1. Psychostimulants
Chapter 11

2. Psychostimulants Cocaine Amphetamines Caffeine Nicotine Amphetamine
Methamphetamine
Ephedrine
Cathinone – khat
MDMA – ecstasy
Caffeine
Nicotine
Psychostimulant – drugs with mood-elevating or antidepressant effects
First two stimulate transmission of monoamines E, NE, DA, 5-HT
1. Amphetamines (amphetamine, methamphetamine, ephedrine, Cathinone – khat, MDMA – ecstasy) – structurally similar to DA molecule
2. Cocaine -
3. Caffeine – 80-90% of US adults drink caffeinated beverages regularly, works by anatgonizing adenosine, compound that inhibit neural activity
4. Nicotine – used as a pesticide, toxic to humans in right situation, activates with nicotine ACh receptors, although also has influences on other NTs as well

3. Amphetamine and related psychostimulants
There are a number of different compounds for amphetamines
They all have a chemical structure that is very similar to DA
Not surprising that it has a very strong effect on dopaminergic systems
Types of Amphetamines -
Ephedrine
First amphetamine used
natural source from a plant, used > 5,000 yrs ago by Chinese, reduces appetite, more energy, used to treat asthma (widens airways in lungs)
unstable and naturally occurring so limited resource, needed a synthetic version.
Also, can elevate blood pressure and lead to heart attack/stroke; Steve Bechler, pitcher, died during training, using to control his weight, Med Ex said ephedra likely cause
Amphetamines
synthesized in 1887 but not tested until 1910 and not suggested for use until 1927
first marketed as Benzedrine, then Dexedrine
- Uses - first used to treat asthma, narcolepsy, weight loss, mild antidepressant, stim to keep people awake.
In WWII most armed forces distributed amph. to their troops to reduce fatigue, increase mood, increase endurance.
Some believe that near the end of the war, Hitler was suffering from amph. induced psychosis.
"No one who has read about his behavior during this time or his pronouncements at the situation conferences…can fail to recognize what it was that made him conjure up….such harebrained schemes. The rapid alternation of depression and euphoria, exhaustion and artificially induced buoyancy clearly reflect Hitler's dependence on the stimulants prescribed…" (Maser in Grilly p. 184)
After war still prescribed for dieting and depression but stopped since it could induce a worse depression and suicidal thoughts.
Students in 50s-60s using like we use caffeine today
1970's government pressure on pharma. To slow production, # of legitamate uses reduced, gen pop. & physicians became more aware of the hazards.
Also had antidepressants coming on the scene so could switch.
Cocaine replaced amp. Recreationally, seen as safer by users.
In 90's became pop again, methamphetamines. Purity is much better and plenty of supply so get a more potent product (don't cut).
Cathinone (khat) – from a evergreen shrub, again since antiquity, not stable so generally used where it grows (East Africa and Arabian penisula)
MDMA – ecstasy

4. 11.16 Khat for sale in an Ethiopian marketplace
IV. Cathinone -
Methcathinone - newest on the scene in US, but forever in places where it grows.
- appears to be as addictive as crack & methamphetamine
originally synthesized in Germany in 1928 and used as an antidepressant in the Soviet Union in the 30's and 40's
1950's an American pharmaceutical company started testing it but found many side effects and it's therapeutic effects were identical to amphetamine so gave it up.
1980's it reappeared in the illicit drug market after a student who worked for the company stole a sample and the copies of how to manufacture it
Similar problems as other drugs

5. 11.17 Mechanisms of amphetamine-stimulated DA release
To get rush need to do i.v. or inhale vapors and get more to brain faster
1/2 life 7-14 hrs but if urine basic then hours, so longer high than from cocaine
Pharmacodynamics
like cocaine, blocks re-uptake
but also increase leakage of catecholamines (E, NE, DA) into cytoplasm of cell and increases release when an action potential
5. DA release in nucleus accumbens - pos reinforcement!
for comparison: cocaine mostly DA, and re-uptake
amphet. mostly NE, mostly release)

6. Effects of amphetamine use Acute
Alertness/decreased fatigue
Self-confidence
Exhilaration
Activation of sympathetic nervous system
Improve performance for tasks that require sustained attention
Impair performance for tasks that require smooth, accurate muscle movements
Effects of amphetamine use
Alertness/decreased fatigue
Self-confidence
Exhilaration
Activation of sympathetic nervous system (increase HR, BP, body temp, vasoconstriction, muscle tension, suppress appetite, bronchial dilation)
Improve performance for tasks that require sustained attention
Impair performance for tasks that require smooth, accurate muscle movements (this task-drug interaction would explain why may see abuse in a football player but not a golfer)

7. Effects of amphetamine use Chronic
psychosis similar to paranoid schizophrenia
get suspicious & antisocial
stereotyped behavior (continuous chewing, grinding teeth, rubbing tongue inside lips)
engage in repetitive thought or meaningless act for hours
pre-occupied with own though processes or engage in grand philosophies
brain damage
Effects of amphetamine use
Chronic
psychosis similar to paranoid schizophrenia
get suspicious & antisocial
stereotyped behavior (continuous chewing, grinding teeth, rubbing tongue inside lips)
engage in repetitive thought or meaningless act for hours
pre-occupied with own though processes or engage in grand philosophies
brain damage from restricted blood flow, depletion of monoamines (E, NE, DA), degenerating fibers
D. Tolerance, Withdrawal, Dependence
Sensitization - to psychotic effects
Don't have complete evidence for withdrawal - after a few days of mod or high users do "crash". Exhaustion, depression, lethargy, hunger - all opp f/x but could be a result from lack of sleep, low blood sugar
Psychological dependence - evidence is overwhelming. Euphoria, self-confidence produced by these drugs is a powerful reinforcer
Animals with free access will continue to inject higher and higher doses up to lethal dose - will induce convulsions.
This rarely happens with other drugs - ex. Opiates, generally stabilize at a fairly constant rate, below the lethal dose
Individ. Variation. Someone may use for months or years before addicted, others may have such an intense first experience they are they get hooked immediately

8. Methamphetamine “Meth mouth” – “ravaged” teeth of chronic meth users
Theories for why:
Causes dry mouth – bacteria like this and grow
Causes thirst – users crave liquids that are sugary
Causes people to grind teeth

9. 11.19 Reduced serotonergic fiber density in the neocortex of squirrel monkeys treated with MDMA
MDMA similar to amphetamine but mild euphoria, enhanced sensory perception, increased desire to interact with others
Works mostly on serotonin instead of other NTs
MDMA tests on monkeys show reduced 5-HT fiber density
Top – frontal cortex, middle – parietal cortex, bottom – visual cortex
Left – saline only
middle – subcutaneous MDMA, twice a day for four days, then nothing for 2 wks
Right - subcutaneous MDMA, same treatment, nothing for seven years

10. Accepted medical uses for amphetamines: Narcolepsy ADHD
Ritalin (methylphenidate)
Dextroamphetamine
Cylert (pemoline)
Strattera (atomoxetine)
Accepted medical uses:
Narcolepsy
ADHD
Ex. ADHD kid shows less hyperactivity (undifferentiated gross motor activity) because he is able to focus attention on task
Ritalin - methlyphenidate - (blocks reuptake of DA & enhance release of NE)
60-80% kids respond favorably to psychostimulants, sometimes it’s dramatic - increase in attention span, decrease in restlessness, reduce aggression & impulsiveness
Caffeine does not work - some parents try this to avoid administering a "drug."
One theory is ADHD kids are understimulated and stims bring them up to normal - think about how their behavior is similar to a drunk adult - a person on a sedative: inattentiveness, belligerence, unconcerned about normal social controls on behavior.)
Studies showing increased DAT in ADHD adults, which means not enough DA in synapse
Also NE - Strattera (atomoxetine), which inhibits NE reuptake
What is confusing is that both drugs that amplify NE (which should logically increase hyperactivity) and drugs that should reduce NE functioning seem to reduce symptoms
(Clonidine activates NE autoreceptors so should decrease production - works with kids that don't respond to the psychostims.)
Confusion in understanding physiopathology of ADHD

11. Treatment of Psychostimulant Abuse
Similar to approaches for alcohol abuse - it’s the person's environment, behavior, and exposure/access that's important - not the specific drug.
Getting a cocaine addict to quit initially is not the problem - preventing a relapse is the big thing.
But depression often precedes use and always follows it so antidepressants have been tried, only the SSRI's seem to be useful.
A number of compounds have been tried - things that block the euphoric effect or decrease craving but only moderate success.