The Major Stimulants: Cocaine and

Amphetamine
Chapter 4
The History of Cocaine

Cocaine:

One of the two major psychoactive stimulants

Is derived from coca leaves grown in the mountainous regions of South America
The History of Cocaine
Cocaine during the last half of the 19 th century

Several patent medicines and beverages were sold that contained

cocaine

Including the original (pre-1903) formulation for Coca-Cola

In the late 19th century,

Cocaine products were used by children as well as adults
The History of Cocaine

Sigmund Freud and Cocaine:

Freud was an early enthusiast of cocaine as an important medicinal drug

Promoted cocaine as a cure for morphine dependence and depression

Eventually he concluded that “cocaine is the third scourge

of humanity” after alcohol and heroin.
How to Make Cocaine

From Coca to Cocaine

Cocaine is extracted from the coca plant.

Coca leaves are soaked in various chemical solvents so that cocaine can be drawn out of the plant
material.
 Free Base and Crack

which has been chemically treated with ammonia or baking-soda to free the potent base material from

ve step process in which the hydrochloride salt was heated with water and a volatile liquid such as eth

ment with baking soda instead of flammable liquids.

t easily be injected or sniffed. Instead, it is usually smoked from pipes; burnt on a piece of tin foil; or
Cocaine Administration

✤ 1. Chew it

✤ 2. Snort it in a water soluble salt of cocaine form (cocaine hydrochloride)

✤ 3. Smoke it in crystal form

✤ 4. Inject it (cocaine hydrochloride)

Pharmacokinetics Cocaine

Absorption:

Cocaine HCL:
- absorbed via membranes *vasodialator*
70-80% biotransformed by the liver before reaching the brain
20-30% of initial dose crosses BBB.

IV - absorption complete onset 30-60s

Cocaine Base:
smoked, rapid nearly complete absorption
 Pharmacokinetics Cocaine
Distribution:
- penetrates brain rapidly
- freely crosses the placenta

nd Excretion:
me butyrycholinesterase acts on cocaine producing major metabolite benzoyle
detected in urine for ~48 h
users up to 2 wks, and can be found in hair up to 3-4 months later
 Cocaine Psychological Effects

ess, euphoria, giddiness enhanced sense of self

igilance, paranoia, extreme cases paranoid psychosis

lowed by a compensatory depression that is more sever at higher doses and of

Effects of Cocaine on the Body
3 prominent Actions

1. Local anesthetic - Na+ channel blocker

2. Vasoconstrictor - reduces bleeding, increases BP
3. Psychostimulant
How Cocaine Works in the Brain

Cocaine blocks re-uptake of all monoamine

neurotransmitters
Dopamine, Norepinephrine, and serotonin

Recall that blocking re-uptake produces an

increase of these NT’s in the synaptic cleft

Therefore the activity of these NT’s is

increased within the CNS
How Cocaine Works in the
Cardiovascular System

Cocaine acts in the peripheral nervous system on the sympathetic nerve fibres to
stimulate the cardiovascular system.

Cocaine blocks the reuptake of norepinephrine in the heart, causing the heart to
contract and the heart rate to increase.
Long Term Cocaine Use Can:
1. Cause damage to cardiovascular health and increase probability of stroke and
congenital heart failure

2. Produce hallucinations

3. Cause deep depression

4. Cause physical deterioration of the nasal membranes, if cocaine is administered

intranasally

5. Cause cocaine psychosis, a serious mental disorder

Chronic Effects of Cocaine

Cocaine psychosis:

A set of symptoms, including hallucinations, paranoia, and disordered thinking,

produced by chronic use of cocaine.

Kindling effect:

A phenomenon in the brain that produces a heightened sensitivity to repeated

administrations of some drugs, such as cocaine.

This heightened sensitivity is the opposite of the phenomenon of tolerance.

Medical Uses of Cocaine

Accepted medical application:

The use of cocaine as an anaesthetic for nasal, lacrimal duct (tear duct),
and throat surgery remains its only legitimate medical application.
 Metabolic Interaction: Cocaine and
Ethanol

nteraction occurs when alcohol and cocaine are used concurrently

mes involved in metabolism of the two drugs make an active metabolite called

ne is as good at block DA reuptake as cocaine

Ca2+ channel blocker - heart
nger than cocaine around 150min.
 Cocaine Abuse and Comorbidity

endent people are frequently young (12-39 y.o.a) male and dependent on at le

nd to have coexisting psychopathology:

disorders
depression
paranoia

de: bipolar depression, antisocial PD, PTSD, ADD/ADHD

 Cocaine and Pregnancy

Cocaine use in Pregnant Mothers Linked to:

- increased risk for spontaneous abortion early on (NE effects on uterus)
- low birth weight
- decreased head circumference

genital Anomalies
of infants have brain and or cardiovascular irregularities
drawal in ~1/3 of infants (seizures, lethargy, vomitting, diarehea, restlessness)

Cocaine use as a risk factor for infant neglect and abuse

Also polysubstance use
Treatment Programs for Cocaine Abuse
Cocaine abusers can receive treatment through:
Inpatient programs
Outpatient programs
A combination of the two types of programs

Relapse is a continual concern for recovering cocaine abusers.

 Pharmacological Treatment of Stimulant
Dependence
None currently approved

Strategies include:
1. Blocking euphoria
2. decreasing withdrawal
3. decreasing craving

DA/NE approaches
- cocaine use results in compensatory up regulation of DA transporter -
DA in cleft decreases - cravings
- Solution use a DA agonist many have been tried (L-Dopa, Wellbutrin,
Ritalin, Modafinil)
Pharmacological Treatment of Stimulant
Dependence

GABA/ glutamate approach

GABA inhibits DA release in brain reward areas

But GABA is so widespread - side effects

Vigabatrin - anti epileptic used in Europe

Increases GABA and decreases DA in the N. Acc

But has side effects - damage to visual field

 Pharmacological Treatment of Stimulant
Dependence
Metabolic Enzyme Approach

Counteract cocaine before it reaches the brain using enzymes

Using drug or gene therapy approaches

Vaccine Approach

Drug antibodies that bind to cocaine to

prevent it from crossing the BBB
Amphetamines
The History of Amphetamines:

The second of the two major psychoactive stimulants

Have their origin in Chinese medicine—an herb used for 1000s of years
as a bronchial dilator

The active ingredient, ephedrine, was isolated in 1887.

In 1932, the U.S. pharmaceutical company Smith, Kline and

French Laboratories marketed a synthetic form of
ephedrine
Called amphetamine

A nonprescription CNS stimulant, appetite suppressant, and

bronchial dilator
Amphetamines
The History of Amphetamines:

During World War II, soldiers, including Canadian, U.S., and German
troops…

Were given amphetamine to keep them awake and alert

Japanese kamikaze pilots were on amphetamine during their suicide

missions
 How Amphetamines work in the Brain

Modifies the action of DA and NE in several ways

Low doses:
1. binds presynaptic membrane receptors eliciting DA
release
2. interacts with DA vesicles eliciting DA leaking from
presynaptic membrane
3. Blocks DAT and potentially reverses re uptake

Higher Doses:

- Similar actions on both DA and NE neurons

- binds MOA blocking degradation

Amphetamines Psychological Effects:
Acute Effects of Amphetamines
Adverse and potentially lethal bodily changes include:
Convulsions
Chest pains
Stroke

The ACUTE effects resemble those of cocaine

But amphetamines (when taken in large doses) have the particular feature of
producing amphetamine psychosis:

A set of symptoms, including hallucinations, paranoia, and disordered thinking

 Methamphetamine

amphetamine BUT:

e is much longer (11+hrs) comparatively amphetamine is (9-11hrs) and cocain

y Neurotoxic

With the emphasis on cocaine abuse

during the 1980s, amphetamine
abuse was less prominent in the
public mind.

However, recently, there has been a

resurgence of amphetamine-abuse
cases involving methamphetamine.
 Methamphetamine and Neurotoxicity

amage to 5HT and DA nerve terminals - replaced by glial cells

damage - slower motor function and possibly increased risk for Parkinsons Dis

hronic Use:
decrease in gray matter (neurons)
ncrease in white matter (inflammation)
increase in ventricle size

ecrease in tissue within hippocampus

Methamphetamine in Pregnancy

No clear cut congenital abnormalities

- lower growth rate and birth weight

Compared to Non Users:

-50% of mothers delivered pre term (17% control)

-more deliveries via c -section because of unregulated BP

-2/3 of users reported less than 5 prenatal care visits (10% in controls)

-4% of infants died after birth (1% in controls)

 Synthetic Cathinones (Bath Salts)

acathione

ethylenedioxyprovalerone

, orally, rectally, IV or IM

of euphoria, increased alertness, increased energy, increased libido

ehaviours similar to that observed using PCP - self mutilation, suicide attempts