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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.
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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].
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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.
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Ellinwood, E.H., Kilbey, M.M., Castellani, S., and Khoury,
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(1979). J. Ethnopharmacol. 1, 69-78.
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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].
Experiments in animals revealed that amphetamine
craving and addiction could be suppressed by use of prazosin
[39] or by administration of p-methyltyrosine and NaHCO3.
Continuous administration of amphetamine leads to
development of physical dependence and appearance of the
abstinence syndrome on abrupt discontinuation of drug intake.
The withdrawal symptoms usually observed include: Lethargy,
hunger, lasstitude, withdrawal from the society, apathy,
psychasenia, prolonged sleep (20h/day for several days),
increased REM sleep with many dreams. Thus, for treatment of
amphetamine addicts, the drug should be withdrawn gradually
[24, 32].
Amphetamine Antagonists:
Experiments in mammals revealed that the actions of
amphetamine can be antagonised by dopamine receptor
blockers such as chlorproazine, haloperidol [11, 31], pimozide,
(+) sulpride [35]; by alpha-adrenoceptor blockers e.g.
phentolamine, tolazoline; by calcitonin or by LH-RH.
82
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J. Pharmacol. 123, 287-294.
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Life Sci. 38, 1617-1623.
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26. Luttinger, D. and Durivage, M.E. (1986). Pharmacol.
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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.
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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,
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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.
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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
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R.W.
(1967).
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Metab. Dispos. 6, 507-509.
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19. Hirsch, K.S. and Fritz, H.I. (1981). Teratology. 23, 287289.
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Immunophrmacol. 381-392.
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47-51.
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(1980). Phytochemistry. 19, 719-720.
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1169-1170.
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(1977). Neurochem. Res, 2, 265-279.
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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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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. Chronic use of the drug also leads to
development of physical dependence [34, 40].
Indeed
withdrawal symptoms have been observed in phencyclidine
dependent rats after administration of 5-HT S2 receptor
blockers. These included jumping, wet dog shakes and ptosis
[34].
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