Nov 9

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Nov 9 Amphetamines and Cocaine
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• Amphetamine
• A. General characteristics
• Psychostimulant that produces effects in CNS and
  PNS more potent in CNS
• 2 rotational forms dextro (d) and levo (l)
• In CNS, d-amphetamine is 3-4 times more potent
  than l amphetamine
• Methamphetamine is more potent that d amphetamine
  and is the main drug of abuse Ice, crystal
• D amphetamine used as a prescription medication
  for attention deficit hyperactivity disorder,
  narcolepsy, and short term treatment of obesity

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• Amphetamine
• Obesity 5-10 mg given 30-60 min before meals
  tolerance in 2-6 weeks
• Narcolepsy 10 mg/day recommended no
  significant tolerance
• ADHD (Adderal) 0.1-0.5 mg/kg/day no tolerance
• Absorbed well orally effects begin in 30 min,
  peak 2-3 hours later may last 7 hours
• Half-life is 12 hours

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• B. Mechanism of action of d-amphetamine
• Increases release of norepinephrine and dopamine
  and serotonin from axon terminals in
  dose-dependent manner
• Low dose mostly norepinephrine alerting
  effect anorectic effect
• Medium dose NE and DA motor stimulation
  reward
• High dose also serotonin psychosis
  hallucinations
• Also blocks reuptake of NE and DA
• Causes increased heart rate, elevated blood
  pressure, tremor, increased alertness, increased
  motor activity,decreased need for sleep appetite
  suppression
• Methamphetamine more potent in CNS and effects
  NE, DA and serotonin at most doses that would be
  taken.

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• Amphetamine
• C. History
• 1930s U.S. benzedrine marketed for treatment of
  asthma, narcolepsy, depression, appetite
  suppression (bennies)
• Also used to keep soldiers alert during combat in
  WWII
• After war, prescribed for fatigue and appetite
  suppression
• Social problems began in 1940s-1950s
• Problems continued particularly students, truck
  drivers, athletes, businessmen - 75 cents for
  1000 tablets in 60s

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• Hippy subculture did not endorse amphetamine use
  a lowly drug speed freaks not calm and
  peaceful but agitated and violent gave other
  mind-expanding drugs a bad name
• All the nice gentle dope fiends are getting
  screwed up by the real horror monster
  Frankenstein speed freaks who are going around
  stealing and bad mouthing everybody Ginsburg,
  1965
• 1965 FDA given authority to regulate
  manufacturing and distribution
• But so easily made by amateur chemists, did not
  work
• 1970s still available but from illegal
  manufacturers
• 1970s- 5-10 for 100 tablets widely used and
  readily available

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• History
• Use declined in 70s and 80s but now back up and
  primarily methamphetamine that is smoked,
  snorted, injected or taken orally Ice, crank,
  crystal, speed, meth, chalk
• San Diego methamphetamine capitol of the world
  4-5 tons/year in illegal labs
• Snorting or oral use produces euphoria, but not
  an intense rush
• Ice (glass) heated in glass pipe and smoked or
  melted and vaporized and inhaled Rush in
  seconds, lasting 6-8 hrs
• Ice abusers may smoke 1 gram/day about 500/day
  habit

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• 2005 Monitoring the Future Study
• 6.2 percent of high school seniors reported
  using methamphetamine (MA) at least once in their
  lifetime
• 5.3 percent of 10th grade students have used MA
• 8th-graders reporting significant decreases in
  lifetime, annual, and 30-day use.
• (Be wary of reports of declining illegal drug
  abuse put out by the government the full story
  is that these are more than made up for by
  increasing prescription drug abuse.
• 2005 9.5 of 12th graders reported using
  Vicodin or Oxycontin in the past year)

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AP, Mar 7, 2006 Press Release Restrictions aimed
at methamphetamine production were approved by
the U.S. Senate as part of the renewal of the
U.S. Patriot Act. Pharmacies nationally would
have to restrict purchases of medications that
contain chemicals which can be used to make
illicit methamphetamine. Beginning Sept. 30,
buyers of drugs containing ephedrine or
pseudoephedrine -- including popular cold
medicines like Sudafed -- will have to get them
from behind a pharmacy counter, sign a log book,
and produce ID. Maximum purchase amounts also
will be set 120 20mg pills daily, and 300
maximum per month. Downside?
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AP, Mar 7, 2006 Press Release The law will have
the unfortunate side-effect of increasing
trafficking of more potent meth from Mexico to
fill the market void left by local cooks.
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D. Research on amphetamine 1. 10 mg oral dose of
d-amphetamine to naïve users causes CNS mostly
NE Wakefulness reduced fatigue Mood
elevation alertness/improved concentration Increa
sed motor activity Increased speech Improved
performance on simple tasks Improved physical
performance in athletes PNS effects at alpha
and beta receptors for NE Increased heart rate
increased blood pressure relaxed bronchial
muscles (helps asthma) tremors sweating
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• Controlled Substances Act 1970 created DEA Drug
  Schedules legal, not scientific
• Schedule I (very high potential for abuse no
  medical use) MDMA (heroin many opiates LSD
  marijuana)
• Schedule II (medical use) amphetamine
  methamphetamine cocaine crack (prescription
  opiates Oxycontin, morphine)

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The federal penalty for the manufacture, sale or
distribution of small amounts of Schedule I and
II drugs First offense 5-40 years
imprisonment and/or not more than a two million
dollar fine for an individual (where death or
serious injury occurs, not less than 20 years
imprisonment and not more than life
imprisonment) Second offense - not less than 10
years imprisonment and not more than life and/or
a fine of not less than four million dollars for
an individual (where death or serious injury
occurs, not less than life imprisonment).
Penalties are doubled in many cases for the
manufacture, sale or distribution of larger
amounts of Schedule I and II drugs.
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D. Research on amphetamine 1. 10 mg oral dose to
naïve users 2. Withdrawal following prolonged
use in 10-30 mg range sleep disturbances
depression fatigue. May take 2 months for sleep
to normalize. 3. 15-30 mg range d-amphetamine for
naïve users NE DA and SE toxic
range Restlessness Irritability Euphoria Tremor
weakness confusion Dizziness insomnia anxiety
Fever paranoid hallucinations Panic
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D. Research on amphetamine 1. 10 mg oral dose to
naïve users 2. Withdrawal following prolonged
use in 10-30 mg range 3. 15-30 mg range for
naïve users NE DA and SE 4. 60 mg/day d
amphetamine for at least 2-3 days clear
Amphetamine toxicity lasting about a week after
discontinuation. (This applies to regular
methamphetamine use as well.) Amphetamine
psychosis paranoia disordered thought
hallucinations Parisitosis (formication) feeling
of having bugs on or under the skin peripheral
nerve endings in skin pick skin may probe with
a knife Stereotyped behaviors (tweaking) repeat
acts over and over for hours. Pacing, cleaning,
stringing beads, etc.
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D. Research on amphetamine 1. 10 mg oral dose to
naïve users 2. Withdrawal following prolonged
use in 10-30 mg range 3. 15-30 mg range for
naïve users NE DA and SE 4. 60 mg/day for at
least 2-3 days (seen in users) clear Amphetamine
toxicity lasting about a week after
discontinuation 5. After stimulant phase
crash Fatigue severe depression increased
appetite Cardiovascular effects headache
chills flushed appearance (look pale) heart
arrhythmias hyper or hypotension Anorexia
nausea vomiting diarrhea abdominal cramps
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D. Research on amphetamine 6. Lethal dose in
naïve users 120 mg/kg d amphetamine - overdose
reaction stroke convulsions coma
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• D. Research on amphetamine Regular
  Users/Abusers
• Pattern of use several day run of use (4-6 day
  binge), then crash and may sleep for 2 days
  cycles. In crash, person is lethargic for days
  then symptoms gone in about a week.
• But cardiovascular and mental effects show
  marked tolerance in regular users
• 400-2000 mg can be taken by regular user
• One reported case had 17000 mg intake in 24
  hours without acute illness

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D. Research on amphetamine - Nature of
tolerance Fast for effects on heart and appetite
suppression. Fast for euphoria Slowest for
effects on attention and narcolepsy when used at
recommended doses Receptors for NE, DA, SE down
regulate by reducing sensitivity Then when usage
stopped, more receptors are formed Normal
production of neurotransmitters is inadequate to
stimulate causes craving and anhedonia
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D. Research on amphetamine Pre 80s - Usage
escalation of d amphetamine often at a
1000mg/day level of pill use, users want more
effects and switch to methamphetamine and to
other routes - smoking or IV use. But today,
start with meth. Methamphetamine speed of old
days IV methamphetamine effects felt within 5
min. Rush described as orgasmic and euphoric.
May inject 10x/day (2 g/day) for 4-6 days then
crash. Sleep 2 days then start again. Get
Malnourished.
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• D. Research on amphetamine - Todays use
  (crystal crank chalk Ice glass)
• Still snort or take orally, but more commonly
  smoked or injected by abusers
• Ingestion 15-20 minutes for effects high, no
  intense rush last 6-8 hours.
• Snorting high, but no intense rush. Feel
  effects in 3-5 minutes. Lasts 6-8 hours.
• Ice (glass) heated in glass pipe and smoked
  or melted and vaporized and inhaled Rush in
  seconds, lasting 12 hrs
• Ice abusers may smoke 1 gram/day now cost
  500-2700/oz or 50-150/g
• Rush attributed to dopamine release in reward
  centers

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• Street terms for Methamphetamine 
• Chicken feed cinnamon Crack
• Crystal Meth Geep
• Granulated Orange HotIce Ice
• Lemon Drop LA glass
• Peanut Butter OZs
• Yellow Powder Sketch Stove Top
• Tick Tick Trash Wash
• Working Man's cocaine

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• Long term consequences of abuse
• Paranoid psychosis homicidal and suicidal
  thoughts rage violence hallucinations.
  Typically lasts 1 week, but for some, some
  psychosis remains as a problem.
• damage to dopamine-producing neurons
• damage to serotonin neurons
• long term effects on cognition and affect
  (depression verbal memory executive function)
• damage to heart and blood vessels
• skin abscesses
• increased risk for hepatitis B and C HIV among
  IV users (rough sex issue)
• (acute lead poisoning due to contamination)

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• Long term consequences of abuse
• damage to dopamine and serotonin nerve terminals
• reduced enzyme activity, monoamine content, and
  transporters for dopamine and serotonin
• Mechanism?
• production of reactive oxygen (metabolism of
  dopamine) species ? oxidative stress from free
  radicals
• increased extracellular concentrations of
  Glutamate secondary to GABA inhibition causes
  excitotoxicity through reactive nitrogen species
  ? free radicals again causing cytotoxicity
• altered energy metabolism due to mitochondrial
  dysfunction (inhibited) ? cell damage/death

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Fetal effects increased miscarriage increased
prematurity withdrawal seen in infants long
term behavioral effects suggested in animal
studies
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Ecstasy (MDMA)
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• MDMA Ecstasy
• I. General Information
• MDMA designer drug that is a modified
  methamphetamine molecule - 3,4
  methylenedioxymethamphetamine
• Across the amphetamine analogues, structural
  differences effect the CNS potency and specifics
  of action.
• structures resemble that of NE, E, DA (and SE)
  neurotransmitters
• Methoxylation of the benzene ring adds
  serotonergic action
• Structure of MDMA also resembles mescaline,
  psychoactive compound in peyote cactus, a
  serotonergic hallucinogen

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Gray carbon White hydrogen Red
oxygen Blue - nitrogen
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ECSTASY
SEROTONIN
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• II. History
• patented in 1914 by a German Company as an
  appetite suppressant then withdrawn due to side
  effects
• MDMA introduced in US as adjunct to
  psychotherapy in 1968 illicit sources not made
  by a pharmaceutical company
• initial illegal use mostly in Boston and
  Chicago, then spread
• some psychotherapists (Harvard and elsewhere)
  support its use as an empathogen means to
  enhance empathy, introspection,communication,
  intimacy, reduce fear/anxiety.
• 2004 federally funded study to reduce fear in
  terminally ill cancer patients so efforts still
  ongoing

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• mid 1980s, the DEA classified MDMA as a Schedule
  I drug high abuse potential, no medical use,
  unsafe and illegal
• then protests occurred and it was removed from
  Schedule I status in 1/27/1988 psychiatrists
  argued that it was safe when used under physician
  supervision
• Then 2/22/88 changed again to Schedule I where
  it is now
• as recreational drug, between 1993 and 1999, use
  increased 500 -mostly adolescents and young
  adults
• over 2 million tablets are smuggled into US each
  week and also made here
• illegal manufacturers (Holland Belgium Israel)
  have their own logos Butterflies Lightning
  Bolts Four Leaf Clovers

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• III. Acute Actions
• taken as tablets or capsules in doses of 1-2
  mg/kg (usually 50 to 150 mg)
• doses often piggy-backed in a series over a few
  hours
• on empty stomach, some absorption in stomach
  most in small intestine
• effects begin in 15 minutes, last 2-6 hours
• MDMA blocks both the Serotonin and the Dopamine
  transporter and increases release
• effects are more pronounced on serotonin than on
  dopamine system (revolving door)
• high levels of serotonin get released and remain
  in synapse

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Functional Effects Increased mood Increased
perceptual intensity Increased sense of closeness
to others Increased motor activity Decreased
fatigue Increased blood pressure and heart rate
(cardiac arrhythmias may occur) Increased body
temperature (malignant hyperthermia can
occur) Decreased appetite and drinking
(dehydration can occur) Some develop an acne-like
rash sign for high risk for liver damage
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IV. After-effects (several days) Depression Anxie
ty Irritability/Aggression Impulsivity Sleep
problems Chills or reduced body
temperature Animal studies suggest 2 weeks for
serotonin levels to return to normal.
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V. Long term effects
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Specific studies 1. Human users studied
history of 6 times/year for more than a year
(average total use of 75 times) Drug clear for 2
weeks, then given MDMA twice in 1 week Measured 2
weeks later - reduced attention and working
memory (verbal and visual) - decreased blood
flow in brain (remember serotonin plays role in
intracranial blood flow) 2. Other research on
human users at 6 mo. post-use - reduced
manufacturing of serotonin - reduced memory
performance 3. Primate research suggest
abnormalities at 6-7 years post.
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Clear effects on memory. Ex-users may be worse
than current because they stopped due to more
problems or longer history (or were different to
start with)
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Reduced serotonin levels (should show more
lavender like normals)
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6-7 year reduction in serotonin in primate
studies.
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VI. Effects on the fetus Vorhees work in rats
long term dose-related effects on memory and
learning Human as yet unknown many
confounding variables