vasospasms, loss of motor ability, convulsions, respiratory depression and apnea followed by death [1, 6, 39]. These toxic symptoms are aggravated by the presence of the impurities present in illicity synthesized phencyclidine such as 1-piperidinocyclohexane which is a very potent inhibitor for phencyclidine metabolism in the liver [11] and 1-piperidinocyclohexane carbonitrile [12] which releases the toxic CN ions in the body [12]. It should also be noted that the smoking of phencyclidine leads to release of 1-phenyl-cyclohexene as a result of heat pyrolysis [11]. This compound is shown to inhibit antibody forming cells in the thymus [18]. For treatment of acute intoxication with phencyclidine the patient may be administered the dopamine antagonists e.g. chlorpromazine (25-50 mg i.m.) or haloperidol (2.5 - 5 mg i.m.). The convulsions may be suppressed by i.v. diazepam (10 mg). The specific phencyclidine receptor blocker metaphit [9] may also be used. Other drugs that are reported to antagonise some of phencyclidine actions include: naloxone [14, 16], cyproheptadine, cinanserin [26] and haloperidol [22, 26]. Metabolism of Phencyclidine: When phencyclidine is taken orally 72% of the administered dose is usually absorbed [10]. However when smoked it is greatly degraded by pyrolysis so that only 40% of the smoked quantity is absorbed intact. After absorption, the drug is metabolised both in the liver and the lungs [20]. Its major metabolites are: cis-4-phenyl-4-piperidinocyclohexanol [10, 27] and 1-(1-phenylcyclohexyl)-4-hydroxy piperidine [33]. The metabolites are excreted in urine [10, 11]. Some may be excreted in sweat [10], saliva [10] and milk. Phencyclidine protein binding is in the range of 57.5 - 65% [10]. Its half-life in the plasma ranged from 17 - 21 h. Phencyclidine and its metabolites can be detected and estimated in plasma or urine by using: radio immunoassays, GC/MS, TLC/enzyme immunoassays or HPLC methods [33]. 131 Tolerance to and Dependence on Phencyclidine: Chronic intake of phencyclidine results in appearance of tolerance to its various effects [40]. As a result the drug users tend to increase their doses to obtain the effects usually obtained by small doses. It should also be noted that start of intake of this drug motivates the user to use the drug continuously. It thus causes psychic dependence. 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