The War on Drugs

1
The War on Drugs

• The Ethics Rationale Behind the Federal
  Governments Other War

2
The War on Drugs

• Robert Portley
• Isuru Kumarasinghe
• Brooke LaFlamme
• John Widen
• Arvind Vijayasarathi
• Scientific and Ethical Aspects of Behavior
  Modification
• Dr. Victor Hruby
• 18 April 2006

3
Presentation Overview

• Introduction History and Controversial Features
• The Chemistry of Illicit Drugs Physiological
  Effects/Mechanisms
• Treatment Options The Anti Drug
• The Global Drug Trade Supply Issues
• Conclusion Summary Ethical Aspects

4
Introduction

• The History and Controversy

5
War on Drugs Policy

• The Modern War on Drugs began in 1971 when Nixon
  identified abuse of illicit substances as
  "America's public enemy number one."
• In 1988 the Anti-Drug Abuse Act created the
  Office of National Drug Control Policy (ONDCP)
• This branch of the executive office was created
  to centrally coordinate the political aspects of
  the war on drugs under direction of the Drug Czar.

6
Objectives of the War on Drugs

• Reducing drug related crime and drug caused
  health problems by reducing drug use
• Drug addiction was moved from being a personal
  problem to a public problem
• It is the declared policy of the United States
  Government to create a Drug-Free America by 1995
  Anti-Drug Abuse Act 1988

7
What constitutes abuse?

• A drug is a substance to affect mood or behavior
• For U.S. public policy purposes, drug abuse is
  any personal use of a drug contrary to law.

8
ONDCP

• John P. Walters current Drug Czar since 2001
• 2006 National Drug Control Strategy
• Goals
• Stopping drug use before it starts
• Healing drug users
• Disrupting the market for illicit drugs.

9
Drug War Expenditures

• FY 2002 funding for the war on drugs was 18.8
  billion according to ONDCP
• http//www.drugsense.org/wodclock.htm

10
History

• Harrison Narcotics Tax Act 1914
• Tax on opium and cocaine
• Marihuana (sic) Tax Act 1937
• Imposed a tax on commercial distribution and lead
  to eventual ban
• Controlled Substance Act 1970
• 5 Schedules (classes) determined by DEA and HHS

11
History (Cont.)

• Drug Prohibitions targeted racial groups
• Opium as a way to target Chinese Immigration
• Cocaine due to racist fears about African
  Americans
• Marijuana during the depression targeted Mexicans
  
• Despite popular belief to the contrary, there was
  never evidence that the laws were necessary, or
  even beneficial, to public health and safety

12
Constitutionality

• The Controlled Substances Act stresses the impact
  of intrastate drug offences on "interstate
  commerce" and the "general welfare" of the
  American people.
• Therefore circumventing any constitutional
  objections regarding states rights
• Medicinal Marijuana usage was initially approved
  by the ninth circuit but lost in the Supreme
  Court in 2005

13
Schedule 1 Drugs

• (A) The drug or other substance has a high
  potential for abuse.
• (B) The drug or other substance has no currently
  accepted medical use in treatment in the United
  States.
• (C) There is a lack of accepted safety for use of
  the drug or other substance under medical
  supervision.
• These include
• GHB, LSD, Marijuana, Heroin, Ecstasy, Peyote

14
Schedule 2 Drugs

• A) The drug or other substance has a high
  potential for abuse.
• (B) The drug or other substance has a currently
  accepted medical use in treatment in the United
  States or a currently accepted medical use with
  severe restrictions.
• (C) Abuse of the drug or other substances may
  lead to severe psychological or physical
  dependence.
• These include
• Cocaine
• Ritalin
• Opium, morphine, oxycodon
• Amphetamines

15
Schedule 3 Drugs

• (A) The drug or other substance has a potential
  for abuse less than the drugs or other substances
  in schedules I and II.
• (B) The drug or other substance has a currently
  accepted medical use in treatment in the United
  States.
• (C) Abuse of the drug or other substance may lead
  to moderate or low physical dependence or high
  psychological dependence.
• Includes Anabolic Steroids

16
Schedule 4 Drugs

• (A) The drug or other substance has a low
  potential for abuse relative to the drugs or
  other substances in schedule III.
• (B) The drug or other substance has a currently
  accepted medical use in treatment in the United
  States.
• (C) Abuse of the drug or other substance may lead
  to limited physical dependence or psychological
  dependence relative to the drugs or other
  substances in schedule III.
• Includes Xanax and Valium

17
Schedule 5 Drugs

• (A) The drug or other substance has a low
  potential for abuse relative to the drugs or
  other substances in schedule IV.
• (B) The drug or other substance has a currently
  accepted medical use in treatment in the United
  States.
• (C) Abuse of the drug or other substance may lead
  to limited physical dependence or psychological
  dependence relative to the drugs or other
  substances in schedule IV.
• Includes codeine containing cough suppressants

18
How big is the drug problem?

• We dont know
• Unable to accurately determine number of drug
  users or money spent on illegal drugs due to the
  nature of the subject
• 34.8 million Americans ages 12 or over (14.5 of
  the US population ages 12 and over) used an
  illicit drug during the previous year.

19
Drug Mortality Statistics (per year)

• Tobacco kills about 390,000.
• Alcohol kills about 80,000.
• Second hand smoke from tobacco kills about
  50,000.
• Cocaine kills about 2,200.
• Heroin kills about 2,000.
• Aspirin kills about 2,000.

20
Drug Mortality Statistics (contd)

• Marijuana kills 0.
• There has never been a recorded death due to
  marijuana at any time in US history.
• All illegal drugs combined kill about 4,500
  people per year, or about one percent of the
  number killed by alcohol and tobacco. Tobacco
  kills more people each year than all of the
  people killed by all of the illegal drugs in the
  last century.

21
Non-Drug Related Deaths in U.S.

• Air pollution - 50,000 - 100,000
• Diabetes - 73,000
• Alzheimers - 60,000
• Automobile - 30,000
• HIV 23,000
• Suicide 13,000
• Still almost 100,000 less than tobacco related
  deaths

22
Health Impact

• Rockefeller University concluded that "Tobacco is
  unquestionably more hazardous to the health than
  heroin."
• Forty percent of all hospital care in the United
  States is for conditions related to alcohol.
• As a medical hazard, few drugs can compete with
  alcohol or tobacco on any scale.

23
Do Drugs Cause Crime?

• Alcohol is the only drug
• whose consumption
• has been shown to
• increase aggression
• Alcohol Prohibition gave rise to a violent
  criminal organization. Violent crime dropped 65
  percent in the year Prohibition was repealed.

24
Policy Causes Crime
25
Policy Causes Crime (contd)

• In 1933 the homicide rate peaked at 9.7 per
  100,000 people, which was the year that alcohol
  prohibition was finally repealed.
• In 1980, the homicide rate peaked again at 10
  per 100,000, coinciding with the escalation of
  the War on Drugs.

26
Crime Societal Impact

• The vast majority of drug-related violent crime
  is caused by the prohibition against drugs,
  rather than the drugs themselves
• Illegal drugs and violence are linked primarily
  through drug marketing
• Drug-related crime is a
• direct result of drug prohibition's
• distortion of immutable laws of
• supply and demand.

27
Mandatory Minimum Sentencing

• Low level drug offenders are often imprisoned
  longer than rapists, child molesters, bank
  robbers, and those convicted of manslaughter
• Since the enactment of mandatory minimum
  sentencing for drug users, the Federal Bureau of
  Prisons budget has increased by 1,954. Its
  budget has jumped from 220 million in 1986 to
  more than 4.3 billion in 2001
• Drug courts and drug treatment programs are seen
  as money saving alternatives to imprisonment

28
Average Federal Sentences

• Drug offenses-6.5 years
• Sex offenses-5.8 years
• Manslaughter-3.6 years
• Assault-3.2 years
• Racketeering-5 years
• Extortion-5 years

29
Costs to Society

• The cost to put the average drug offender in jail
  is about 450,000
• 1.5 million people in prisons across the United
  States
• Drug Offenses 59.6
• Of the 1,745,712 arrests for drug law violations
  in 2004, 81.7 (1,426,247) were for possession of
  a controlled substance. Only 18.3 (319,465) were
  for the sale or manufacture of a drug.

30
Federal Prisoners (By Offense)
31
Common Myths Influencing Drug Policy

• Myth 1 Experimentation with drugs is not a
  common part of teenage culture
• Myth 2 Drug use is the same as drug abuse
• Myth 3 Marijuana is the gateway to drugs such
  as heroin and cocaine
• Myth 4 Exaggerating risks
• will deter young people from
• experimentation.

32
Drug War Programs

• National Youth Anti Drug Media Campaign
• DARE
• The High-Intensity Drug Trafficking Area Program
• Drug Endangered Children

33
Inefficacy of Anti-Drug Campaigns

• The National Youth Anti-Drug Media Campaign is a
  multi-dimensional effort to educate and empower
  youth to reject illicit drugs.
• Congressional Appropriations committee deeply
  disturbed by the lack of evidence that the
  National Youth Anti-Drug Media Campaign has had
  any appreciable impact on youth drug use in 2002.

34
DARE

• Drug Abuse Resistance Education (K-12)
• National Youth Program that teaches kids to just
  say no to drugs
• Zero Tolerance - one of the creators at a 1990
  testimony before the U.S. Senate said that the
  casual user ought to be taken out and shot,
  because he or she has no reason for using drugs.
  When asked about this outrageous testimony, he
  stressed that he was not being facetious and
  asserted that marijuana users were guilty of
  treason.

35
DARE Ineffectiveness

• Glamorizes drugs
• Mixed message
• Self fulfilling prophecy
• Hidden agenda

36
The High-Intensity Drug Trafficking Area Program

• Areas within the United States which exhibit
  serious drug trafficking problems and harmfully
  impact other areas of the country
• Provides additional federal resources to those
  areas to help eliminate or reduce drug
  trafficking and its harmful consequences. Law
  enforcement organizations within HIDTAs assess
  drug trafficking problems and design specific
  initiatives
• HIDTA-designated counties comprise approximately
  13 percent of U.S. counties, they are present in
  43 states, Puerto Rico, the U.S. Virgin Islands
  and the District of Columbia.

37
Drug Endangered Children

• Programs have been developed to coordinate the
  efforts of law enforcement, medical services, and
  child welfare workers to ensure that children
  found in environment where illegal substances are
  produced receive appropriate attention and care.
• Risks children face in these environments
  include inhalation or ingestion of chemicals,
  fires, neglect, and generally hazardous living
  conditions.
• There were 1,660 children affected by or injured
  or killed at methamphetamine labs during calendar
  year 2005.

38
Possible Solution

• The overwhelming weight of the scholarly evidence
  on drug policy supports decriminalization. Every
  major study of drug policy in history has
  recommended a non-criminal approach.
• The best analysis done to date by any Federal
  official shows that "legalization" of the now
  illegal drugs would result in a net 37 Billion
  annual savings. This estimate is considered
  conservative.

39
Alternative Policies

• Harm reduction diminishing individual and social
  risks associated with potentially dangerous
  behaviors.
• Decriminalization without legalizing the
  currently banned substances decriminalizing them
  would relieve the burden from law enforcement and
  society
• Non incarceration deterring offenders to
  treatment and rehabilitation rather than
  imprisonment

40
Benefits of Decriminalization

• Decriminalization would increase the use of the
  previously criminalized drug, but would decrease
  violence associated with attempts to control
  illicit markets and as resolutions to disputes
  between buyers and sellers.
• Moreover, because the perception of violence
  associated with the drug market can lead people
  who are not directly involved to be prepared for
  violent self-defense, there could be additional
  reductions in peripheral settings when disputes
  arise.

41
Non-Incarceration

• Drug courts and local policies which favor
  treatment
• In 1996, Arizona Proposition 200, the Drug
  Medicalization Prevention and Control Act which
  sends first and second time non-violent drug
  offenders to treatment rather than incarceration.
  
• Saved Arizona taxpayers 6.7 million in 1999.
• In addition, 62 of probationers successfully
  completed the drug treatment ordered by the
  court.

42
California Non-incarceration

• In November 2000, 61 percent of California voters
  passed Proposition 36, the Substance Abuse and
  Crime Prevention Act (SACPA), an initiative aimed
  at rehabilitating rather than incarcerating
  non-violent drug possession offenders. Under
  SACPA, certain persons convicted of non-violent
  drug possession offenses are given an opportunity
  to receive community-based drug treatment in lieu
  of incarceration.
• By treating rather than incarcerating low level
  drug offenders, SACPA would save California
  taxpayers approximately 1.5 billion over the
  next five years and prevent the need for a new
  prison slated for construction, avoiding an
  expenditure of approximately 500 million.
• 36,000 would be diverted to alternative treatment
  programs

43
Admission of Defeat

• A report released in December 2005 by the
  Government Accountability Office showed that,
  despite U.S. law to the contrary, the more than
  50 plus agencies working on the National Drug
  problem have little effect on the overall
  production and consumption of illegal drugs

44
The War on Drugs Could be Won If

• We could stop drug production in other countries.
  
• We could stop drugs at the border.
• We could stop the sale of drugs within the United
  States.
• However, these are unattainable goals, so why do
  we continue?

45
References

• Eddy, Mark. War on Drugs Legislation in the
  108th Congress and Related Developments. 4 April
  2003.
• Rosenbaum, Marsha. Safety First A reality based
  approach to teens drugs and drug education. Drug
  Policy Alliance 2004.
• US Department of Justice, Bureau of Justice
  Statistics, Sourcebook of Criminal Justice
  Statistics 1996 (Washington DC US Dept. of
  Justice,1997), p.20
• Executive Office of the President, Budget of the
  United States Government, FY 2002 (Washington DC
  US Government Printing Office,2001), p.134.
• U.S. National Center for Health Statistics,
  Health, United States, 2004.
• Negro Cocaine Fiends New Southern Menace, New
  York Times, February 8, 1914
• Controlled Substances Act - U.S. Drug Enforcement
  Administration 1970
• www.druglibrary.org
• www.drugwarfacts.org
• www.drugpolicy.org

46
The Chemistry of Illicit Drugs
Physiological Effects and Mechanisms
47
Section Overview

• Drugs classification
• Drugs mechanism of action
• Illegal drugs and their mechanism of action

48
Receptors, Agonists Antagonists

• Receptor
• Any target molecule with which a drug molecule
  has to combine in order to elicit its specific
  effect.
• When drug molecule binds to receptor molecule,
  there will be cascade of reactions adrenaline
• Agonist and Antagonist
• Agonist binds to the receptor and activates the
  receptor, but antagonist binds to the receptor
  and does not activate the receptor and it
  prevents binding agonist to the receptor.

49
Drug Specificity

• Drugs specificity
• Drug must act selectively on particular cells or
  tissue. It must show high degree of binding
  specificity. Remove or substitute an amino acid
  from a peptide drug lose it selectivity for the
  target molecule. No drug acts complete
  specificity. Side effects are due to non
  specificity.
• Lower the potency of the drug, higher the dose
  needed. Binding and activation are two distinct
  steps
• Tendency of drug molecule to bind to the receptor
  called affinity and tendency for it once bound
  activate the receptor is denoted by its efficacy.
• Drug with high potency generally have high
  affinity for the receptor thus occupy significant
  proportion of receptor even at low
  concentrations.

50
Agonists Antagonists
K1
? a
Drug ( agonist) (A)
Receptor (R)
AR
AR

Response
K-1
K1
No Response
Drug ( agonist) (A)
Receptor (R)
AR

K-1

• Agonist has high efficacy
• Antagonist has zero efficacy
• Drug with intermediate levels of efficacy such
  that even when 100 of the receptor are occupied
  the tissue response is sub maximal are called
  partial agonist.

51
Receptor Binding

• The binding of a drug to a receptor can often be
  measured directly by the use of radio active drug
  molecule. Radio active ligand should bind with
  high affinity and high specificity.
• Method is incubate the sample of tissue with
  various concentrations of radio active drug until
  equilibrium is reached. Tissue is then removed or
  isolate and radio activity amount will be
  quantitated.

52
Binding curves
Specifically bound (Fmol /mg)
This is the relationship between concentration
and amount of drug bound
Concentration (nmol /l)
Dose response curve
Biological response Rise in blood
pressure Activation of enzyme Contraction or
relaxation of strip of smooth muscle
E max maximal response that the drug can
produce Emax EC50 or ED50 Concentration or
dose needed to produce a 50 maximal response
53
EC50 or ED50 values used to comparison of
potencies of different drugs that produce
qualitatively the similar effect Dose response
curve can not be used to measure the affinity of
agonist drugs for their receptor
Agonist occupancy decreases in the presence of
antagonist in competitive antagonism
10
20
30
54
Biological response (max)
In the presence of agonist
(100 efficacy)
100
Partial agonist
(Sub maximal response)
50
occupancy
50
100
Inverse agonist
(Negative efficacy)
Inverse agonist - Ligand that reduces level of
constitutive activation
55
Targets for the drug action

• Enzymes
• Carrier molecules
• Ion channels ( voltage sensitive sodium channel
  for local anesthetics)
• Receptors
• Exceptions some drugs binds to plasma protein,
  site of action of some drugs is still unknown.
  Antimicrobial drug and antitumor drugs, mutagenic
  and carcinogenic agents interact directly with
  DNA

56
Receptor

• Receptors are the sensing elements in the system
  of chemical communication that coordinates the
  function of all the different cells in the body
• Drugs act as agonist or antagonist on receptor

Ion channel opening and closing
Direct
Agonist molcule
Enzyme activation and inhibition Ion channel
modulation DNA transcription
Transduction mechanism
Receptor
Antagonist molcule
No effect endogenous mediators blocked
Receptor
57
Types of receptors
Binding domain
Catalytic domain
G protein coupling domain
Channel
DNA Binding domain
Ligand gated ion channel
G protein coupled receptor
Kinase linked receptor
Nuclear receptor
Response in seconds. These are for hormones and
slow neurotransmitter E.g Adrenoreceptor,
acetylcholine, dopamine and opiate receptors.
Fast response (milliseconds).These are for
neurotransmitter E.G.Nicotonic acetylcholine
receptor, GABA receptor, gluatmate receptor
Response in hours. Features Receptors for
insulin, cytokines and growth factors
Response in hours regulate the gene expression.
Receptors for steroid hormones or thyroid
hormones.
58
G protein coupled receptor families
Shares same heptahelical structure but differ in
length of N terminus and location of agonist
binding domain. What is importance of having
cytoplasmic loop? How it relates to response?
Mechanism of receptor activation
Rhodopsin is activated by light induced cis-trans
isomerization For thrombin, protease activate the
receptor by cutting first N terimnal tail (41
residue), then the liberated N terminal binds to
the receptor domains in the extra cellular loops
and function as agonist (tethered) Inactivation
is by phosphorylation. Due to the mutation in
the receptor, it can be constitutively active.
Several human diseases associate with this.
59
Signal transduction is by GPCR First stage of
signal transduction is through G proteins
Resting state
G proteins is made of 3 subunits a,ß, ?. There
three types Gi, Gs, or Gq G proteins are able to
diffuse in plane of membrane Agonist binds to the
receptor. GDP/GTP exchange happens. Dissociation
of complex occurs. a-GTP and ß? are active form
of G protein. They can activate/or inactivate
enzymes and ion channels (effectors). Process is
terminated when GTP hydrolyze to GDP. Then a
subunit dissociate from the effector and reforms
complex with ß and ? These enzymes produce
products and they act as second messengers
60
Lipase inactive
Second messenger
Increased lipolysis
Protein kinase(inactive)
ATP
Lipase active
Glycogen synthase (active)
cAMP
Reduced glycogen synthesis lipolysis
Protein kinase (active)
Glycogen synthase (inactive)
Phosphorylase kinase (inactive)
Increased glycogen synthesis

• 80 of Drugs in the market target for G
  proteins. Since GPCR controls different cell
  function through followings
• Adenylate cyclase enzyme responsible for cAMP
  formation (it regulates magnitude of cAMP
  Formation) cAMP controls energy metabolism, cell
  division, ion transport, ion channels and
  contractile protein in smooth muscle. cAMP
  ultimately activates of protein kinase in turn
  activate or deactivate enzymes or ion channels
• Phospholipase C The enzyme responsible for
  inositol phosphate and diacylglycerol formation
• Ion channels Calcium and pottasium channels

Phosphorylase b inactive
Phosphorylase kinase (active)
Phosphorylase b active
61
Hydrolysed products of cAMP
cAMP
Methylxanthine, Theophylline, Caffeine Slidenfil(v
iagra)
phosphodiesterase
62
Ion channels
Blockers
Permeation blocked
E.g. voltage gated sodium channel
Increased or decreased opening probability
modulators
Ion channels known as ligand gated ion channels.
These open only when agonist molecule occupies
the receptor. Other has different
mechanism. Interaction of the agonist molecule is
direct or indirect. Direct is drug binds to it
and change is fuction. Indirect mechanism happens
through G protein coupled receptor
63
Enzymes
Normal reaction inhibited
inhibitor
False substrate
Abnormal metabolite produced
prodrug
Active drug produced
Agonist /normal substrate
Many drugs target the enzymes. Often the drug
molecule is substrate analogue that act as
competitive inhibitor of the enzyme reversibly or
irrevesibly. Drugs also act as false substrate,
where drug molecule undergoes chemical
transformation to form an abnormal product that
subverts from normal metabolic pathway e.g.
Flourouracil Drug toxicity can happen when
enzymes converts the drug molecules to reactive
intermediates Drugs require the enzymetic
degradatation activty converts from inactive
prodrug to active drug molecule
64
Biosynthesis of PGs
Phospholipids
Phospholipase A2
Lipoxygenase pathway
Arachidonic acid
Leukotriene
Cyclooxygenease reaction
Block by NSAIDS e.g. naproxen, ketoprofen,
ibuprofen
PGG2
Cyclcoxygenase peroxidase reaction
PGH2
PGI2
TXA2
Prostacyclinsynthease
Thromboxan synthase
Promotes plattlet aggregation
Develops inflammation Dialate small blood
vessel Vascular permeability (causes
swelling) Sensitize the peripheral nerve ending
nociceptors to transmit pain signal to brain
Isomerase
PGE2
PGD2
reductase
Cytoprotective propoeties in GI track Control the
renal function since PGs act as a
vasodilator Plattlet aggregation
(TXA2) Bronchodialation (PGE2)
PGF2a
65
Transporters
Normal transport
inhibitor
Agonist /normal substrate
False substrate
Abnormal compound accumulated
Transport of ions or organic molecule through the
lipid membrane requires the carrier protein
because permeating molecules are always too
polar. (glucose , amino acids, Na, K , Cl Carrier
protein molcules or transport molecules always
has a special site for recognize the permeating
ions. These recognition sites are always targets
for drugs that block the transport system
66
It is extracted from cannabis sativa In 300, AD
people found that the cannabis increases hunger
and appetite particularly for sweet and palatable
food ?9 Tetrahydrocannabinol (THC) is the
active component ?9 Tetrahydrocannabinol (THC)
contains 1-10 of weight of marijuvana and
hashish. Marijuvana is name given to dried leaves
and flower heads prepared as smoking mixture.
Until 20 th century due to antimarijuana
attitude research in this area was neglected
67
Receptor for Cannabis

• Cannabis interacts with two types of receptors
  CB1 and CB2
• Cannabinoid receptor belongs to G protein coupled
  receptor superfamily
• Cannabis activates the receptor by modulating
  adenylate cyclase, activating potassium and
  inhibition of calcium channels.
• CB1 mainly found in CNS. So we called this one as
  brain type cannabinoid receptor where as CB2
  mainly expressed in immune cells it considered as
  peripheral part.
• This classification is wrong since some CB1
  express in periphery and someCB2 express in brain
• In brain, CB1 modulates the release of
  neurotransmitter including gaba aminobutyric
  acid, dopamine, noradrenaline, glutamate and
  serotonin

68
Pharmacological Effect

• This acts mainly on CNS and producing the mixture
  of psychotomimetic and depressant effect
• Gives a feeling of relaxation and well being
  similar to the effect of ethanol.
• Gives feeling of sharpened sensory awareness
• Central effect that can be directly measured by
  human and animal studies. Those are impairment of
  motor coordination and increased appetite and
  analgesia
• Regulates the feeding behavior
• Peripheral effect
• Vasodilatation, reduction of intraocular
  pressure, bronchodilation

69
Dronabinol treat for chemotherapy induced
nausea

• These are substance extract from plants and
  several synthetic compound. (3 ring)
• Analogues of ?9 Tetrahydrocannabinol (THC)
• Third is used for experimental models
• Mimic the effects of plant derived ?9
  Tetrahydrocannabinol (THC). But structure is not
  similar.

Antagonist this use for therapy for obesity and
eating disorders
70
Tolerance of Marijuana

• Tolerance
• Tolerance to cannabis occurs in minor degree and
  mainly in heavy users. Withdrawal effect is as
  same as withdrawal effect of opiate and ethanol
  e.g. nausea, agitation, irritability, confusion.
• Overall it can not be classified as addictive
• Smoking marijuana is better tolerated than the
  oral administration of the principle component

71
Adverse Effects of Marijuana

• THC is relatively safe in overdose proving
  drowsiness and confusion.
• It is safer than most abused substance e.g.
  opiate and ethanol.
• Cannabis lowers the plasma testosterone and a
  reduction of sperm count
• Smoking cannabis may be officious in no of
  conditions. It provide relief of pain relief of
  other types of chronic neuropathic pain.
• Improvement of appetite
• Also gives relief from chemotherapy induced
  nausea

72
Heroin
73
Heroin (Contd)

• Diamorphine- is the diacetyl derivative of
  morphine. This rapidly deacyletate to morphine in
  the body
• Because of the lipophilicity, it will pass blood
  barrier more rapidly than morphine
• It can be used as an analgesic
• Half life is 2 hours because its very rapid
  action, Causes dependence
• Agent produces euphoria, analgesia, respiratory
  depression and sleep. Nausea and vomitting,
  constipation. Overdose causes the coma

74
Heroin (Contd)

• Mechanism of action is through G protein coupled
  receptors. It inhibit the adenylate cyclase. So
  it reduces the intracellular cAMP amount. Also it
  effect to the ion channel. It opens k
  channel.(causes the hypoploarization) and closes
  the Ca channel (inhibiting transmitter release).
  Three different receptors. Alpha, beta and mu(
  mostly reside in brain). Analgesia effect is from
  mu receptor
• For heroin abuse, patients are treated with
  naloxone.

75
Cocaine
76
Cocaine (Contd)

• This is potent stimulant of the central nervous
  system. Exact mechanism of action is unclear
• Cocaine acts by inhibiting catecholamine uptake
  (especially dopamine) by nerve terminals. It
  blocks the noradrenaline and dopamine
  transporters. This causes dopamine
  overaccumilation in certain regions of brain.
• Cocaine also interact with GABA and opioid
  receptor

77
Cocaine (Contd)

• Produces euphoria, increases motor activity
• Duration of action is shorter
• Behavioral effects of cocaine are similar to
  those of amphetamines
• Causes the strong psychological dependence
• Still this uses as a local anesthetics
• Treatment for the cocaine abuse has to be
  multitarget.

78
Amphetamines and Methamphetamines
Pharmacological effect
Methamphetamine
Locomotor stimulation Euphoria and
excitement Stereotyped behavior anorexia
Amphetamine
Releases the monoamines from nerve terminals in
the brain Effects mainly from release of
catecholamines such as noradrenaline and
dopamine. 5 Hydroxytryptamine (5-HT) release
also occurs Stimulant effect lasts for few hours,
after then depression and anxiety Amphetamine
psychosis can develop due to prolong use
79
References

• Endogenous cannabinoid system as a modulator of
  food intake, International journal of obesity
  (2003),27,289-301
• Molecular approaches to treatment for cocaine
  abuse, Journal of molecular structure (2003),
  259-267
• Pharmacology, fifth edition, H.P Rang, M. M Dale,
  J.M Ritter, P.K Moore, 2003,pp 7-45

80
Treatment Options
The Anti-Drugs
81
National Policy on Drug use3 parts

• Stopping Drug use before it starts through
  education
• Healing Americas drug users through treatment
  and intervention
• Disrupting the market

82
Chapter 2 Healing Americas Drug Users

• Even though drug use is down, because of
  increased education, the Administration has made
  intervention and treatment a top priority
• The ONDCP states that 19.1 million Americans have
  used an illicit substance in the past month.
• The governments goal is to decrease the use of
  illegal drugs while providing help to addicts

83
Healing Americas Drug Users--Strategies

• Support Many non-medical support systems exist
  for recovering addicts. Examples include AA,
  Oxford House, and other faith-based groups.
• Medical treatment Using drugs to combat drug use

84
The Anti-Drugs Marijuana

• Marijuana is the most commonly used illicit
  substance (ONDCP)
• In 2001, 14.7 (about 255,394) of drug treatment
  admissions in the U.S. were for marijuana use
• 56.8 of those were referred through the
  criminal justice system
• We may have a drug to cure your marijuana
  addiction!

Marijuana is a schedule 1 substance in the U.S.
(eg heroin, LSD) There are NO legal uses of
marijuana under federal law
85
Rimonabant (SR141716A)

• SR141716A was first introduced in 1994 as an
  antagonist of the brain cannabinoid receptor, CB1
  (Rinaldi-Carmona, et al. 1994)
• The drug will be sold by Sanofi-Aventis as
  Acompila for the treatment of obesity starting
  this year. The FDA is requiring further
  information before it can be sold in the U.S.
• Studies are being conducted on the effectiveness
  of Rimonabant in treating addiction to tobacco,
  alcohol, and marijuana

86
RimonabantWhat does it do?

• A study in humans showed this drug prevents
  symptomatic hypotension in marijuana smokers
  (dizziness, lightheadedness
• Rimonabant produces withdrawal symptoms in lab
  animals addicted to cannibinoids (eg Beardsley
  Martin, 2000)

• SR141716A binds to the central cannabinoid
  receptor (CB1), but not to the peripheral
  receptor CB2, with nanomolar affinity
• CB1 is a G-protein coupled receptor found in the
  brain and some peripheral tissues. Natural
  ligands include anandamide and 2-AG. This
  receptor system is thought to play a role in
  regulating blood pressure, etc.
• Acute administration of SR141716A decreased
  glucose intake of rats, especially in those
  tolerant to THC (Freedland, et al. 2002)

87
The highest density of CB1 receptors is in the
basal ganglia
88
Other anti-marijuana drugs

• Rimonabant blocks the receptor for ?9-THC, but it
  does not help withdrawal symptoms.
• The following drugs have been tested in animals
  for their use in treating withdrawal symptoms
  associated with cannabinoid abstinence (reviewed
  in Hart, 2005)
• Clonidine (Lichtman, et al. 2001) reversed some
  withdrawal-related symptoms (paw tremors, head
  shakes) in mice
• Prostoglandin E2 (Anggadiredja, et al. 2003)
  alleviated withdrawal symptoms
• Lithium (Cui, et al. 2001) blocked withdrawal
  symptoms

89
If you want to learn more

• Rinaldi-Carmoni, M., et al. (1994) SR141716A, a
  potent and selective antagonist of the brain
  cannabinoid receptor. FEBS Letters 350 240-244.
• Marx, J. (20 Jan 2006) Drugs Inspired by a
  Drug. Science 311 322-325.
• Gorelick, D.A., et al. (2006) The Cannabinoid
  CB1 Receptor Antagonist Rimonabant Attenuates the
  Hypotensive Effect of Smoked Marijuana in Male
  Smokers. Am Heart J 151 754e1-e5.
• Cohen, C., et al. (2005) CB1 Receptor
  Antagonists for the treatment of Nicotine
  Addiction. Pham Biochem Beh 81 387-395.
• Hart, C. (2005) Increasing Treatment Options for
  Cannabis Dependence A Review of Potential
  Pharmacotherapies. Drug and Alcohol Dependence
  80 147-159

90
The Anti-Drugs Opiates

• ONDCP heroin is highly addictive and considered
  one of the most abused opiates. It is a Schedule
  I drug.
• A rough estimate of the hardcore addict
  population in the United Statesbetween 750,000
  and 1,000,000
• Many drugs exist to treat heroin addiction

91
The anti-drugs Opiates

• Buprenorphine
• Methadone
• Naltrexone
• RF9

92
Opioid Agonists
methadone
buprenorphine
Heroin (diamorphine)

• Buprenorphine µ agonist/? antagonist
• Also shown to be an effective antidepressant
  (Bodkin, et al. 1995)
• May be more effective at reducing heroin use in
  depressed addicts (Gerra, et al. 2005)

• Methadone Chemically, the simplest opiate.
  Methadone is a Schedule II drug (eg cocaine,
  Ritalin)
• Can be administered orally or by injection
• Almost always, methadone must be taken
  indefinitely

93
Opioid Antagonists

• Naltrexone Competitive antagonist at opioid
  receptors, completely blocks action of opioid
  agonists (Comer, et al. 2006), except
  buprenorphine
• Used in rapid detox regimens
• Can cause increased sensitivity to opioids after
  use.
• Shown to be more effective at treating cravings
  than methadone (Grusser, et al. 2006)

naltrexone
94
Opioid Antagonists

• RF-9 Antagonist of a different receptor (NPFF
  receptor) involved in pain modulation and
  tolerance to opiates (Simonin, et al. 2006)
• Prevents tolerance to opiates by decreasing
  hyper-analgesic effects
• Only tested so far in rats not currently under
  consideration for treatiment of heroin addiction

95
If you want to learn more

• Comer, S.D., et al. (2006) Injectable,
  Sustained-Release Naltrexone for the Treatment of
  Opioid Dependence. Arch Gen Psychiatry 63
  210-217
• Coffin, P.O., et al. (2006) Support for
  Buprenorphine and Methadone Prescription to
  Heroin-Dependent Patients among New York City
  Physicians. The American Journal of Drug and
  Alcohol Abuse 32 1-6
• Grussser, S.M., et al. (2005) A New Approach to
  Preventing Relapse in Opiate Addicts A
  Psychometric Evaluation. Biological Psychology
  71 231-235
• Gerra, G., et al. (2005) Buprenorphine Treatment
  Outcome in Dually Diagnosed Heroin Dependent
  Patients A Retrospective Study. PNPBP 30
  265-272
• Simonin, F., et al. (2006) RF9, a Potent and
  Selective Neuropeptide FF Receptor Antagonist,
  Prevents Opioid-Induced Tolerance Associated with
  Hyperalgesia. PNAS 103(2) 466-471

96
The Anti-Drugs Cocaine

• In 2000, chronic users were estimated at
  2,707,000 (ONDCP)
• Occasional users were estimated at 3,035,000
• No drugs are currently approved to treat cocaine
  dependence, but many are being tested

97
Drugs for Cocaine Dependence

• Disulfiram Currently prescribed for alcohol
  dependence. Studies suggest effectiveness against
  cocaine dependence
• This drug acts by inhibiting sulfylhydryl-containi
  ng enzymes (eg acetylaldehyde dehydrogenase)
• Baclofen GABA agonist. Reduced cravings for
  cocaine in studies with humans
• Modafinil Subjects reported reduced cravings for
  cocaine and amphetamines. Increases alertness in
  narcoleptic patients and has been tested for
  treatment of ADHD.

For a review, see Vocci, F.J., et al. (2005)
Medication Development for Addictive Disorders
The State of the Science. Am J Psychiatry 162
1432-1440
98
The Anti-Drugs Methamphetamine

• Available in pure form as a prescription
  (Desoxyn) for ADHD, obesity, and narcolepsy
• It is a Class II substance
• Social stigma attached
• Can be made from household products (dont try
  this at home!)
• 597,000 people in U.S. over 12 report past month
  usage (ONDCP)
• Combat Methamphetamine Epidemic Act of 2005
  passed this March

99
The anti-drugs - Methamphetamine

• Selegiline Used in the treatment of Parkinsons
  and Alzheimers diseases
• Potential in treating ADHD, cocaine, and
  methamphetamine abuse
• Studies on the safety of selegiline in
  combination with methamphetamine have been
  conducted (eg Schindler, et al. 2003)
• Prometa Clinical trials (phase II and III) have
  been registered, but not yet started as of Dec.
  2005
• Preliminary studies show decrease in cravings and
  minimal withdrawal symptoms (Alcoholism and Drug
  Abuse Weekly 24 Oct 2005)
• Also being marketed for alcohol and cocaine
  dependence (Hythiam, Inc.)

Selegiline
Meth
100
Does Treatment Work?

• For heroin
• Methadone treatment works for certain
  individuals, but almost no one ever gets off
  methadone completely
• In one study, 2/3 of participants could not
  complete a methadone taper. 13 successfully
  switched to bupe/naltrex (Calsyn, et al 2005)

• For marijuana
• To date, no medication has been shown to alter
  cannibis self-administration by humans (Hart,
  2005)
• Side effects of Rimonabant include depression and
  anxiety
• We dont know the effects of messing with the
  endocannabinoid pathway

101
Does Treatment Work?
Gerra, et al. 2006

• MD major depression
• GAD generalized anxiety disorder
• PD personality disorder
• SC schizophrenia
• SUD substance abuse disorder

• Buprenorphine works for some people, best for
  those with major depression

102
Does Treatment Work?

• Treatment for heroin, continued
• Naltrexone completely blocks the effects of
  opiates. It would work great, except that people
  generally just stop taking it
• Sustained release injectable naltrexone as well
  as implants may help compliance, but not entirely
  fix the problem
• Naltrexone can cause rapid and severe withdrawal
  symptoms

Comer, et al 2006
103
Does Treatment Work?

• Treatment for cocaine dependence
• Disulfiram
• SIDE EFFECTS
• (See CONTRAINDICATIONS, WARNINGS, and
  PRECAUTIONS.) O.T.(C) NEURITIS, PERIPHERAL
  NEURITIS, POLYNEURITIS, AND PERIPHERAL NEUROPATHY
  MAY OCCUR FOLLOWING ADMINISTRATION OF DISULFIRAM.
• Multiple cases of hepatitis, including both
  cholestatic and fulminant hepatitis, have been
  reported to be associated with administration of
  disulfiram.
• Occasional skin eruptions are, as a rule, readily
  controlled by concomitant administration of an
  antihistaminic drug.

104
Disulfiram (contd)

• In a small number of patients, a transient mild
  drowsiness, fatigability, impotence, headache,
  acneform eruptions, allergic dermatitis, or a
  metallic or garlic-like aftertaste may be
  experienced during the first two weeks of
  therapy. These complaints usually disappear
  spontaneously with the continuation of therapy,
  or with reduced dosage.
• Psychotic reactions have been noted, attributable
  in most cases to high dosage, combined toxicity
  (with metronidazole or isoniazid), or to the
  unmasking of underlying psychoses in patients
  stressed by the withdrawal of alcohol.
• http//www.rxlist.com/cgi/generic/disulfiram_ad.ht
  m

105
Does Treatment Work?

• Baclofen side effects
• an allergic reaction (difficulty breathing
  closing of your throat swelling of your lips,
  tongue, or face or hives)     
• Seizure
• an irregular heartbeat.
• Other, less serious side effects are more likely
  to occur
• drowsiness, dizziness, weakness, or unusual
  fatigue     
• a headache     
• constipation     
• stuffy nose     
• blurred vision     
• Rash
• frequent urination.
• For more information see ? http//baclofen.drugs.c
  om/

106
Does Treatment Work?

• Modafinil
• Side effects headache, nausea, nervousness,
  rhinitis, diarrhea, back pain, anxiety, insomnia,
  dizziness, and dyspepsia
• http//www.rxlist.com/cgi/generic2/modafinil_ad.ht
  m
• For methamphetamine dependence
• Selegiline
• Side effects This medication may cause stomach
  upset, loss of appetite, nausea, heartburn or dry
  mouth.
• http//www.medicinenet.com/selegiline-oral/article
  .htm
• may increase dopaminergic activity by interfering
  with dopamine re-uptake at the synapse
  (http//www.rxcarecanada.com/Eldepryl.asp?prodid6
  62)
• Selegiline irreversibly inhibits the enzyme
  MAO-B. The mechanism of action is uknknown

107
Law of Unintended Consequences?General points of
interest

• The mechanisms of action of many of these drugs
  are unknown for any of their uses
• In some cases, such as methadone, treatment may
  lead to addiction to the medication, though it
  may be safer than addiction to the illicit
  substance
• The biggest concern is noncompliance. Doctors are
  therefore interested in taking the
  decision-making out of the patients hands. An
  example is naltrexone implants (not yet proven
  100 effective).
• What might be some of the unintended consequences
  of taking the problem of addiction out of the
  addicts hands?

108
The Drug Trade

• Where Drugs are Being Produced, and How Much are
  Coming into the United States

109
Global Economics of the Drug Trade

• Total trade in illicit drugs is 400 billion
  annually
• The Drug Trade accounts for Slightly more
  commerce than the textile industry

110
US Drug Policy Foreign Focus

• US drug policy emphasizes source control,
  including interdiction and eradication
• Targeting the source of drugs is often
  ineffective as new suppliers fill the demand
• A new set of suppliers quickly emerged after the
  fall of the Medellin Drug Cartel in Columbia

111
Cocaine Supply

• 75 - 90 of cocaine comes form Columbia
• 50 world wide and 60 in US is controlled by
  FARC (Revolutionary Armed Forces of Colombia)
• FARC has used the money to wage a 41-year war

112
Is Interdiction the Answer?

• Successful interdiction can lead to a
  decentralization of the illicit industry
• On the other hand, it could also lead to an
  increase in the concentration of the product
• Examples of the latter include the concentration
  of alcohol during Prohibition, and the
  concentration of Marijuana in the 1960s

113
International Implications of the US Drug War

• When considering the ethics of legalized drugs
  should we be concerned with its effect on foreign
  society?
• It is important to keep in mind that the US War
  on Drugs is part of a larger international
  effort, and thus has a number of wide-ranging
  international implications

114
Conclusion

• Connecting the Issues Ethical Analysis

115
Connecting the Issues

• Historical Statistical Analysis of the War on
  Drugs and the surrounding controversy.
• Physiological and neurobiological effects of drug
  abuse Marijuana, Cocaine, Methamphetamines,
  Heroin.
• Treating Drug abusers the Anti Drug
• Global Implications of the War on Drugs
  Combating the Supply
• Case Studies

116
Analysis of the Drug War

• The War on Drugs, in its modern form, began in
  1971.
• Overarching Goal of the War on Drugs To create a
  Drug free America
• Method of choice Arrest Incarceration of drug
  users/sellers
• Implications of the War on Drugs
• Financial - 18.8 Billion per yr. of taxpayers
  money
• Workforce Over 50 government agencies involved
  with the War on Drugs
• Prison system Drug related criminals account
  for the largest demographic of prisoners in the
  United States

117
Criticisms of the Drug War

• Drug laws have been oftentimes selectively
  enforced, arguably as a way to target racial
  minorities.
• Tobacco Alcohol account for 100 times more
  deaths than illicit drugs.
• The majority of drug-related crime stems from the
  laws that prohibit drug use/possession, not the
  effects of the drugs themselves.
• Imprisonment of drug-offenders is a severe drain
  on the nations economy.
• Some minor drug offenders face sterner
  punishment than rapists, child molesters, and
  bank robbers.

118
Failed Federal Initiatives Policies

• The National Youth Anti-Drug Media Campaign has
  produced no observable results, despite receiving
  millions of dollars in federal funding.
• Drug Abuse Resistance Education (DARE) has been
  found to send mixed messages and may actually
  serve to glamorize drugs
• The plethora of government agencies that aim to
  combat drugs have been for the most part
  ineffective.
• Is it time for a national overhaul on drug
  policy?

119
The Chemistry of Illicit Drugs

• Marijuana Schedule 1 Drug CNS Depressant
• Heroin Schedule 1 Drug Analgesic that causes
  Euphoria
• Cocaine Schedule 2 Drug CNS Stimulant
• Methamphetamine Schedule 2 Drug Stimulant
  Depressant

120
Treatment Options

• Are non-invasive measures such as drug treatment
  and rehabilitation therapy effective?
• Is it safe to use ethical drugs to treat illicit
  drug addiction?
• In the case of heroin, methadone is used as a way
  to treat addicts. However, methadone treatment
  leads to methadone addiction, rather than Heroin
  addiction, because methadone stops your body from
  going through Heroin withdrawal symptoms.
• Essentially, methadone treatment requires
  lifelong use to be effective, at what point does
  the treatment become worse than the problem?

121
The Global Drug Trade

• The Illicit Drug Business is responsible for
  upwards of 400 billion US dollars in trade
  annually.
• Though international interdiction efforts stop
  about 10-15 of illicit drugs, UN estimates show
  that at least 75 of the international drug
  shipments would need to be intercepted in order
  to have any major effect on the industry.
• It is very difficult to reduce drug supply
  because suppliers produce excess amounts in
  anticipation of government seizures
• According to Rydell Everingham, in order to
  reduce US cocaine consumption by 1 ...
• 34 million dollars is needed in drug treatment
  programs
• (or)
• 783 million dollars towards supply reduction

122
Case Study 1

• OShea Jackson, a young African-American man is
  pulled over on a routine traffic stop. The police
  officers conduct a basic search of his car and
  uncover a minimal amount of marijuana in the ash
  tray. Mr. Jackson is immediately arrested for
  Marijuana possession, and is subsequently taken
  to the local jail. After about 5 hours, Mr.
  Jackson is brought in front of a local night
  court judge. He and his public defender are
  presented with two basic options. The first
  option is to plead not guilty to felony
  possession of marijuana (perhaps the Marijuana
  was not his, but was left by another driver). By
  pleading not guilty, Mr. Jackson would spend
  upwards of 4 months in jail while awaiting trial

123
Case Study 1 (Contd)

• On the other hand, Mr. Jacksons second option is
  to simply to plead guilty, and go home in a day
  or two on Probation. Option two seems to be a lot
  more practical and preferable, as no one wants to
  spend 4 months in jail. However, by pleading
  guilty, Mr. Jackson now has a criminal record,
  and if he subsequently commits even the most
  minor of infractions he can be imprisoned for a
  number of years without a trial, for violating
  his Probation. In a three strikes state, Mr.
  Jackson is now only two minor felonies away from
  a life sentence.

124
Ethical Issues

• Mr. Jacksons situation is all too common given
  the current legal policy on Drug possession
• The people most likely to be suspected of and
  searched for illegal drugs are racial minorities
  with low socioeconomic status.
• Examples like Mr. Jacksons situation illustrate
  the way in which anti drug laws can be
  selectively used by law enforcement to target
  groups that they want to incarcerate.

125
Ethical Issues (Contd)

• This was especially prominent in the 1960s and
  70s as Black Panthers, War Protestors, and
  revolutionary students were the target of intense
  anti-drug law enforcement.
• How would Mr. Jacksons situation be different if
  he was an elite Hollywood celebrity, or an upper
  middle class white male?
• Do Drug Laws Law Enforcement that discount
  equity in favor of selective implementation
  constitute a just/ethical response to the
  nations drug problem?

126
Case Study 2

• Gross disparities in resource allocation exist
  between the ever growing US Prison Budget and the
  majority of other government expenditures. In
  1998, the US Prison system warehoused over 1
  million non-violent / low risk prisoners, the
  vast majority of whom were incarcerated due to
  drug related offenses. The taxpayer cost
  necessary to house these 1 million inmates was
  approximately 24 billion US dollars. When
  compared with the 16.6 Billion dollars the
  government spent on Welfare for 8.5 million
  people, and the 4 billion dollars the government
  spent on childcare for 1.25 million children,
  these drug related criminals are
  disproportionately draining our economy tax
  revenue.

127
Case Study 2 (Contd)

• Meanwhile, as the US Prison Budget balloons to
  never before seen heights, states are cutting
  funding for universities and K-12 programs
  nationwide. In addition, since these non-violent
  offenders (mostly drug offenders) are being
  housed with the worst that society has to offer,
  the majority of them will leave the prison system
  in worse shape than they entered. Unable to get
  back on their feet and with the added burden of a
  prior prison stint on their record, almost all
  undoubtedly be back.

128
Ethical Issues

• Why do the Federal and State governments
  essentially have carte blanche in regards to
  drug-related spending?
• The 24 Billion Dollars per year (1998) spent on
  imprisoning the more than one million non-violent
  criminals in the US represents only a moderate
  portion of the entire expenditure related to the
  War on Drugs.
• The money spent on the Drug War each year could
  easily serve to insure the nearly 50 million
  Americans who lack basic healthcare.
• If even 10 of the money allocated to the War on
  Drugs was redirected to K-12 education, the
  public school system could enjoy vast
  improvements, perhaps truly leaving NO child
  behind.
• Are we essentially tossing billions of dollars at
  an unsolvable problem, in hopes of winning an
  impossible war?

129
Overarching Ethical Questions

• Are the motives behind the War on Drugs just?
• Does the War on Drugs constitute a necessary and
  effective use of public/federal resources?
• Can a clear line be drawn between legal drugs and
  illicit drugs?
• By what criteria does the government (FDA) decide
  which drugs are legal or illegal?
• Is there a better approach?

130
Motives behind the War on Drugs

• From the ONDCP standpoint, the War on Drugs aims
  to reduce drug related crime and drug related
  health complications by eradicating illegal drug
  use.
• From the research that we have presented/reviewed,
  the War on Drugs in its current form has clearly
  failed in its aim to eradicate illegal drug use.
• Ha