Amphetamines and cocaine
I.  History:cocaine
 A.  Leaves of coca plant were chewed by Incas of Peru.  People labored longer and harder but ate less under its influence.
 B.  Active ingredient was isolated by a German chemist between 1840-1870.
 C.  Freud said it relieved depression and was useful in treatment of  morphine addiction.  He thought it was safe.  Called it a magical drug.
 D.  Freud changed his mind when he recommended it to a friend suffering from morphine addiction.  Friend became tolerant needed large doses.  Spent night with friend suffering from cocaine psychosis.
 E.  At about same time a colleague of Freud's found that cocaine was a powerful local anesthetic.  Revolutionized surgery, specially  ophthalmological surgery.
 F.  During last portion of 19th cent cocaine was present in large numbers of patent medicines and in coca cola.
 G.  In beginning of 20th muckraking journalists talked about "Crazed cocaine takers"
 H.  Cocaine became illegal under the Harrison narcotics act of 1914, so its sale and possession has been illegal since.
II.  History amphetamines
 A.  Amphetamine was synthesized in 1887. It is not a natural product.
 B.  First used medically in 20s as bronchial dilator.
 C.  used for narcolepsy and depression in 1937
 D.  effect on ADHD (attention deficity hyperactivity disorder)  children discovered in 1937
 E.  amphetamines went to war in 1939, used to keep soldiers alert and reduce fatigue
 F.  after war, psychiatrists used amphetamines to treat depression but this was not effective.
 G.  Amphetamines were banned in inhalers 1959 because people took benzedrine (an amphetamine) out of inhalers and swallowed it.
III.  Epidemiology for past month usage (this information only for cocaine, not available for amphetamines).
 A.  about 1.5-2.0% of the population used in last month.
 B.  twice as many males as females.
 C.  max in 1985, about 8 percent of population used in past month
 D.  Use is greater if 18-34 yrs old, male, less educated, unemployed
IV.  Subjective effects of acute use.
 A.  Very reinforcing.
 B.  Produces euphoria: i.v. use can produce a rush. Elation and energy followed by depression.
  1.  anorexia: monkeys will choose cocaine over food and starve if allowed to.
  2. Animals will select cocaine over sex.
 C.  alertness.  This can be replaced by a driven feeling at higher doses. Prevents REM sleep.
 D.  increased self-confidence
 E.  social interactions may be enhanced
 F.  inc in sexual pressure with delayed ejaculation or orgasm. Prolonged use is followed by impotence and decreased sex interest.
 G.  unpleasant mood changes in some people
  1.  agitation, apprehension
  2.  dysphoria
  3.  delirium
 H.  anorexia
V.  Patterns of use:amphetamine
 A.  One group of amphetamine users begin with prescriptions for obesity or depression (these are no long considered proper indications for amphetamine prescription).  These people then become habitual user. Or truck drivers or students use to say awake.  These groups rarely use i.v.
 B.  A second group, iv users, obtain drug illicitly initially. Note that i.v. use  of amphetamines presents a more severe problem than does oral use.
  1.  uses large quantities, eg. 500 mg
  2.  seeks rush not alertness
  3.  lives in drug subculture
  4.  i.v. amphetamine user may inject every 2-4  hours around clock for several days, eat little sleep not at all, then crash.
VI.  Patterns of use: cocaine
 A.  No toxicity when used in Andes to stave off fatigue and hunger, or to prolong work, but young people in urban Peru have similar amphetamine problems to those of users in North American cities
 B.  A cocaine user uses every 30-40 min to  retain euphoric effects.  High lasts 5-15 min. With i.v. use,  tolerance is rapid so that subjective effects of cocaine are over when the user still has high level in blood.
VII.  Pharmacology:
 A.  Route of administration and dosage. Amphetamine
  1.  doses: 15-30mg is a moderate dose.   100 mg is large dose. Fatalities can occur at 400-5000 mg, but not uniformly, especially not in tolerant users.
  2.  Whether taken orally, inhaled as a vapor, or used i.v. a dose  lasts several hours
 B.  Routes of administration and dose. Cocaine
  1.  routes of administration
   a.  Intranasal
   b.  i.v.  (rare)
   c.  Freebasing: process hydrochloride salt with volatile solvents to make white crystals smoked in water pipe.  Salt cannot be smoked as it is destroyed by heat.
   d.  Crack: crystalline form of free base. Cocaine hydrochloride is converted to base with baking soda and water.
  2.  Street dose of cocaine is 20-50 mg.
  3.  half life of cocaine about 40 min.
 C.  excretion is faster if acidify urine because amphetamine and cocaine are basic. Both drugs  will be ionized in acidic urine and not reabsorbed from kidney into blood.
VIII.  Mechanisms of action
 A.  acute effects on monamine transmitter systems
  1.  Cocaine blocks reuptake
  2.  Amphetamine has 3 effects
   a.  blocks reuptake
   b.  causes release of newly synthesized transmitter
   c.  increases amount of transmitter released in response to action potential.
  3.  Thus both cocaine and amphetamine increase monoamines in synaptic cleft
  4.  initial response of receptors would be down-regulation. This may be a mechanism for tolerance.
  5. eventual transmitter depletion may cause up-regulation of receptors (supersensitivity).
 B.  reinforcing properties probably due to increase in DA in the cleft
 C.  can cause permanent damage to monamine transmitter systems.
  1.  Amphetamine eventually causes depletion of transmitters from axon terminals. May explain why people take repeated doses.  Each dose causes more depletion so person wants another dose to boost DA levels.
  2.  This may explain schizophrenia-like symptoms. In animals this may show up as hyperactivity and stereotypy.
  3.  methamphetamine is  toxic to DA and 5HT neurons, cocaine is not.
 D.  Regions of brain affected:
  1. DA reward pathway
  2. Craving may be due to increase activity in prefrontal cortex or amygdala
   a. In these regions, addict has increased metabolic response to cocaine cues and neutral cues.
IX.  Tolerance and withdrawal.
 A.  Tolerance (see pg. 238)
  1.  Acute tolerance to euphoric effects.  Can occur during a cocaine run of 12-24 hrs. Tolerance is lost in 24 hrs.
   a. During a single run, there is no tolerance to cardiovascular effects.
  2. With chronic use there is tolerance to anorexic effects  and some tolerance to cardiovascular effects.
  3.  reverse tolerance or supersensitive to some effects, e.g.  sterotypy and psychotic behavior may increase with use.
 B.  withdrawal
  1.  mental depression and fatigue
  2.  may sleep 12-18 hrs
  3.  wakes up hungry
  4.  craving for drug occurs after a binge. Person cannot enjoy normal activities. Craving may last weeks.
  5.  lethargy may last  many days.
  6.  Person usually returns to normal after several weeks, but
   a.  some people may continue to think about drug continuously
   b.  after long term use, depression may last a long time. Some say can be permanent.
X.  Physiological effects (similar for cocaine and amphetamine)
 A.  Sympathetic stimulation
  1.  Cardiovascular effects can be lethal.
   a.  raises blood pressure
   b.  increase heart rate, moderate doses.
   c.  cardiac arrhythmias-large doses
   d.  damage to small blood vessels in brain can cause stroke
   e.  can end in circulatory collapse..
  2.  bronchodilation
  3.  methamphetamine causes less dramatic sympathetic effects so people who want central effects prefer it.
 B.  weight loss
 C.  sleeplessness
 D.  freebase smoking bad for respiratory system, constricts blood vessels
 E.  CNS:
  1.     tremor, hallucinations, confusions, convulsions, nausea, muscle twitches, agitation.
  2.  very high doses: CNS is depressed: loss of reflexes, respiratory depression, unconsciousness, death.
 F.  Nonspecific effects on health
  1.  if rats allowed to self administer cocaine, 90% died in 30 days.  Lost weight, had seizures.  Cause of death not clear. (JAMA 254,81).
  2.  "speed kills" refers to deteriorating mental and physical  condition of user, deaths due directly to amphet are rare and etoh usually complicates the matter.
   a.  hepatitis,
   b.  violence.
   c.  undernourished
   d.  dehydrated
   e.  lack of sleep
   f.  skin sores due to formication.
   g.  poor wound healing- infections.
   h.  lack of self care
 G.  Effects specific to cocaine.
  1.  Snorted cocaine relaxes bronchial muscles, constricts blood vessels.  When drug wears off, muscles contract and blood vessels relax so get nasal stuffiness and tender nasal membranes.
XI.  psychiatric problems
 A.  abnormal motor behavior
  1.  restlessness, irritability, tremor, anxiety, delirium, attention and concentration problems.
  2.  formication-picking at skin, occasionally may even cut it.
  3.  stereotypy: bathe all day, clean same object over and over.  Compulsion to take things apart but too disorganized to put together
  4.  animals show pacing, gnawing,  stereotypy. Monkeys will repetitively manipulate object with hands for a long time.
 B.  abnormal thoughts
  1.  fascinated with philosophical meanings
  2.  talk too much; very boring to listen to.
  3.  portentious
 C.  Schizophrenic behaviors can result from chronic use, vivid hallucinations and paranoid delusions. Some users develop thought disorders. After person stops using, recovery is usually rapid,  within a week.
XII.  Human Performance
 A.  Some types of human performance can improve with single small doses (These changes were measured with amphetamines, but similar changes probably occur with small doses of cocaine): (These improvements do not occur with continued use or large doses.)
  1.  Improves ability to concentrate
  2.  reduces attention lapses that occur when performance has decreased due to fatigue, e.g. performance in a flying simulator.
  3.  improves reaction time when it is increased by fatigue.
   a. increased ability to do simple mental tasks: controversial, depends  on the task.
  4.  improves vigilance
  5. Increase in athletic performance (1-4%).  This is small but statistically significant.
   a.  measured for runners swimmers, weight throwers.
   b.  if task requires smooth accurate motion, amphetamines may interfere
  6.  fine dexterity may be reduced.
  7.  eventually fatigue begins to hurt performance.
 B.  behavioral toxicity: accidents, violence (often unprovoked), suicides
XIII.  Medical uses
 A.  narcolepsy
 B.  obesity: effectiveness limited by tolerance
 C.  ADHD. Amphetamine treatment:
  1.   Most  randomized studies show clear effects of 6 months treatment on core symptoms: inattention, hyperactivity, impulsivity, low academic achievement.
  2. Paradoxical calming and improved cognitive performance may be because the child is  less distractable.
   a.  increase attention span, ability to attend.
   b. children's social interactions come to resemble those of peers more
   c. mothers become less controlling, children more compliant, but not more compliant than normals
  3. Pharmacological issues
   a. methylphenidate better than amphetamine because less anorexic effect.
   b. Tolerance does not develop when amphetamines are used to treat ADHD.
   c. Not clear how long treatment should last.
   d. symptoms usually come back when treatment is discontinued
   e. often have similar symptoms as adults.
XIV.  Effects of prenatal cocaine on early childhood development:
 A. Why this is hard to study.  environment of children exposed to cocaine as infants is poor. Greatest effect on IQ is poverty.
 B. Mother submitted to drug tests in pregnancy.  Cocaine babies had trouble focusing on new toys. They were easily distracted and impulsive
  1. When older these children could not ignore irrelevant stimuli.  For example they had  trouble in a reaction time task, e.g. push a button when you see a car,  when distractors are added.
 C.    Cocaine exposed animals have similar problems. Cocaine exposed rabbits have no trouble learning to blink in response to a tone that predicts a puff of air. They have trouble if have to distinguish between 2 tones, only one of which predicts air puff (Science 278, 39).
 D. Cocaine exposed animals brains have fewer cortical cells and the cells are  improperly positioned.