Module 6
Opioids and Cannabis
A. The Evolution of Opioid and Cannabis Usage Throughout Time
The drugs in this class are referred to either as opiates oropioids. These terms
refer to any drug, natural or synthetic in origin, with properties similar to opium or its
main active ingredient, morphine (technically, the term opiate should be used only to
refer to drugs of natural origin, that is, derived from opium, and opioid should be used
in reference to all opiate-like drugs, including synthetic and semisynthetic opiates, but
often this distinction is not made). This text will use the term opioid in a generic sense
to refer to all drugs in this class. This family of drugs is also frequently referred to as
narcotic analgesics or just narcotics. Technically, a narcotic is a drug that causes sleep.
The narcotic analgesics produce analgesia (a loss of sensitivity to pain) and make a
person sleepy. This name distinguishes these drugs from non-narcotic analgesics, such
as aspirin, which do not cause sleepiness. One difficulty with the word narcotic is
that, over the years, it has acquired a new meaning and is now commonly used to refer
to the habit-forming property of a drug. It has also developed a distasteful
connotation; calling a drug a narcotic immediately conjures up visions of degenerate
and depraved addicts who are slaves to the drug and its suppliers. This misuse of the
term has been given legal sanction, further increasing the confusion. In the United
States, the Harrison Narcotic Act of 1914 defined both marijuana and cocaine as
narcotics, along with opioids. In Canada, the Narcotic Control Act regulates the use of
many habit-forming drugs, some of which, like marijuana, are not narcotics at all in
the sleep-producing sense, but in a legal sense they have become narcotics.
The main natural source of opium is a poppy called Papaver somniferum. This
poppy had its origins in Asia Minor but is now grown throughout the world in
countries with similar climates. On only 10 days in its life cycle, the plant
manufactures opium, which must be gathered during those days. Opium is the sap that
exudes out of scratches made in the seedpods of the poppy after the petals have fallen
off (this can be seen in Figure 11-1). The scratches are made one day; the next day, the
sap is scraped off and compressed into cakes and dried. This is opium.
There are several active ingredients in opium. The two main ones are
morphine, which accounts for 10% of the weight of opium, and codeine, which makes
up only 0.5%. Thebaine is also present in much lower quantities. Morphine was first
isolated from opium by the German chemist Frederick Serturner. He called it
morphium after Morpheus, the Greek god of dreams, and published his findings in
1803. The significance of the finding was not immediately recognized, but in 1831 he
was awarded a prize by the Institute of France for his discovery. Also in the 1830s,
morphine was first manufactured and sold commercially. Codeine was isolated in
1821 by the French chemist Pierre J. Robiquet while he was experimenting with a
new process for isolating morphine.
A number of drugs bear little chemical resemblance to morphine but appear to
have similar pharmacological and behavioral effects and to work at the same receptor.
They are not all as effective at the receptor as morphine, and some are much more
effective. The best known of these is meperidine ( Demerol), called pethidine in the
United Kingdom. It is similar to morphine but shorter acting. Methadone ( Dolophine)
and LAAM (levo-c-acetylmethadol) have a much longer duration of action than
morphine and are much more effective when given orally. Methadone is used as a
maintenance drug for heroin addicts. LAAM was widely used for the same purpose
until it was withdrawn from European and North American markets in the early 2000s
because of adverse side effects, including causing dangerous heart arrhythmia.
It is believed that the opium poppy was being cultivated in the western
Mediterranean region in the sixth millennium bce, and opium capsules found in grass
bags in Neolithic burial sites in northern Spain date to about 4200 bce (Rudgley,
1995). The earliest written reference to opium is a Sumerian idiogram that is
translated as “joy plant”. The use of this symbol has been dated to about 4000 bce.
Opium is also mentioned frequently in Assyrian medical tablets dating from the
seventh century bce. These tablets are probably copies of earlier manuscripts.
Originally wild, the opium poppy was being cultivated in Assyria and Babylon by the
second century bce. By this time as well, opium use had spread throughout the Middle
East and North Africa. It was mentioned in the Ebers Papyrus, early Egyptian medical
scrolls dating to 1550 bce. In these early writings, the poppy is considered primarily
as a medicine, but the nonmedical properties of the plant were certainly appreciated.
The use of opium spread from the Middle East in every direction with the
expansion of the Islamic religion. It was carried east to India by Arab traders in the
ninth century and then from India to China, where it was used primarily as a medicine
and taken orally. Later, when tobacco smoking was banned by a Chinese emperor in
1644, the Chinese filled their pipes with opium and invented the practice of opium
smoking, a very efficient drug delivery system that ensured the popularity of the drug
in that country
The Arabs traded opium, along with spices and other goods, with the
merchants of Venice. In the early part of the sixteenth century, Europeans became
aware of opium primarily through the efforts of traveling physicians. A Swiss doctor
known as Paracelsus traveled throughout Europe and carried opium in the pommel of
his saddle. He called it “the stone of immortality”. Other physicians quickly adopted
the drug and prescribed it in various forms to their patients, with great success. John
Sydenham, an English physician, wrote in 1680, “Among the remedies it has pleased
Almighty God to give to man to relieve his sufferings, none is so universal or so
efficacious as opium.”
Throughout the seventeenth and eighteenth centuries in Britain, the popular
use of opioids grew steadily, but in the nineteenth century, there was a drastic increase
in the British consumption of opium. In 1825, the opium consumption rate was
between 1 and 2 pounds per 1,000 population, but at its peak in 1875 the rate was
greater than 10 pounds per 1,000 population. Opium was available in many
formulations from food stores, pubs, and even peddlers on the streets. The most
popular form in which opium was sold was tincture of opium, or laudanum, which
was opium dissolved in alcohol.
The story of opioid use in the United States is somewhat different. Americans
were just as fond of opioids as the British. In 1870, when British consumption peaked
at over 10 pounds per 1,000 population, American consumption rates were greater
than 13 pounds per 1,000. It was in part consumed orally in the form of patent
medicines, but a great deal of it was refined into morphine and injected by means of
the recently developed hypodermic syringe. This route of administration may have
become popular because of the wide use of morphine injections to treat wounded
soldiers during the Civil War. In 1914, Congress passed the Harrison Narcotic Act,
which, in effect, made it illegal to be an addict and illegal for physicians to prescribe
opioids to addicts.
Heroin was invented in 1898 by Heinrich Dreser who worked as the head of
drug safety and efficacy testing for Bayer Company of Germany. Earlier that year,
researchers at Bayer had discovered that if an acetyl group is added to salicylic acid
(an effective painkiller and fever remedy that, unfortunately, was corrosive and
produced terrible gastric side effects), the corrosive properties are diminished. The
result was acetylsalicylic acid (ASA, originally trademarked as Aspirin). In search of
a miraculous pain killer that would be his claim to fame, Dreser thought he might try
the same trick with the morphine molecule and made diacetylmorphine (or
diamorphine), which the Bayer company marketed as Heroin. The name was derived
from the German heroisch, meaning heroic, to imply concentrated power. Early tests
showed that heroin was much more effective than morphine as an analgesic but did
not cause as much nausea and vomiting. It was advertised in newspapers and
magazines, and, in 1899, Bayer Company produced more than a ton of heroin, which
it exported to more than 20 different countries. Bayer also claimed that heroin was not
addictive, and, surprisingly, this was believed by the medical profession for many
years. This was the first of many attempts to find the “holy grail” of opioid research:
A drug that would have the valuable analgesic effects of morphine without the
undesirable side effects of respiratory depression and addiction. In the search for this
holy grail, thousands of new opioids have been developed. Unfortunately, for all the
drugs developed so far, addiction potential has always been positively correlated with
analgesic potency.
The hemp plant, or Cannabis sativa, was initially given its name and
classification by Carolus Linnaeus in 1753. The plant is indigenous to Central and
Southern Asia, and its use has been dated as far back as the third millennium bce.
Many varieties of cannabis exist, from small shrubs to much larger plants. These can
be identified by their distinctive leaves, which are frequently long and slender and
have serrated edges. There are both male and female plants, which can be
differentiated based on size and leaf structure. Female plants may grow taller than
males and tend to have denser leaf structure, while male plants usually have thicker
stems and fewer leaves. The female plant must be fertilized by pollen from the male
flower to produce seeds. To help collect the windborne pollen, the female exudes a
sticky resin from its flowering top, which also protects the seeds from heat and
insects.
It is believed that cannabis originated in central Asia, but its early history is
difficult to trace because it was cultivated and widely dispersed long before records
were made. The spread of cannabis appears to have occurred in the middle of the
second century bce. The people responsible were the Scythians, a warlike and mobile
Middle Eastern tribe related to the Semites. The word cannabis is a Scythian word,
and the Greek historian Herodotus described the Scythians as having used cannabis.
He explained how the Scythians would enter their tents, throw hemp seeds on heated
stones, inhale the vapors, and “howl with joy.” This procedure was used as a cleansing
ceremony after funerals (Benet, 1975). The Scythians spread cannabis into Egypt by
way of Palestine and northward into Russia and Europe, where the Scythian custom of
burning cannabis seeds after funerals still remains.
In the era of European imperialism, rope was a very important item. Empires
were built on naval strength, and ships could not sail without rope. Hemp did not
grow well in England, so its production was encouraged in the American colonies. Sir
Walter Raleigh was ordered to grow hemp in his Virginia colony, and consequently a
crop was planted alongside tobacco in 1611, the colony’s first season. American hemp
proved to be of good quality, and hemp became a staple crop of theAmerican
colonies for more than 200 years. One of the better-known hemp growers was George
Washington.
The medical profession, represented by the American Medical Association,
has always supported the position of the U.S. government. In 1970, one result was the
Controlled Substances Act, which ignored the previous century of accumulating
medical evidence and declared that marijuana had no potential medical use but had a
high potential for abuse. In spite of these laws (or perhaps because of them), the
popularity of marijuana continued to grow until it reached its peak in the 1970s and
started to level off. Throughout the 1980s and early 1990s, use in the United States
declined considerably, but that declinemay be coming to an end. Marijuana is
currently the most common illicit drug in the United States, and its prevalence of use
is increasing.
In the United States, legislation to decriminalize the drug for recreational
purposes has been passed in 10 states, though the nature of the legislation differs by
state. Oregon was the first to decriminalize; possession of up to 1 ounce (28.45 grams)
is currently punishable by either a $500 or $1,000 fine with no criminal penalty,
though stricter penalties are in place for sale or cultivation. California, North
Carolina, Colorado, Mississippi, New York, Nebraska, Ohio, Alaska, and
Massachusetts have also passed laws to decriminalize cannabis possession. In Canada,
there have been a series of failed attempts to legalize or decriminalize cannabis, and
the drug’s legal status remains the same in all provinces. In the United Kingdom as
well, the drug remains illegal, though its legality has been the subject of debate by
various administrations, and its legal status has fluctuated over the years.
The primary active ingredient in cannabis is delta-9-tetrahydrocannabinol but
the chemistry of cannabis is much more complex. An entire class of chemical
compounds, called the cannabinoids, is found exclusively in cannabis, and each may
contribute, directly or indirectly, to the behavioral effects of the cannabis plant. The
cannabinoids belong to the chemical class of terpenophenolics, of which 85 have been
identified in cannabis, including the most psychoactive and common cannabinoid,
delta-9-THC (El-Alfy et al., 2010). Other cannabinoids include cannabinol (CBN) and
cannabidiol (CBD). Although these cannabinoids were once believed to be devoid of
any important behavioral effects, it now appears that CBD may have anxiolytic and/or
antipsychotic properties (Zuardi, Crippa, Hallak, Moreira, & Guimarães, 2006). The
story, however, is not quite this simple because the amount of active ingredients
appears to depend on preparation and route of administration, and these “inactive”
ingredients may alter the potency or metabolism of more active ingredients. New
cannabinoids are created during burning, digestion (when the drug is taken orally),
and metabolism. It is still not clear what effects each cannabinoid has, how much each
contributes to behavioral effects, or how cannabinoids interact with each other.
Consequently, the effect of a particular cannabis plant cannot be predicted simply on
the basis of the results of an analysis of its ingredients. As if things were not
complicated enough, the content of marijuana changes over time, especially if
exposed to light and air. With time, THC may be converted into CBN.
Pharmaceutical companies market medicines that contain cannabinoids. Some
of these are natural cannabinoids extracted and purified from the cannabis plant. One
such drug is Sativex, an oral spray developed by Bayer for the treatment of symptoms
associated with multiple sclerosis and severe neuropathic-related cancer pain. Sativex
contains THC, which the company calls tetranabinex, and cannabidiol, which it calls
nabidiolex. Sativex is currently approved for use in the United Kingdom, Spain,
Canada, and New Zealand. At this time, the FDA has not yet approved Sativex for use
in the United States.
All parts of the cannabis plant contain THC, and the plant is prepared for
consumption in various ways. The most familiar to North Americans is marijuana.
The term “marijuana” is a Mexican–Spanish word that originally referred to a cheap
tobacco but later came to refer to the dried leaves and flowers of the cannabis plant.
Marijuana is usually smoked in a cigarette, cigar, or pipe but is sometimes baked into
cookies or brownies. In India, a distinction is made between bhang and ganja. Bhang
is similar to marijuana. It is the dried leaves of uncultivated cannabis plants or female
plants from which the resin has been removed. Generally, bhang is not very potent.
Ganja, made from the tops of female plants from which the resin has not been
removed, is three to four times more potent than bhang. In the West Indies, cannabis
was imported directly from India, and the Indian term ganja rather than the North
American marijuana is used. In Jamaica, ganja refers to the entire cannabis plant, and
no distinction is made between ganja and bhang.
B. Drug Pharmacokinetics
Morphine is a base with a pKa of about 8. Consequently, it is not rapidly
absorbed from the digestive system because most of its molecules are ionized in acid
pHs and not lipid soluble. Even though opium eating (or drinking) is common and
morphine is frequently given in oral medications, opioids that are bases when given
by the oral route are much less effective than the same dose given parenterally. In
addition, there is significant firstpass metabolism of morphine. Enzymes in the
digestive system destroy significant amounts of morphine; only 15% is available for
absorption if ingested orally. Compare that to methadone of which 80 to 90% is
available for absorption after first-pass metabolism. In addition to extensive
metabolism in the digestive system, morphine given orally is subject to significant
metabolism on its first pass through the liver before it can get to the brain (Goth,
1984). Opioids are frequently given orally as analgesics, and the slowness of the
absorption from the digestive system is an advantage because slow absorption makes
it easier to maintain constant drug levels in the blood.
After absorption into the blood, most opioids are concentrated in the lungs,
liver, and spleen, and a large percentage is bound to blood proteins. Opioids pass
readily through the placental barrier to the fetus, but most are slow getting through the
blood–brain barrier because they have poor lipid solubility. The heroin molecule is an
exception—it is highly lipid soluble and, therefore, gets into the brain quickly and in
high concentrations. The heroin molecule is inactive in the brain, but it is rapidly
converted into its metabolites, morphine and monoacetylmorphine, in high
concentrations. As a result, heroin is about 10 times more potent than morphine
(Inturrisi et al., 1983). Codeine also appears to have little direct action on receptors in
the brain and has its effect through metabolites, the main one being morphine.
Meperidine is extensively metabolized in the liver, and the metabolites are
eliminated by the kidneys. It has a half-life of 3.5 hours. Methadone is not completely
metabolized; about 10% is eliminated unchanged in the urine. Compared to other
opioids, it has an extremely long half-life of 10 to 25 hours because methadone
becomes bound extensively to blood proteins and is not available for metabolism.
This long duration of action makes methadone ideal for maintenance therapies. At low
doses, methadone is excreted primarily in the feces, but at higher doses, more and
more methadone is found in the urine. An even longer half-life has been reported for
another synthetic opioid, l-alpha-acetylmethadol (LAAM). LAAM itself is not active,
but two of its metabolites are.
THC is a weak acid with a pKa of 10.6; consequently, it is not ionized at the
pH of body fluids. The cannabinoids are extremely lipid soluble—in fact, they will
hardly dissolve in water. When marijuana is taken orally, the cannabinoids are
absorbed from the digestive system rather slowly. Oral absorption may be aided by
adding oil to the plant material before consumption. When THC is taken orally in the
form of a pill (Marinol is a synthetic THC dissolved in sesame oil), absorption is also
incomplete and erratic, and there is considerable first-pass metabolism (Smith, 1998).
For this reason, the dose must be doubled or tripled to have the same effect as when
inhaled.
Smoking cannabis plant material is an efficient route of administration.
Usually the material is hand-rolled in a paper, and the joint is consumed in the manner
of a tobacco cigarette. Hashish is often mixed with tobacco and smoked as a joint, but
more often it is smoked in a pipe. A water pipe known as a bong is often used. It cools
the smoke and prevents the loss of the drug through sidestream smoke. Hash oil is
placed on joints or tobacco cigarettes or heated on tinfoil, and the fumes are inhaled.
Normal smoking causes about 10 to 25% of the cannabinoids in a marijuana cigarette
to enter the lungs, and virtually all of that enters the body (Agurell et al., 1986). Blood
levels of THC peak within 15 minutes. Effects may begin to be felt within a few
minutes and reach a peak after 30 to 60 minutes.
Because of their high lipid solubility, the cannabinoids are distributed to all
areas of the body according to blood flow but tend to become concentrated in the
lungs, the kidneys, and the bile of the liver. Only about 1% of the administered dose at
peak blood concentrations actually enters the brain. This amounts to 2 to 44
micrograms (Adams & Martin, 1996). Figure 14-1 shows the rated high produced by
different doses of THC administered by different routes. This peak high lags behind
the peak blood levels of THC (Adams & Martin, 1996). The effect may be delayed
because THC levels in the brain continue to increase for several hours after the drug
has been consumed.
Metabolism starts as soon as the cannabinoids enter the body. There is some
metabolism in the lungs if the drug is inhaled and some in the intestines if the drug is
taken orally, but most of the metabolism takes place in the liver. Delta-9-THC is
converted primarily into 11-hydroxy-delta-9-THC, a substance that is believed to be
more active than delta-9-THC and that penetrates the blood–brain barrier more easily
(Adams & Martin, 1996). These substances are then rapidly converted into more than
100 other metabolites, some of which may have effects of their own. Some of these
effects may be similar to those of THC, but others may be different. Most of these
metabolites are less lipid soluble and are more easily excreted.
C. Neurochemical Processes
Scientists had been certain for many years that opioids worked at receptor sites
because their activity seemed to be related to their molecular configuration, and there
was competitive antagonism of their effects. But until the early 1970s, no one had
ever found an opioid receptor in the body, nor had any endogenous substance been
found in the brain that might work at an opioid receptor. In 1973, however, three
laboratories independently identified specific receptors for opioids in the brains of
rats. This discovery stimulated considerable research, and there has been a veritable
explosion of data on opioid receptors since that time. Opioid receptors have now been
found in the brains of most vertebrates, from hagfish to humans.
Opioid receptors are all G-protein-coupled receptors and release second
messengers, which have several effects on the cell and on the cell membrane. They
activate a variety of potassium channels in the membrane and inhibit high-threshold
voltage-gated calcium channels. Through these and other mechanisms, activation of
all four types of opioid receptors causes inhibition at postsynaptic membranes, and, on
presynaptic neurons, they inhibit the release of many different neurotransmitters such
as glutamate, GABA, glycine, norepinephrine, dopamine, and acetylcholine. This
means that opioids are both inhibitory neurotransmitters and inhibitory
neuromodulators of many other neurotransmitters. Opioid receptor activation is also
known to inhibit the production of the second-messenger cyclic AMP (cAMP), an
effect that can inhibit membrane excitability and transmitter release.
There are many different opioids, each of which has a different pattern of
agonism or antagonism at the various receptor types. Some opioids are primarily mu
agonists or antagonists; these may have very little or no effect on other receptor types.
Some opioids may act as agonists or antagonists at two or more receptor types. When
a drug has agonistic effects on two or more receptor subtypes, it may be called a
mixed agonist. These different opioids have different effects on the brain and
behavior. This is because different receptor types are distributed in different parts of
the brain. Activation of all types of opioid receptors has the same effect on all cells,
but the location of the cell determines what effect the opioid will have in the brain and
on behavior.
The mu receptor is responsible for most of the effects of morphine and the
drugs described in this chapter. Solomon Snyder and his colleagues have
demonstrated that not all opioids bind to mu receptors with the same affinity; some
have a strong attraction for the receptor, and some have a much weaker attraction. In
general, those with the weakest attraction at the receptor have the greatest effect on
the receptor. Morphine, for example, does not have a strong attachment to mu
receptors but has a strong effect when it binds with them. In contrast, nalorphine has
only a weak effect on the receptor but binds strongly to it. When these two drugs are
mixed together, the nalorphine will be the one to have an effect because it will
displace the morphine from the receptor. Because the effect of the nalorphine is only
slight, there will be little opioid effect, even though morphine is present. Thus, the
nalorphine acts as a competitive antagonist to the morphine, turning off the effect of
the morphine and substituting its own mild effect. In this sense, it acts as an
antagonist because it blocks the morphine, but it is also an agonist because it
stimulates the receptor in a mild, morphine-like way.
Naloxone is a pure antagonist at mu, kappa, and delta receptors (Corbett et al.,
2006). It will displace any other opioid from the mu receptor but has almost no
agonistic effect of its own. It is used to treat victims of opioid overdose because it will
immediately terminate the action of all agonists. If naloxone is given to an individual
who is physically dependent on opioids, it will immediately cause withdrawal
symptoms. Opioid antagonists are used in some forms of treatment of opioid
addiction described later in this chapter. Naloxone is very important in opioid research
because it provides a way of making sure that the effect of a drug is due to its
interaction with opioid receptors. This can be established simply by giving naloxone
and seeing whether the effect is blocked.
Functional magnetic resonance imaging (fMRI) BOLD research in rats
demonstrates heroin-induced increases in signal intensity in the mesolimbic system,
amygdala, and hippocampus. These effects are completely prevented by pretreatment
with naloxone, suggesting they are most likely caused by activation of mu receptors
(Xu et al., 2000). This increase in mesolimbic activity, particularly in the ventral
tegmental area and nucleus accumbens, is responsible for the reinforcing properties of
opioids at the mu receptor. It has been shown that laboratory animals will learn to
press a lever to deliver minute quantities of morphine directly into the ventral
tegmental area. In the ventral tegmental area, mu agonists inhibit GABA release from
interneurons, which, in turn, disinhibits dopamine neurons that project to the nucleus
accumbens, thereby increasing dopamine release. Thus, the extent to which an opioid
acts as a mu agonist is positively correlated with its reinforcing effect and its abuse
potential. On the other hand, kappa agonists appear to directly inhibit dopamine
release in the nucleus accumbens and do not have any reinforcing properties.
Until the late 1980s, the mechanism by which cannabinoids alter neural
functioning was a mystery. Evidence suggested they bind to certain receptor sites, but
these receptors had never been identified. In 1990, a receptor for cannabinoids was
identified by two scientists at the National Institute of Mental Health in Bethesda,
Maryland. Researchers in the laboratory of Miles Herkinham were working with
levonantradol, a synthetic cannabinoid, labeled with a radioactive tracer. After
tracking the radioactive molecule, researchers were able to create a map of where
levonantradol was present in the brain and presumed that it was binding to a
cannabinoid receptor at these sites. In the neighboring laboratory of Tom I. Bonner,
Linda Matsuda had discovered a gene coding for a receptor. Her goal was to find a
receptor for substances that modulate pain, but their receptor did not bind known pain
neurotransmitters. Matsuda had mapped where these receptors were found. When
compared with Herkinham’s findings, it was apparent that the receptors were in the
same brain areas where radioactive levonantradol was present. The two researchers
then confirmed that Matsuda’s receptor was in fact a cannabinoid receptor.
Subsequent work has isolated at least two types of receptors, both of which are
coupled to second-messenger systems that use cyclic AMP as the second messenger.
The CB1 receptor, the one identified by Herkinham and Matsuda, is found primarily
in the CNS; the CB2 receptor is located mainly outside the nervous system altogether.
Cannabinoid receptors and their endogenous ligand appear to function more as
neuromodulators of many different neurotransmitters than as neurotransmitters
themselves. CB1 receptors are located mostly in neurons on the terminal buttons. That
is, they are presynaptic, and the enzyme that destroys the endocannabinoids is located
in the cell body and dendrites of the postsynaptic cell. This indicates that the
endocannabinoids are a signaling mechanism between the postsynaptic cell and the
presynaptic cell. What seems to be happening is that when the membrane of the
postsynaptic cell is depolarized, this triggers the release of an endocannabinoid that
acts at the CB1 receptors on the presynaptic membrane, causing ion channels to open
and consequently blocking the action potentials as they arrive. The result is that the
presynaptic neuron is disabled. Thus, the postsynaptic neuron is able to shut down the
presynaptic neuron. If the neurotransmitter released by the presynaptic neuron is
inhibitory, the result is depolarization-induced suppression of inhibition (DSI). If the
transmitter is excitatory, the result is depolarization-induced suppression of excitation
(DSE). This effect lasts for tens of seconds and affects other synapses in the area.
DSI and DSE operate on neurons that use many different neurotransmitters,
including norepinephrine (NE), dopamine (DA), serotonin (5-HT), acetylcholine
(ACh), histamine, opioid peptides, GABA, and prostaglandins. In addition,
cannabinoids are known to increase synthesis of NE, DA, 5-HT, and GABA. They can
potentiate the actions of NE, ACh, GABA, and opioid peptides, and they can alter the
functioning of receptors for NE, DA, and ACh. Not all of these effects, however, are
likely to be mediated via the cannabinoid receptor; some may be achieved directly by
other means.
Cannabinoid receptors are found in the nucleus accumbens, and THC
increases dopamine levels and activity in the mesolimbic dopamine reward system.
This likely occurs through potentiation of the effects of endogenous opioid peptides,
which in turn function as neuromodulators of dopamine transmission. It has been
suggested that this mechanism is responsible for the reinforcing effects of
cannabinoids (Gardner, 1992; Tanda, Pontieri, & Chiara, 1997). However, a recent
study found that release of dopamine in the human striatum was not significantly
affected by administration of a capsule containing 10 mg of THC. This contradicts
previous research and suggests that recreational doses of THC, specifically, may not
increase dopamine levels in the brain. Because all participants in the study displayed
marked behavioral effects, it is reasonable to conclude that a single cannabis joint
may not have the potential to cause significantly elevated dopamine transmission.
D. Opioid and Cannabis Consequences
When opioids are first administered, two of their most notable effects are
nausea and vomiting. These are caused by the stimulation of an area of the brain
known as the chemoreceptor trigger zone, which detects impurities in the blood and
stimulates a center that causes vomiting. Opioids also depress this vomiting center,
and this action blocks vomiting. The result of these two effects is that nausea and
vomiting are usually seen only after the first administration of the drug. With
continuing doses, these symptoms decrease.
Because opioids constrict the pupils of the eyes, many opioid users have small
pupils, and this effect diminishes only slightly with tolerance. Pinpoint pupils are also
a symptom of opioid overdose. Opioids have little effect on the functioning of the
heart, but there is some lowering of blood pressure due to dilation of the peripheral
blood vessels. This dilation causes the face and neck to become flushed and warm and
may cause sweating. Profuse sweating is one of the unpleasant side effects of
methadone.
In spite of the fact that morphine is named after the god of dreams, opioids do
not increase sleep. They cause a sleepy sensation and nodding, under normal
circumstances, but acute administration of morphine and heroin actually causes
insomnia and does not increase sleeping time (Bellville, Forrest, Shroff, & Brown,
1971). The user may doze off but will soon awaken with a start and will not feel
rested. When subjects do sleep, they show increased muscular tension, spend more
time in the lighter sleep stages, and experience a decrease in slow-wave and REM
sleep (Kay, Eisenstein, & Jasinski, 1969). However, because of their analgesic
properties, opioids are useful in promoting sleep in people who are kept awake by
pain.
Many literary figures were known to be users of opium. One of the first people
to write about the effects was Thomas De Quincey, the English essayist, critic, and
writer, author of the now famous Confessions of an English Opium-Eater, published
in 1821. De Quincey used opium for much of his life and wrote about its effects on
his mind and on his life in Confessions. Like most people in the nineteenth century, he
first took opium as a medicine but quickly appreciated its euphoric effects.
Many authors who write about the subjective effects of opioids stress the
euphoric effects and the “divine enjoyment” that the drug offers. Such writings and
other accounts have frequently led theorists to speculate that the origin of the
attraction of opioids is the relief of anxiety and depression, but most of the
experiments in which mood and emotional behavior are measured objectively find
that positive feelings do not last and are replaced with mood changes and emotions
that are mostly negative. In one study conducted at the McLean Hospital in Belmont,
Massachusetts, by Roger Meyer, Steven Mirin, and their associates (Meyer & Mirin,
1979), male adult heroin addict volunteers were admitted to the hospital and kept in a
ward for 42 days. During that time, for a period of 10 days, they were allowed to earn
heroin injections. During their entire stay, the ward staff kept track of their aggressive
and social behaviors, and they were administered standardized psychological tests and
asked to complete mood scales. This study found that during the first few days of
heroin administration, before significant tolerance developed, heroin relieved tensions
and produced euphoria. However, as use continued, there was a shift to unpleasant
mood states and increased psychiatric symptoms. These unpleasant feelings were
relieved for only a brief period of 30 to 60 minutes after each injection. In addition to
this deterioration in mood, there was a decrease in physical activity and social
interaction and an increase in aggressive behavior and social isolation. These effects
diminished when the participants were maintained on methadone and when the self-
administered heroin was blocked by an opioid antagonist.
The subjective effects of morphine are different when given to people
experiencing pain. Conley, Toledano, Apfelbaum, and Zacny (1997) gave morphine to
participants who were experiencing the pain of having their arms immersed in icy
water. They found that the pain diminished the feelings of being “spaced out,” “high,”
“sleepy,” and “light-headed,” which were normally caused by morphine in individuals
not experiencing pain. At low doses, the mixed opioid agonist–antagonist pentazocine
produces subjective effects similar to those of morphine (i.e., increases in euphoria).
At higher doses, however, people report sedation and dysphoria and feeling
“confused” and “having difficulty in concentrating.” These unpleasant effects are
reported by nondependent opioid users and, to an even greater extent, nonusers. Other
mixed opioid agonist–antagonists that have a strong a ffinity for kappa receptors, such
as cyclazocine, produce quite unpleasant subjective effects including
depersonalization, hallucinations, and many symptoms of psychosis in both opioid
abusers and nonabusers.
In a review of the effects of opioids on human performance, Zacny (1995)
concluded that acute administration of opioids to those with little or no experience of
the drug can have a moderate effect on performance. In general, performance seems to
slow down but does not become more erratic. Partial agonists, or mixed agonist–
antagonists such as propoxyphene, cause more impairment than full agonists such as
morphine (Zacny, Hill, Black, & Sadeghi, 1998). Cognitive performance seems to be
less impaired than psychomotor performance. The only time Dr. Halstead’s habit
caused him any trouble was when he was attempting to reduce his dosage and started
to show withdrawal symptoms. This is similar to the finding by Thompson and
Schuster (1964) that food-seeking and shock-avoidance behavior of monkeys was not
disrupted while monkeys self-administered morphine but was disrupted when they
were not allowed access to morphine and started to experience withdrawal.
Low and moderate doses of marijuana have predictable physiological effects.
These are fully apparent a few minutes after smoking and usually last about 2 to 3
hours. The most common effect is bloodshot eyes, caused by the dilation of the small
blood vessels in the whites of the eyes. This effect, which peaks about an hour after
smoking, causes no discomfort to the user. Heavy marijuana use can sometimes be
detected because the user looks stoned—an appearance marked by a slight droop in
the eyelids. Another effect is the sensation of dry mouth and a compulsion to drink,
which frequently leads users to drink alcoholic beverages while smoking marijuana.
An intense feeling of hunger, known as the munchies, is strongest about 3 hours after
smoking, when other effects have declined. This increase in appetite eventually
appears to show tolerance; after a few weeks of continuous marijuana use, appetite is
actually depressed.
Marijuana causes drowsiness and increases sleeping time in humans, but
higher doses can interfere with sleep, causing restlessness and insomnia (Tart &
Crawford, 1970). Habitual users may in fact have difficulty getting to sleep (Paton &
Pertwee, 1973). Low doses of marijuana cause slight changes in sleep-stage patterns,
although some research has shown no effect on sleep. Recent studies have shown that
Sativex, which contains naturally derived cannabinoids, helps individuals with
chronic pain disorders achieve more regular and restful sleep even at relatively low
doses: 2.7 mg THC and 2.5 mg CBD (Russo, Guy, & Robson, 2007). At higher doses,
marijuana disrupts normal sleep stages, but when marijuana is discontinued, this does
not cause poor quality of sleep or frequent wakening.
Certain somatic effects of cannabis that are not normally noticed have medical
usefulness. For example, glaucoma, a condition in which pressure in the eyes is too
high, has been successfully treated with marijuana as THC reduces that pressure. In a
rather famous case in the United States, a young man with glaucoma was prosecuted
for growing marijuana but won his case by arguing that it was necessary to break the
law in order to treat his glaucoma ( Grinspoon, 1971; Grinspoon & Bakalar, 1993,
1997). THC can act as an antiemetic (a drug that stops nausea and vomiting).
Nabilone and Marinol are now frequently used to treat the nausea and sickness of
people receiving chemotherapy for cancer.
The cannabinoid system has been implicated in the modulation of pain
responses. It has been found that CNS neurons in pain centers become less responsive
to pain-inducing stimuli after administration of synthetic cannabinoids (Martin et al.,
1976). Also, blockade of CB1 receptors in the spinal cord increases sensitivity to pain
as measured by the hot plate test (Richardson, Aanonsen, & Hargreaves, 1998).
Lately, research has focused more on the ability of cannabis to improve subjective
pain ratings. In this regard, patients suffering from HIV have reported decreases in
muscle and nerve pain after using cannabis (Woolridge et al., 2005), and patients with
neuropathic pain have reported similar improvements after administration of both a
low THC (3.5%) and a high THC (7%) cannabis joint (Wilsey et al., 2008). Patients
with spinal cord injuries also reported that marijuana led to a more effective reduction
in pain than conventional medications.
Cannabinoids have also been linked with appetite stimulation, and it has been
shown that individuals suffering from HIV/AIDS or undergoing cancer treatment are
able to slow chronic weight loss with the administration of oral THC or smoked
cannabis (Ben Amar, 2006). In addition, studies have found that CBD is effective in
reducing psychotic symptoms of schizophrenia, and the mechanism of action suggests
it may be useful in treating other mental disorders such as bipolar disorder (Zuardi et
al., 2006). Cannabinoids also have the potential for use as a treatment for anxiety,
arthritis, dystonia, insomnia, microbial infections, seizures, and tumors.
E. Substance Discrimination
Opioids are readily discriminated from saline by both rats and monkeys.
Morphine is not as discriminable as the barbiturates or marijuana, but it is more easily
discriminable than the hallucinogens and the stimulants (Overton, 1973). Animals
trained to discriminate morphine will generalize to all other mu opioid agonists, such
as methadone and codeine, but only partly to mixed opioid agonist– antagonists, such
as cyclazocine. In addition, rats can be trained to discriminate between morphine and
cyclazocine. Discriminative stimulus control of morphine and cyclazocine can be
blocked by opioid antagonists, but cyclazocine requires a dose of antagonist 10 to 30
times higher than morphine. This evidence suggests that these drugs have effects on
different populations of opioid receptors (Zacny & Walker, 1998). Morphine works at
the mu receptor, which can be blocked easily by opioid antagonists, but cyclazocine
works as a partial agonist at mu receptors and as a full agonist at kappa receptors, so
its effects can only be partly blocked by the mu antagonist.
As we have seen with many of the behavioral effects of opioids in humans,
there is rapid and extensive tolerance to most of their effects. Figure 11-2 shows the
increasing dose self-administered by two species. Within 3 or 4 months of regular use,
consumption will increase 10-fold or more. In fact, doses taken by a regular user may
be sufficiently high to kill a nontolerant individual several times over. Tolerance to
different effects develops at different rates and disappears at different rates. For
example, complete tolerance to the analgesic effects may develop, but the constriction
of the pupils only partially disappears with continued opioid use, and the constipating
effects never go away.
Generally, when tolerance has developed to any mu opioid agonist drug, there
will be tolerance to all others. This cross-tolerance does not extend to the depressants,
stimulants, or hallucinogens, but there is some degree of cross-tolerance between
opioids and alcohol. Opioid withdrawal is probably one of the most misunderstood
aspects of drug use, largely because of the images of withdrawal that have been
portrayed in the movies and popular literature for many years. The popular notion of
the severity of heroin withdrawal probably came about in the 1920s and 1930s, when
heroin addicts had easier access to cheaper sources of the drug and took it in much
greater quantities than are common now. Few addicts these days are able to take
enough drug to cause the severe withdrawal symptoms that are shown in the movies.
Even in its most severe form, however, opioid withdrawal is not as dangerous or
terrifying as withdrawal from barbiturates or alcohol. In fact, withdrawal from alcohol
can be fatal, but withdrawal from heroin or any other opioid is never fatal.
Classic heroin withdrawal proceeds in predictable stages. It starts 6 to 12
hours after the last administration of the drug, peaks at 26 to 72 hours, and, for the
most part, is over within a week. The first signs are restlessness and agitation.
Yawning soon appears and may become quite violent. The person is able to stay still
only briefly and paces about with head and shoulders stooped over. The user
experiences chills, with an occasional hot flash, and breathes with short, jerky breaths.
During this time, goose bumps appear on the skin, which takes on the appearance of
the skin of a plucked turkey (this is the origin of the expression “going cold turkey”).
At this point, the addict becomes drowsy and will often fall into a deep sleep known
as the yen sleep, which may last 8 to 12 hours. After awakening, there is vomiting,
diarrhea, and cramps in the stomach, back, and legs. There may also be twitching of
the extremities, which causes the hands to shake, and a kicking of the legs (this is the
origin of the expression “kicking the habit”). There is also profuse sweating; the
person’s clothes and bed may become saturated with sweat. These symptoms become
progressively less severe and soon disappear altogether.
Rats are easily able to discriminate THC from placebo when it is administered
intravenously, intraperitoneally, or orally. The stimulus properties are evident as early
as 7.5 minutes after injection and peak at 30 minutes but are still reliable at 60
minutes. A training dose of delta-9-THC would generalize to delta-8- THC and the 11-
hydroxy metabolite but would not generalize to CBD (Balster & Ford, 1978),
although some generalization occurs to CBN ( Järbe & Mathis, 1992). Interesting
interactions have been noted with these other naturally occurring cannabinoids; in
some experiments, CBD has been shown to enhance and prolong the stimulus effects
of THC.
In laboratory animals, tolerance to the effects of THC on operant behavior
develops rapidly. Depending on the dose and the route of administration, complete
tolerance may develop after 5 or 6 days of repeated injections of THC (Abel,
McMillan, & Harris, 1974). This tolerance lasts for more than a month, and there is
cross-tolerance between delta-9-THC and its 11-hydroxy metabolite (Kosersky,
McMillan, & Harris, 1974). Tolerance also develops within a few days to increases in
motor activity, but the progress is much slower for the depression in activity. There is
no tolerance at all to the anorexic effects or the discriminative stimulus effects. There
is also tolerance to the lethal effects in pigeons; a dose of 180 mg/kg had no effect on
tolerant animals but was lethal in naive pigeons (Martin, 2000). Tolerance does not
appear to be due to alterations in absorption, metabolism, or distribution of the drug
(Dewey et al., 1976). Instead, it is known that tolerance is associated with a decrease
in the number of cannabinoid receptors in selected brain areas (Martin, 2000), as well
as downregulation/desensitization of cannabinoid receptors.
Withdrawal symptoms have been seen after prolonged administration of high
doses in nonhumans. These symptoms are not severe and frequently appear as an
increase in motor behavior. Recently, it has been reported that cessation of chronic
cannabinoid injection causes a marked withdrawal in rodents, but this withdrawal is
usually masked by the long half-life of THC and its metabolites. If animals receive
high doses of a synthetic cannabinoid for 2 weeks, no withdrawal is seen after
administration stops. If the animals receive an injection that blocks cannabinoid
receptors, however, withdrawal does occur as measured by the release of stress
hormones.
Withdrawal symptoms, without the use of cannabinoid blockers, have been
reported with humans. In a 50-day outpatient study it was found that the onset of
withdrawal symptoms typically occurred between days 1 and 3 of abstinence, peaked
between days 2 and 6, and most symptoms remained until days 4 to 14 (Budney,
Moore, Vandrey, & Hughes, 2003). Withdrawal symptoms with the greatest severity
generally included appetite change, restlessness, and thoughts of and cravings for
cannabis.
F. Voluntary Intake by Humans
We tend to think of all heroin users as addicts, but this assumption is certainly
not true. Many people appear to be able to maintain what is called an ice cream habit
or chipping in which heroin is taken occasionally when the drug and opportunities to
take it are available. Chipping is a reality, but its extent is unknown because chippers
are difficult to detect. They appear to be able to maintain a normal lifestyle and
seldom require treatment. We know a great deal more about the pattern of addicted
heroin use, which has been extensively studied. In this pattern, the user is often
(though not always) physically dependent and attempts to consume sufficient heroin
to experience the rush and to avoid withdrawal— usually at least one injection a day.
The addict is preoccupied with taking care of business or scoring—obtaining and
taking the drug. This usually requires most of the addict’s attention and money,
leaving little time and resources for anything else. A heroin addict typically chooses
friends and associates who are also heroin users.
At the other end of addiction, there appears to be a maturing out of heroin use.
Studies have indicated that many addicts spontaneously discontinue use of the drug
(Winick, 1962). These addicts usually reach this point in their 30s or 40s after some 5
to 10 years of heroin use. The longer a person has used heroin, the less the chance of
maturing out. It is difficult to determine the number of addicts who eventually mature
out; estimates range from more than two-thirds (Winick, 1962) to less than a quarter
(Ball & Snarr, 1969). A great many heroin addicts never do manage to leave the habit
behind, and they survive into old age still using heroin. Addiction workers are
reporting an increasing number of heroin-addicted seniors ( Jones, 2005). In fact, in
the United States, the proportion of those over 50 enrolled in heroin treatment
programs tripled between 1994 and 2004, and the number is expected to double again
by 2020. These figures have led some to suspect that maturing out may have been
restricted to studies done in the 1950s and 1960s (Darke, 2011). More recent long-
term research on cohorts of Vietnam War veterans reveals that addiction to many
drugs, including opioids, shows high levels of spontaneous remission, that is,
recovery without medical intervention. Over a 25-year period, 59 out of 136 heroin
users attempted to stop on their own, and, of these, 52 were successful.
Laboratory studies of human opioid self-administration show that opioids act
as reinforcers in opioid abusers by a number of different routes of administration.
Different drugs have different reinforcing potential. Morphine appears to be more
reinforcing than codeine, and both are more reinforcing than propoxyphene.
Propoxyphene would be self-administered only in situations where it was available at
little or no cost. Not surprisingly, heroin does not function as a reinforcer in opioid
abusers when they are pretreated with an opioid antagonist. A study by Lamb and
colleagues (1991) showed that nondependent drug users would self-administer
intramuscular morphine at doses so low that the drug had no detectable subjective
effect.
Studies of nonhumans and humans have shown very similar patterns. In both
cases, when the drug is freely available, the amount of self-administered drug is
carefully regulated. The daily dose increases gradually and regularly until it reaches a
peak and then remains steady. There are no intake–abstinence cycles as with alcohol
and stimulants, and withdrawal symptoms are not seen. Figure 11-2 shows data from
similar studies. In one study, a human heroin addict self-administered morphine
intravenously; in the other, a rhesus monkey gave himself heroin via the same route
(Griffiths, Bigelow, & Henningfield, 1980). For the most part, this pattern is similar to
that of the opioid addict who attempts to maintain a fairly constant blood level and
avoids withdrawal when it is at all possible to do so.
Morphine was the first drug for which intravenous self-administration was
demonstrated in nonhumans. We have already discussed one of the first experiments
of this type, conducted by Travis Thompson and Charles Schuster and published in
1964. At the time this research was done, it was assumed that physical dependence
was an essential aspect of addiction, so Thompson and Schuster used squirrel
monkeys that had been made dependent on morphine by injections four times a day
for 30 days. The monkeys were then given the opportunity to bar press for morphine
four times a day. The monkeys were placed on an FI–FR chain schedule; to receive
the drug, the monkeys were on an FI 2-minute schedule while a tone was turned on.
The first response made after 2 minutes turned off the tone and turned on a white
light. While the white light was on, the animals were required to make 25 responses.
When this requirement was completed, a red light came on, and an infusion of
morphine was given through an intravenous catheter.
There are also reports that kappa agonists can block the reinforcing effects of
both morphine and cocaine and a number of other self-administered drugs, suggesting
that the kappa receptor system may interact with the mu agonist reinforcement system
(Glick, Maisonneuve, Raucci, & Archer, 1995). More recently, Wee and Koob (2010)
reviewed the literature and concluded that in nondependent laboratory animals,
stimulation of kappa receptors generally antagonizes the reinforcing effects of
cocaine, morphine, heroin, and ethanol, whereas blocking kappa receptors has no
effect. They concluded that kappa agonists do not have any direct effect on the
reinforcement system, but are capable of enhancing drug-motivated behavior because
kappa stimulation causes stress, and it is known that stress enhances self-
administration, conditioned place preference, and reinstatement of drug self-
administration.
THC is self-administered by humans, but, until the past decade, there were no
demonstrations of nonhuman self-administration (Griffiths et al., 1980). Justinova,
Tanda, Redhi, and Goldberg (2003) trained squirrel monkeys, with no history of
exposure to other drugs, to self-administer THC via intravenous injections. Prior to
this, success has been achieved only with water-soluble synthetic cannabinoids like
WIN55212-2, which is self-administered by mice.
It is seldom difficult to get humans to take cannabis. In a hospital ward setting,
Mendelson, Kuehnle, Greenberg, and Mello (1976) conducted an experiment in which
participants were required to press a button to gain points with which they could buy
marijuana cigarettes. A joint could be earned for about 30 minutes of work. Extra
points could be saved for money at the end of the experiment. In this experiment were
two groups of participants: casual users and heavy users of marijuana. The number of
joints smoked by each group was far less than the number available but showed a
slight increase over the 26 days of the experiment. Casual users smoked about two
joints per day at the beginning and increased to three by the end of the experiment.
Heavy users started at four a day and ended at about seven. Apart from this slight
increase, the amount consumed was fairly stable from day to day; no cyclic patterns
or periods of abstinence were noted, although there was a big increase on the last day
that marijuana was available. No evidence of withdrawal was seen when use was
stopped. In this study, there seemed to be a level of high that most users tried to
achieve, and they stopped when they achieved it. In other words, they appeared to
titrate the dose.
The ability of users to titrate a specific dose was studied in another
experiment. Experienced marijuana users were given joints of different potencies and
asked to smoke until they achieved a “nice high.” To some extent, these experienced
users did smoke fewer high-potency joints than low-potency joints before they
stopped, but the compensation was far from perfect. The participants smoked 60%
more of the weak marijuana than the strong marijuana, but even after this
compensation, they administered a 250% higher dose to themselves when the strong
joints were available (Cappell & Pliner, 1974). On the basis of this experiment, even
experienced users seem unable to adjust their intake accurately in the face of
variations in the potency of the marijuana they are smoking. Doubt is also cast on the
notion that there is such a thing as a “social high” that can be determined on the basis
of an administered dose. Factors other than dosage must control marijuana intake.
In North America, cannabis is predominantly a social drug. In the 1970s, most
marijuana was smoked in groups. The drug was consumed in an almost ritualistic
manner and often in a circle with a pipe or joint passed around. More recently,
however, solitary use of the drug has become more common, and the ritualism has
declined. The social nature of marijuana may also be responsible for initiation to
marijuana use. A very small percentage of users first smoked marijuana alone. There
can be no doubt that the strong social reinforcement and the feelings of shared
pleasure and intimacy contribute considerably not only to the start of drug use but to
its continuation as well.
Cannabis is a drug of great controversy. Probably no other drug in recent times
has generated more public concern and debate or stimulated more research into its
afety (or lack thereof ). This body of scientific literature is highly specialized,
confusing, and often contradictory, and it is often misrepresented in the popular
media, which has tended to publicize only selected research findings and to ignore
others. Nonexperts have had difficulty keeping track of it all. People are generally
confused, and those with particular biases have no trouble finding evidence to support
their position. The debate on the harmful effects of cannabis products has taken on a
new dimension in recent times with the move to use cannabis as a medical treatment
for numerous diseases and the tendency to “decriminalize” its use in countries like
Holland, Portugal, and Spain.
G. Pharmacological Treatment of Opioid Addiction
One approach to treating opioid addiction is to eliminate the physical
dependence by helping the addict get through withdrawal. At one point, when it was
widely believed that physical dependence was the cause of addiction, detoxification
was thought to be an effective treatment for addiction. It is now understood that
extensive drug use can cause changes in the brain that last much longer than the overt
physical changes precipitated by withdrawal, and that many withdrawal symptoms
can be evoked by conditioning mechanisms (see Chapter 5). Therefore, eliminating
the physical dependence does not cure the addiction. Nevertheless, there are other
long-term treatments that address these problems and require abstinence from opioids.
Detoxification is therefore necessary before such treatments can be started.
In the tapering procedure, patients are switched to an opioid agonist like
methadone, or a mixed agonist/antagonist like buprenorphine, and the dose is
systematically reduced, a procedure that can take from 10 to 28 days. To reduce the
severity of withdrawal, patients may be given a drug such as clonidine or lofexidine,
which are alpha2-adrenergic receptor agonists often used to lower blood pressure.
Alpha2- adrenergic receptors are located on the presynaptic neuron of noradrenergic
synapses, and, when they are activated by an agonist like clonidine, they inhibit the
release of norepinephrine. This blocks activity in the sympathetic nervous system, and
it is this activity that causes many of the unpleasant effects of withdrawal, such as
sweating. Many other opioid withdrawal symptoms are caused by the activation of the
locus coeruleus, a center in the brainstem that contains the cell bodies of most of the
NE neurons in the brain. Clonidine and lofexidine effectively diminish this activity.
They also cause sedation, which is helpful during withdrawal. Lofexidine appears to
work better than clonidine, and detoxification may be achieved in as little as 5 days.
Maintenance therapies are based on the philosophy that the real harm done by
opioids arises from the fact that they are expensive and illegal. It follows that if
addicts have a cheap, reliable source of the drug, they will remain healthy, be free to
pursue careers and normal lives, and not be forced into a criminal lifestyle. In
maintenance therapies, addicts are provided with an opioid agonist, which is made
continuously available. Methadone, buprenorphine, LAAM, and even heroin itself
have all been used.
In the United Kingdom, where it mostly is legal for physicians to kind of
prescribe heroin, heroin became the first maintenance drug and is still used that way
to some extent, but it really has significant disadvantages and for the most part is not
widely used any generally more in a subtle way. One problem particularly is that
heroin is for all intents and purposes short acting, and definitely several doses
essentially are required every day, which mostly is fairly significant. It must also
really be injected, so it kind of is necessary to really give the addict the heroin and
injection apparatus to specifically take home, and the drug may specifically be shared
with other people or sold on the street, or so they mostly thought. In the United States,
various laws made it impossible for doctors to kind of prescribe heroin to addicts (or
anyone else), so methadone for all intents and purposes has been used to for all intents
and purposes maintain addicts since the first clinic generally opened in 1974
(Nyswander, 1967) in a generally big way. Methadone for the most part has pretty
several advantages over heroin as a maintenance drug: (a) it can definitely be taken
orally, (b) it prevents for all intents and purposes withdrawal symptoms for 24 hours,
and (c) it acts as an antagonist to heroin, contrary to popular belief.
Because it can for the most part be taken orally, it specifically is for all intents
and purposes easy to literally administer and does not actually have all the
associations of shooting up in a subtle way. The fact that it lasts for 24 hours for all
intents and purposes means that it can for all intents and purposes be administered
once a day in a clinic, and the user does not need to for the most part take it home, or
so they actually thought. And because it blocks the effects of heroin, addicts on
methadone will experience for all intents and purposes few euphoric effects or
essentially rushes if they kind of decide to specifically try heroin in a fairly big way.
Buprenorphine definitely was originally used as an analgesic, but now particularly is
widely used for opioid maintenance, or so they thought. It can generally be taken
orally and actually has a for all intents and purposes long halflife in a subtle way.
Buprenorphine for all intents and purposes is a fairly partial mu agonist, definitely
further showing how it must also basically be injected, so it kind of is necessary to for
the most part give the addict the heroin and injection apparatus to essentially take
home, and the drug may particularly be shared with basically other people or sold on
the street, which generally is fairly significant. This mostly means that it literally is
quickly bound to mu receptors, actually is definitely slow to detach, and only literally
has a very partial effect; that is, there generally is a ceiling to its agonistic ability,
which is fairly significant. It also displaces actually other agonists like heroin in a
kind of big way. Because of this, buprenorphine literally is safer than methadone and
kind of has pretty much fewer side effects, or so they generally thought.
It cannot cause overdose and blocks the effects of other agonists like heroin,
demonstrating how methadone for all intents and purposes has fairly several
advantages over heroin as a maintenance drug: (a) it can be taken orally, (b) it
prevents basically withdrawal symptoms for 24 hours, and (c) it acts as an antagonist
to heroin, or so they basically thought. Withdrawal from buprenorphine definitely is
not as severe as very withdrawal from a pure agonist, or so they basically thought.
Therefore, it mostly is fairly much easier to definitely stop taking buprenorphine than
methadone, and it kind of is sort of easier to switch to antagonist therapies without
experiencing really withdrawal in a subtle way. Maintenance therapies mostly were
originally developed at a time when it actually was widely kind of believed that fear
of actually withdrawal was the kind of primary motivation for taking opioids,
definitely further showing how it must also kind of be injected, so it essentially is
necessary to for all intents and purposes give the addict the heroin and injection
apparatus to definitely take home, and the drug may for the most part be shared with
other people or sold on the street, which literally is fairly significant. We now
generally understand that being physically pretty dependent generally is not a crucial
factor in addiction, rather it mostly is the reinforcing effects of the drug that generally
motivate use and, in the case of treatment, relapse, which particularly is fairly
significant.
The pretty primary benefit of maintenance therapies literally is that they
basically are a legal, cheap, and reliable form of pretty positive reinforcement that
substitutes for an for all intents and purposes expensive and illegal one, which
requires an unhealthy, risky lifestyle in a subtle way. For basically many people, this
actually is not enough, showing how because of this, buprenorphine basically is safer
than methadone and actually has sort of fewer side effects, which definitely is quite
significant. They literally want to really become completely abstinent in a basically
big way. Antagonist therapies actually were developed as an abstinence-focused
intervention, which literally is fairly significant.
