Chapter 6
Stimulants
Stimulants
 Stimulants are substances can
enhance a person’s mental and
physical state
 Illicit stimulants:
 Examples: cocaine and amphetamine
 Licit stimulants:
 Examples: caffeine and nicotine
Stimulants
 For Discussion:
 What is your daily stimulant
use (Type and Amount)
 Is your use about the physical
and mental benefits of the
stimulants for recreational
purposes , or do you use them
for some therapeutic effect?
Cocaine History
Coca
 Coca has been a staple dietary supplement and
cornerstone to Ancient Andean culture (Inca 5000-2500
BC) throughout much of its history. Unprocessed coca
leaves are commonly used in the Andean countries to
make an herbal tea with mild stimulant effects similar to
strong coffee, but is best known in most of the world for
the stimulant drug cocaine that is chemically extracted
from its new fresh leaf tips in a similar fashion to tea
bush harvesting.
However, the alkaloid content of coca leaves is low:
between .25% and .77%, and production of cocaine
from coca requires complex chemical processes. The
Alkaloid concentration increases the extraction of
cocaine.
This means that chewing the leaves or drinking coca tea
does not produce the high (euphoria) people experience
with cocaine.
Cocaine History
 Coca grows well in higher altitudes and is typically
harvested from pruned plants (shrubs)
 Coca was an important part of Inca culture
 Used in religious ceremonies and as currency because chewing on
the leaves increased strength, endurance, reduced fatigue, and
could suppress appetite.
 Some natives of the Andes still chew coca leaves to
reduce fatigue and increase productivity
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Cocaine History
 Cocaine was in use in Europe by the 19th century
Vin Mariani (Angelo Mariani’s Coca Wine) Used
coca leaf extract in many other products including lozenges
and tea
Cocaine History
 Cocaine was also used in the United States in early
versions of Coca-Cola and in many patent medicines
Cocaine History
 Cocaine
 was isolated from the plant before 1860
 processing 500 kilograms of coca leaves yields one
kilogram of cocaine
 By the 1880’s cocaine was undergoing medical
experimentation and could be delivered by a
hypodermic needle
 It was discovered that cocaine could work as a local
anesthesia.
 Sigmund Freud - called cocaine the “magical drug”
(see next slide)
Cocaine History
 Early psychiatric uses:
 Sigmund Freud studied use of cocaine as a treatment for depression
and morphine dependence
 Later opposed use of the drug after nursing a friend through cocaine
psychosis (a form of Stimulant Psychosis, see next slide)
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Stimulant and Cocaine Psychosis
(sources linked)
• Stimulant psychosis is a psychotic disorder that appears in some
people who use stimulant drugs. Most commonly, stimulant
psychosis occurs in drug abusers who take very large doses but, in
rare cases, it can also present in patients taking therapeutic doses
under medical supervision. The most common stimulants involved
are amphetamines and cocaine.
• Cocaine has a similar potential to induce temporary psychosis, with
more than half of cocaine abusers reporting some psychotic
symptoms at some point. Typical symptoms of sufferers include
paranoid delusions that they are being followed and that their drug
use is being watched, often with accompanying hallucinations,
which supports the delusional beliefs. Delusional parasitosis with
formication ("cocaine bugs") is also a fairly common reaction.
Cocaine-induced psychosis shows sensitization toward the psychotic
effects of the drug, meaning psychosis tends to become more
severe with repeated, intermittent use.
Early Legal Controls on Cocaine
 Between 1887 and 1914, 46 states passed laws to
regulate the use and distribution of cocaine.
 Cocaine had become widely used as a pleasure drug
 Cocaine had become identified with despised and outcast
groups of people including lower class whites, criminals, but
especially with blacks
 Press and politicians made unsubstantiated claims
about cocaine use among southern blacks:
 Falsely reported widespread used proportionately among blacks
 Associated with increased violent crime
 In 1900, the Journal of the American Medical Association published an
editorial stating, "Negroes in the South are reported as being addicted to
a new form of vice – that of 'cocaine sniffing' or the 'coke habit.'" Some
newspapers later claimed cocaine use caused blacks to rape white
women and was improving their pistol marksmanship.
Early Legal Controls on Cocaine
 This fear (and negative press) lead congress to the
passage of the Harrison Narcotics Tax Act, 1914.
 46 states passed laws to regulate cocaine
between 1887 and 1914
Forms of cocaine
 Coca paste
• Cocaine paste, also known as coca paste,
paco, or pasta base: a collective name given
to several different cocaine products
• Using simple precipitation methods and
local ingredients — fresh-grown Andean
coca leaf, kerosene, soda ash one is able to
produce a chemically active “crude” cocaine
in an easy and economic preparation in the
same place as coca cultivation. In South
America, this paste is often mixed with
tobacco and smoked.
Forms of cocaine
Cocaine hydrochloride
 Conversion of cocaine paste into cocaine hydrochloride
(salt) that cannot be heated to form vapors for inhalation
even though it mixes easily into water
 Cocaine is a weakly alkaline compound (an "alkaloid"),
and can therefore combine with acidic compounds to
form various salts. The hydrochloride (HCl) salt of
cocaine is by far the most commonly encountered ( most
common form of pure cocaine)
 Often insufflated by users, and may also be injected
intravenously
Forms of cocaine
Freebase vs. Crack Cocaine
•
Normal cocaine (Cocaine Hydrochloride) is the typical white powder people snort. This
form is a water soluble salt of the cocaine free base and the HCl. This form also
vaporizes at a temperature very close to the temperature at which it burns, making it
difficult to smoke.
•
Crack cocaine is a cheap yet inefficient method of freeing the base cocaine molecule
from the salt. It uses baking soda to remove the proton from the base. However, this
safe, cheap method does not involve any purification steps, leaving some water and
baking soda (impurity) along with the newly formed "crack" which forms crystals and
floats to the top. So freebase cocaine along with other impurities are what make up
crack cocaine. Crack or “rock: can be smoked
•
Freebase cocaine is formed by a similar process. However, ammonia is used to remove
the proton and free the cocaine base. Diethyl ether (extremely flammable and
volatile) is used to dissolve and remove the freebase cocaine. This can simply be
siphoned off the top since ethyl ether does not mix with the water/ammonia solution.
The Diethyl Ether evaporates and pure freebase cocaine is left behind.
Contemporary Legal Controls
 Cocaine use increased in the late-1960s because
amphetamines were harder to obtain
 Prior to 1985, the major form of the drug available was
cocaine hydrochloride
 Most often insufflated, and was glamourized in the 1980’s
 Usually sold in bulk amounts that were relatively expensive, and
considered the champagne of recreational drugs
 By 1985, Cocaine use was associated with status, wealth, and fame
 By the mid-late 1980s, crack became available
 Relatively inexpensive ($5 to $10 a hit)
 Street level drugs were typically adulterated, and used to make profits
 Smoked cocaine use was associated with poor, black Americans
Contemporary Legal Controls
 Media and politicians focused on crack use among urban
black Americans
 Associated with violence and dependency (Remember 1914 ???)
 Anti-Drug Abuse Acts of 1986 and 1988 (Ronald Reagan
Presidency)
 Penalties for sale of crack cocaine significantly more severe compared with
powder cocaine
 In 1988, the law was modified so that it applied to individuals convicted of
simple possession of five grams of crack cocaine
 By mid 1990’s congress directed the U.S. Sentencing
Commission to study concerns about policy:
 Penalties’ severity disproportionately impacted blacks (see Table 6.1, and
next slide)
 Exaggerated relative harmfulness of crack
 Penalties too broad sweeping and targeted low level offenders
Federal Cocaine Offenders (by Race)
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Cocaine Users - Discussion
1) Why do you think people are likely to use cocaine?
• What do they think the benefits are?
• What so you think are the risks?
2) Why do you believe that blacks have been historically associated with
cocaine abuse?
• Does our society label users as “good” users and “bad users”?
• Why?
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Mechanism of Action
 Cocaine’s mechanism of action is complex
 Cocaine blocks reuptake of dopamine, serotonin, and
norepinephrine, causing a prolonged effect of these
neurotransmitters.
 “By binding to the transporters that normally remove the
excess of these neurotransmitters from the synaptic gap,
cocaine prevents them from being reabsorbed by the neurons
that released them and thus increases their concentration in
the synapses (see animation). As a result, the natural effect of
dopamine on the post-synaptic neurons is amplified. The group
of neurons thus modified produces much more dependency
(from dopamine), feelings of confidence (from serotonin), and
energy (from norepinephrine) typically experienced by people
who take cocaine.” (source)
Mechanism of Action
 “In chronic cocaine consumers, the brain comes to rely on
this exogenous drug to maintain the high degree of
pleasure associated with the artificially elevated levels of
some neurotransmitters in its reward circuits. The
postsynaptic membrane can even adapt so much to these
high dopamine levels that it actually manufactures new
receptors. The resulting increased sensitivity produces
depression and cravings if cocaine consumption ceases and
dopamine levels return to normal.” (source)
 It is possible the GABA and Glutamate also are affected by
Cocaine
Cocaine Absorption
 Chewing or sucking coca leaves
 Slow absorption through the mucous membranes of the mouth
 Results in slower onset and lower blood concentration of cocaine
 Insufflation
 “Snorting” cocaine hydrochloride
 Absorbed through nasal mucous membranes
 Rapid absorption and onset of effects, reaches the brain quickly
 Intravenous injection
 Very high concentration delivered to the brain
 Rapid and brief effects, thus a favorite among compulsive users
 Smoked
 Smoking Crack is now preferred by most compulsive users
 Route is less invasive and presents rapid and brief effects
Cocaine Elimination
 Cocaine is extensively metabolized, primarily in the
liver, with only about 1% excreted unchanged in the
urine.
• Cocaine is rapidly metabolized and removed from
the system, with a half-life of about one hour.
 The Major metabolites have a half-life of eight hours
 These are detected by urine drug screens
Beneficial Uses
 Local anesthesia:
 Used medically since 1884
 Early applications were eye surgery and dentistry
 Because of the abuse potential, synthetic replacements (procaine;
aka. Novocain) have been developed.
 Cocaine still remains in use for surgery in the nasal, laryngeal, and
esophageal regions
Concerns: Acute Toxicity
 No evidence that occasional use of small amounts is
detrimental to health
 Potential toxicity increases with larger doses
 Acute cocaine poisoning leads to profound CNS stimulation which
can lead to respiratory or cardiac arrest
 Whether a drug produces a toxic effect, depends on the dose
 Illicit cocaine is often adulterated and the adulterants may be more
toxic than the drug
 History of being cut with Levamisole
 By April 2011, the DEA reported the adulterant was found in 82% of seizures
 Levamisole suppresses the production of white blood cells, resulting in neutropenia
and agranulocytosis. With the increasing use of levamisole as an adulterant, a
number of these complications have been reported among cocaine users.
Levamisole has also been linked to a risk of vasculitis. (source)
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Concern: Chronic Toxicity
 Binging
 Drug is taken repeatedly and at increasingly high doses
 Risks of binge use
 Increasing irritability, restlessness, paranoia
 Can result in paranoid psychosis – (see previous slide on Stimulant
Psychosis)
 Most seem to recover once the drug leaves the system
Concern: Chronic Cocaine Use
source
Concerns: Dependence Potential
 Cocaine dependence occurs in some users
 Animal and human studies have shown that cocaine is a powerfully
reinforcing drug
 Example: Animals will readily self-administer the drug by leverpressing
 After binge use, some people experience
withdrawal symptoms
 Cocaine craving, irritability, anxiety, depressed mood, increased
appetite, fatigue
 However, these symptoms vary greatly among individuals, with some
individuals exhibiting little or no symptoms.
Concerns: Reproductive Effects
 “Crack Baby” phenomenon
 Media reports overstated the expected long-term effects
of cocaine exposure
 Recent studies indicate no consistent associations
between cocaine exposure and several developmental
measures
 Cocaine use during pregnancy
 The use of cocaine during pregnancy carries more
immediate risks, including and increased risk of
miscarriage and torn placenta
Current Patterns of Use
 National Survey on Drug Use and Health (NSDUH)
and Monitoring The Future Study (MTF) surveys
indicate:
 Less than two percent of adults currently use cocaine (2010 data)
 Down from a peak of 7 to 9 percent in the 1980s
 In general, usage rates of cocaine and amphetamine
tend to cycle in opposition to each other
 When cocaine use decreases, amphetamine use may increase
Amphetamines History
 Historically the Chinese used a medicinal tea made
from “ma huang” (Ephedra)
 Active ingredient is ephedrine
 Stimulates the sympathetic branch of the autonomic
nervous system (Sympathomimetic)
• The stimulant and thermogenic effects of Ephedra sinica and other
Ephedra species are due to the presence of the alkaloids ephedrine and
pseudoephedrine. These compounds stimulate the brain, increase heart
rate, constrict blood vessels (increasing blood pressure), and expand
bronchial tubes (making breathing easier). Their thermogenic properties
cause an increase in metabolism, evidenced by an increase in body heat.
(source)
Amphetamines History
 Amphetamine
 In the late 1920’s researchers synthesized and studied the
effects of a new chemical that was similar in structure to
ephedra
 Amphetamine was patented in 1932
 Early medical uses:





Asthma (first used here for ephedrine replacement - bronchodilator)
Narcolepsy
Hyperactivity in children
Appetite suppressant
Stimulant
Amphetamines History
 Wartime uses:
 Increased efficiency and reduced fatigue among soldiers and pilots
during WWII
 1960s “speed scene”
 Many IV drug users used amphetamines either alone or in combination
with heroin (speedball) – Speedball is so named because of the rush that
occurs rapidly after injection, thus speeding up the “high”
 Following this practice the street mane for cocaine became “Speed”
 Most street amphetamines came from prescriptions because it was easy
to get a prescription of amphetamines to treat depression or obesity
(most desired on the street was methamphetamine)
 Amphetamines became more tightly controlled (1970s),
leading to:
 Increased cocaine use
 Increased illicit manufacture of methamphetamine
The Return of Methamphetamine
 The Restriction of Amphetamines lead to the Illicit
manufacture of methamphetamine
 “Meth Labs” increases (Some names are "crystal meth",
"meth", "speed", "crystal", "ice” and “crank”)
 This manufacturing is dangerous and associated with toxic
fumes and residue
 The drug often contains impurities that may be toxic
 Not as easy to create Meth as indicated on many internet videos
 Methamphetamine abuse rose in the Western and
Midwestern United States throughout the 1990s
 Increases in Eastern U.S. cities were relatively modest
 Cocaine remained the stimulant of choice
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Amphetamine Pharmacology
 Chemical structure of amphetamine is similar to the
catecholamine neurotransmitters (see Figure 6.2, p.
139, text)
 The methyl group in methamphetamines seems to make the
molecule cross the blood brain barrier more readily, thus
increasing CNS potency
 Ephedrine is less able to cross the barrier
 Thus, produces more peripheral and fewer central nervous system
effects
 Amphetamines are probably more potent releasers of
norepinephrine which in turn mediates the euphoric
effects of amphetamines. The amphetamine effects are
probably the result of interactions with multiple
neurotransmitters
Absorption and Elimination
 Peak effects
 1.5 hours after oral ingestion
 5-20 minutes after intranasal administration
 5-10 minutes following intravenous injection or smoking
 Half-life
 5-12 hours
 Completely eliminated in approximately two days
 Rapid tolerance (tachyphylaxis) can occur after high doses.
 Tachyphylaxis is a medical term describing an acute (sudden) decrease
in the response to a drug after its administration. This can sometimes
be caused by depletion or marked reduction of the amount of
neurotransmitter responsible for creating the drug's effect, or by the
depletion of receptors available for the drug or neurotransmitter to
bind to. This depletion is caused by the cell's reducing the number of
receptors in response to their saturation (source)
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Beneficial Uses
 Depression
 Treatment of choice during the 1950s–60s
 Now used as an adjunctive therapy
 Major advantage = antidepressant effects occur relatively rapidly
 Weight control
 In the 1960s, widely used to reduce food intake and body weight for short
periods of time
 Methamphetamine currently FDA-approved
 Long-term effects on obesity unclear
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Beneficial Uses
 Narcolepsy
 Uncontrolled daytime episodes of muscular weakness and falling
asleep
 Stimulants used to keep patients awake during the day
 “Smart pills”
 At a low level of arousal, may improve performance
 At a high level of arousal, may decrease performance
 Athletics
 Under some circumstances, may produce slight improvements in
athletic performance
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Methamphetamine Effects on Performance
6-39
Beneficial Uses
 Treatment of Attention-Deficit Hyperactivity Disorder
(ADHD)
 Characterized by problems with inattention, hyperactivity, and
impulsivity (see pg 142, DSM-IV-TR)
 Stimulant medications can reverse catecholamine-associated deficits
that may underlie ADHD
 Concerns about abuse and side effects has lead to
other treatment options
 However, data suggest that stimulant is protective against substance
abuse
 Higher doses (non-therapeutic) doses do have abuse /dependence
potential
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Concerns: Acute Toxicity
 Acute behavioral toxicity
 Increases in feelings of power, suspicion, paranoia
 In animals, very high doses may destroy
catecholamine neurons
 Caveat: dosing regimens used in animal studies do not mimic those
used by humans
 Contaminants formed during the illicit
methamphetamine manufacture may be neurotoxic
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Concerns: Chronic Toxicity
 Paranoid psychosis following binge use
 Possible reasons for psychosis include:
 Heavy methamphetamine users may have schizoid personalities
 Primarily due to sleep deprivation
 No good evidence for permanent behavioral or
personality disruption
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Concerns: Dependence Potential
 Can produce psychological dependence in some
individuals
 As defined by DSM criteria
 A potent reinforcer in animals and humans
 Abuse potential is likely dose-dependent
 Small doses for medical use rarely lead to dependence
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Concerns: Dependence Potential
Data from The Lancet suggests
amphetamine is ranked the 9th most
addictive and 6th most harmful of 20
popular recreational drugs.
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Concerns: Dependence Potential
End of presentation
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