Seth Gugliuzza
Rebecca Marshall
Nelson Santana
Michelle Valdez
Lauren Mango
Chris Mason
Psychomotor Stimulants (Chapter 7)
Chapter 7: Cocaine, Amphetamines, and Other Behavioral Stimulants
I. Cocaine: Background
A. The natives of South America have used the leaves of Erythroxylon coca
for religious, mystical, social, euphoriant, and medicinal purposes.
B. The active alkaloid in E. coca was isolated in 1855, purified in 1860, and
named cocaine. Around the late 1800’s it was used as a local anesthetic
for surgical procedures.
C. There were no restrictions on the sale or consumption of cocaine in the
late 1800’s. Even Coca-Cola contained about 60mg of cocaine per 8ounce serving.
D. In 1914 the Harrison Narcotic Act banned the incorporation of cocaine in
medications and beverages. By the late 1930’s it was replaced by newly
available amphetamines.
E. Most users of cocaine are young (12-39 years old) and usually snort the
substance, some smoke crack cocaine, and the least amount of people
inject it.
II. Forms of Cocaine
A. Treatment: The leaves of E. coca are soaked and mashed; the cocaine is
extracted in the form of a coca paste. It is then treated with hydrochloric
acid to form cocaine hydrochloride.
1. Cocaine hydrochloride is water soluble which means that it can
be injected intravenously and absorbed through the nasal
mucosa easily.
2. Since cocaine hydrochloride decomposes when it is heated it
cannot be inhaled.
3. A new and inexpensive form of cocaine was produced and called
crack cocaine. This form of cocaine is insoluble in water.
However, it is soluble in alcohol, acetone, or ether which allows
it to be heated to produce vapors for inhalation.
III. Pharmacokinetics
A. Absorption: through the mucous membranes, stomach, and lungs. It can
be snorted, smoked, injected intravenously, or ingested.
1. Snorted cocaine: cocaine hydrochloride crosses the mucous
membrane poorly. It is a vasoconstrictor. This means that it
constricts the blood vessels in the nose which limits its own
absorption into the plasma (only about 20 to 30 percent is
absorbed). Plasma levels peak at 30 to 60 minutes.
2. Smoked cocaine: some of the particles that are smoked become
trapped in the nose while others reach down to the lung surface.
Plasma levels peak at 5 minutes and only about 6 to 32 percent
reach the plasma.
3. Injected cocaine: bypass all barriers to absorption and place the
total drug dose immediately into the bloodstream.
4. Ingested cocaine: not a common route. Plasma levels peak 1 hour
after ingestion.
B. Distribution: cocaine penetrates the brain rapidly, is quickly
distributed to other tissues, and crosses the placenta freely.
C. Metabolism and excretion
1. Cocaine’s half-life in plasma is only about 30-90 minutes
because of the rapid working enzymes located in the plasma and
liver.
2. It is slowly excreted from the brain (8 or more hours after initial
use).
3. The major metabolite for cocaine benzoylecgonine can test
positive in the urine for up to 48 hours (longer in chronic users).
4. Cocaine + Alcohol = metabolite coaethylene. This metabolite
formed by liver enzymes blocks presynaptic dopamine reuptake
transporters and enhances the euphoric effect of cocaine.
Cocaethylene is also more toxic than cocaine.
Mechanisms of Action
1. potent local anesthetic
2. vasoconstrictor
3. powerful psychomotor stimulant
Dopaminergic Actions
1. blocks reuptake of DA, NE, and 5-HT
2. blockade of DA reuptake important for its behavior reinforcing and
psychostimulant properties
3. Increased DA levels in the nucleus accumbens and other components of the DA
reward system seem to be responsible for euphoric, addictive effects
4. Both DA and cocaine decrease the discharge rate of neurons located in the ventral
tegmental area and the nucleus accumbens, indicating that DA exerts inhibitory
effects on postsynaptic receptors
5. Cocaine increases this decrease in discharge rate which occurs secondary to
blockade of DA reuptake, potentiating its inhibitory action on postsynaptic
receptors
6. Cocaine competes with DA for presynaptic transporter of DA, the cocaine
blocking the binding of DA and prolonging its presence in the synaptic cleft
Serotoninergic Actions
1. In mice lacking DA transporter, DA would not be expected to serve as a positive
reinforcer, but it does which indicates other pathways being involved
2. In mice lacking the 5-HT(1B) receptor, mice were even more motivated to self
administer
3. 5-HT(1B) receptors may antagonize the reinforcing effects of cocaine
Effects of Short Term, Low Dose Use
1. Low dose (25-100 mg) nontoxic physiological responses include increased
alertness, motor hyperactivity, tahycardia, vasoconstriction, hypertension,
bronchodilation, increased body temperature, papillary dilation, increased
glucose availability, and shifts in blood flow from internal organs to muscles
2. Psychological effects include euphoria, giddiness, enhanced selfconsciousness, followed by mild euphoria mixed with anxiety, followed by a
more anxious state
3. thoughts race, talk fast and sometimes incoherently
4. suppressed appetite, delayed sleep, postponed fatigue
5. promotes desire to take more cocaine, even more than the desire to eat
6. as dose or duration increase, rebound depression follows, loss of coordination,
followed by tremors and seizures
7. sexual dysfunction is common in heavy users, though initial use may heighten
feeling
8. In CNS, may cause local depletions of oxygen, vascular thrombosis,
intracranial hemorrhage and hemorrhagic strokes, cerebral atrophy, seizures,
and movement disorders
9. Cardiac complications- cardiac ischemia (lack of oxygen), heart attacks,
death, rupture of aorta
10. Nasal use complications include nasal septal perforation, pulmonary lesions,
hemorrhage, infections
Toxic and Psychotic Effects of Long Term, High Dose Use
1. higher doses lead to anxiety, sleep deprivation, hypervigilance, suspicion,
paranoia, and persecutory fears
2. toxic paranoid psychosis- become aggressive or hostile in response to
imagined persecution
3. depression, dysphoria, violent psychotic disorders that can last days or weeks
after use stops
4. repetitive patterns of behavior
5. vivid visual, auditory, and tactile hallucinations
6. schizophrenic-like symptoms
7. acute toxic dose around 1-2 mg per kg of body weight
Comorbidity: as defined by Webster’s new World Medical Dictionary is “the
coexistence of two or more disease processes.”
1. Chronic cocaine use produces virtually every psychiatric syndrome
according to Julien. Which include: affective disorders,
schizophrenic-like syndromes (paranoia, hallucinations), and
personality disorders are just a few examples
2. The literature agrees with “most cocaine dependent individuals also
have problems with other drugs abused” but Julien confuses the fact
that the pre-existing neuropsychological disorder is not necessary for
cocaine abuse to begin.
3. Cocaine addicts often show a certain profile on personality tests and
the use alcohol or heroin in conjunction with it, there is no way to
determine who is more likely to become addicts just that it is highly
addictive and comorbidity exists.
Cocaine and Pregnancy:
1. Cocaine use in pregnant mothers: produces detrimental effects of the fetus
-easily crosses the placental barrier
-concentrations in the fetus equal or exceed those in mother
-teratogenic and fetotoxic
-direct organ toxicity (heart, CNS, urinary system, GI tract)
2. Indirect Teratogenic Effects:
-caused by vasoconstriction in blood vessels of mother and fetus
-decreases blood flow to uterus and placenta
-fetal hypoxia (reduction of O to fetus)
-increases chances of placental detachment, premature birth,
stillbirth, low birth weight, interauterine growth reduction, small
head size, aberrations in development of CNS
(Restriction of blood flow can affect any developing organ)
3. Direct Treatogenic Effects:
-serious brain lesions which lead to neonatal neurological syndrome
(Syndrome has no clear definition)
-symptoms:
-abnormal sleep patterns, poor feeding, irritability, tremors,
seizures
-increased risk of SIDS
4. Other routes: cocaine can enter the fetus through breast milk for up to 60
hours
5. Statistics:
-15-25% of all babies are born with cocaine in their system
-50,000-100,000 babies per year are affected by cocaine using mothers
6. Additive effects of babies born into drug environments:
-poor nutrition, poor hygiene, and neglect
-decreased ability for mother to respond to child (lack of eye contact,
touching, and language)
-decreased cognitive stimulations that are necessary for optimal
growth and development both intellectually and emotionally
7. Effects in school aged children
-difficulty developing attachments, dealing with multiple stimuli, in
unstructured play
-become aggressive / withdrawn when over stimulated, frustrated
-high incidence of ADHD
Pharmacological Treatment of Cocaine Dependency
-no general consensus
1. Problems Complicating attempts:
-intensity of drug effects, and behavior-reinforcing actions
-tendency for patient relapse
-coexisting disorders with drug dependencies, and or psychiatric disorders
Areas in need of Pharmacological Interventions:
1. Antiwithdrawal Agents for enhancement of DA in hypoactive regions of
the limbic system, and reduction of depression
-no agents clearly identified that work through drug substitution
-need a drug with less abuse potential to stimulate receptors, while new
ones are being formed
Ex. Methylphenidate (Ritalin)
Withdrawal of cocaine:
-leads to a hypofunctional DA system
-long-term use of cocaine leads to a down regulation, and
reduction in the number of DA receptors
-can last for weeks or months
2. Anticraving agents that block DA receptors reducing cue-induced
craving, and blunt euphoric effects
Ex. Ecopipan: selective D1/D2 blocker, decreases craving and euphoric
effects of cocaine
3. Treatment for comorbid psychological disorders, reducing drive for drug
-possibilities in using drugs designed to treat the specific
psychological disorder
Patients w/ depression: Cocaine is mechanically similar to antidepressant
drugs
-possible treatment with antipsychotic drugs in patients who have stopped
use
Studies with antidepressants:
-Bupropion: minimally effective
-Tri-cyclic antidepressants (desipramine, imipramine)
and Fluxotine (which is 5-Ht specific): favorable effects
in mood improvement and maintained abstinence from
cocaine use
Patients with ADHD:
-35% of adult cocaine users had childhood ADHD
-15% may have adult ADHD
Studied: effects of long-lasting Methylphenidate (Ritalin)
combined with relapse prevention therapy. Resulted in the
reduction of adult ADHD and cocaine dependency.
Psychosocial Interventions:
Provide the most promising treatments
-many different approaches
-recovery programs (similar to the 12-step program of AA)
-individual/group counseling
-Cognitive-behavioral therapies
-supportive-expressive psychodynamic therapy
-behavioral reinforcement
APA has published guidelines for the treatment of cocaine related disorders
Best, most effective approach to treatment: combination of intensive
individual and group drug counseling
The main point out of this section is that cocaine abusers usually have a coexisting
disease which could be a direct result of the cocaine abuse or it could have been
present before hand. Literature suggests that the treatment of cocaine dependence
needs to be addressed with issues related to comorbidity of drug abuse with alcohol and
other psychiatric disorders.
Amphetamines – Drugs with a specific chemistry all of which produce a variety of
effects on the CNS and ANS.
Amphetamines:
 Mimic the actions of adrenaline
 Stimulate CNS
 PNS effects probably a direct result of increased Norepinephrine levels
 Effects result from indirect activation of presynaptic DA and Norepinephrine
release
o Minor effects seen from postsynaptic catecholamine receptor stimulation
 Produce:
o Vasoconstriction
o Hypertension
o Tachycordia
o Alert Response
o Tremors
o Increased Motor Activity
o Loss of appetite
o Insomnia
 Increased psychomotor activity results from stimulation of DA receptors in the
mesolimbic system (nucleus accombens)
 Used therapeutically to fight fatigue and delay onset of sleep during WWII
 Today, used to treat narcolepsy and ADHD
o Psychomotor stimulants used illicitly (high addiction liability)
 Users have difficulty distinguishing the subjective effects between 8-10mg of
cocaine and 10mg dextro-amphetamine
 Effective dose varies with type of amphetamine
 Effects of prolonged use:
o Sudden outbursts of aggression and violence
o Paranoid delusions
o Severe anorexia
o Psychosis (methamphetamine)
o Weight loss
o Skin sores
III. Dependence and Tolerance:
1. They are prone to compulsive abuse and physical dependence is
readily produced.
2. The withdrawl syndrome occurs but is less dramatic than barbiturates
or narcotics
3. Julien has mistaken tolerance. Amphetamine and also cocaine use
creates sensitization in the central nervous system. This occurs
because with administration of the same dose on different days the
CNS becomes more sensitive to the drug, seen in increased locomotive
activity. See article on-line.
ICE: A freebase form of Methamphetamine
 Ice: a free form of methamphetamine. It is more potent than dextroamphetamine.
 Today is classifies as an illicit drug but it was actually used to treat ADHD
 ICE refers to the smokeable form of methamphetamine.
 Methamphetamine is broken down at temps that are achieved in order for it to be
smoked ( like cocaine hydrochloride)
 When converted its base, it can be evaporized and inhale as smoke without being
broken down.
 ICE when smoked is absorbed more rapidly the intravenous injection of
methamphetamine hydrochloride
ICE is to Methamphetamine as Crack is to Cocaine. But ICE has a much longer life (12
hours) than crack. This results in an intense persistent drug action
PHARMAKOKINETICS:
 When smoked results in almost immediate absorption continuing over then next 4
hours. Then the level in plasma decline.
It is metabolized in the liver, and end product is excreted in the urine
EFFECTS AND TOXICITY:
 The effects are almost the same as cocaine. It is a psychomotor stimulant and a
positive reinforce to the point that self administration is difficult to control and
modify
 High doses cause a decrease of both serotonin and dopamine in the brain. These
changes after taking place seem to be irreversible
 The toxic effect is directed to the neurons that manufacture both dopamine and
serotonin. Neuron-chemical alterations can be seen in alterations of sleep or
sexual dysfunction, depression, movement disorder and schizophrenia... ice –
induced psychosiscan persist for days or weeks.
NONAMPHETAMINE BEHAVIORAL STIMULANTS.

Non amphetamines share the same action potentiating that amphetamines create
such drugs include: EPHEDRINE, SIBUTRAMINE, METHYLPHENIDATE,
PEMOLINE
1. methylphenidate ( RITALIN) is a behavioral stimulant the regular release
Formulation has a half life of 2-4 hours.
Ritalin increases dopamine concentration by blocking the presynaptic dopamine
transporter (a cocaine like action)
The slow uptake in the brain accounts for the low rate of positive reinforcement effect
of the drug. Ritalin is used to calm the hyperactivity and improve attention in ADHD,
also improvement in academic performance when noted untreated children with
ADHD.
2. Sibutramine ( MERIDIA) is a serotonin, norepinephrine and a dopamine
reuptake inhibitor; it has been recently marketed as an antiobesity agent.
It is structurally similar to amphetamine. It is rapidly metabolized by the liver
to the active metabolite that is responsible for the pharmacologic actions
The metabolites reach their peak plasma concentration in 3-4 hours and the half life is
14-16 hours.
Weight losses for up to one year have been reported and the drug does not seem to
have any potential for abuse
3. Pemoline ( cylert) is a CNS stimulant; it reduces ADHD symptoms by
potentiating CSN dopaminergic transmission. It has a short life of 11-13
hours and its thought to have a low abuse potential... it causes hepatitis in
some instances therefore it is no longer a drug of choice for the treatment
of ADHD. If used patient or parent of the patient must sing an agreement/
concent form of knowing the side effects and what is doing.
4. Modafinil: used in treatment if Narcolepsy, potential used include
improvement of cognitive activity. It is a nonamphetamine
psychostimulant. Its action remains unclear. Its thoguth to potentiate
excitatory neuron transmission and inhibits GABA neurons in the cerebral
cortex and nucleus of accumbens. Altering the balance of glutamate and
GABA.
PHARMACOLOGIC TREATMENT OF ADHD:
Today the drug of choices for treatment of ADHD are RITALIN (methylphenidate) and
CYLERT (pemoline)
ADHD is the most common psychological disorder in children. Affecting 3-5 % of
school children. It is characterized by problem with attention, learning, impulse control
and hyperactivity. The condition seems to be more prevalent in boys than in girls. It
persists beyond childhood and into adulthood in about 40-60% of the cases.
The incidence of comorbid or cocontamant in creases in individuals with ADHD.
The seemed to be a genetic link to ADHD.
TREATMENT: stimulant drugs improve behavior and learning ability in 60-80 % of
children that are correctly diagnosed. The primary drugs for treatment include:
methylphenidate, amphetamines, pemoline, buspirone, bupropione. The first accounting
for more then 90% of the prescription filled. It has a rapid onset and a short duration so it
must be administer a various time in the day.
Feature
methylphenidate pemoline
Half-life
Elimination
Time to peak
Plasma cont
2-3
2-12
dextroamphetamine Racemic
amphetamine
8
7,8
1-3
1-5
3-4
3-4
Onset of
behavioral eff
Duration of
behavioral eff
Daily dose
range
Mg/kg/day
Mg/day
1
3-4 weeks
1
1
3-4
Not available 6-8
6-8
.6-.7
10-60
.5-.3
37.5-112.5
.5-1.25
10-40
.3-1.25
5-40
CH3
NH
CH3
O
O
OH
N-methyl-N-(1-methyl-2-phenylethyl)amine
O
Methamphetamine
CH3
N
Cocaine
CH3
NH2
HO
NH2
1-methyl-2-phenylethylamine
Amphetamine
HO
4-(2-aminoethyl)benzene-1,2-diol
Dopamine (DA)