This document defines various terms related to drug dependence including dependence, tolerance, withdrawal, abuse, addiction and provides diagnostic guidelines for drug dependence according to ICD-10. It discusses the origins of substance dependence including genetic and neurobiological factors. Various classifications of drugs of abuse are described based on their ability to produce dependence, their characteristic effects and mechanisms of action. Specific sections provide details on opioids, cannabinoids, hallucinogens, nicotine, alcohol, benzodiazepines, phencyclidine, ketamine and cocaine.

1. DRUG
DEPENDENCE
Dr. Ashishkumar Baheti
MD Pharmacology
1

2. 2
Definitions
 Drug dependence: (ICD-10)
A cluster of physiological, behavioural, and cognitive phenomena in which
the use of a substance or a class of substances takes on a much higher
priority for a given individual than other behaviours that once had greater
value
 Dependence refers to both physical and psychological elements

3. 3
Contd…
 Physiological or physical dependence
The physiological state of neuroadaptation produced by repeated
administration of drug necessitating continued administration to prevent
the appearance of withdrawal syndrome
 Psychological or psychic dependence
A behavioural pattern of drug abuse characterized by overwhelming
involvement with the use of a drug, the securing of its supply and a high
tendency to relapse after its discontinuation

4. 4
Contd…
 Addiction
Addiction is usually confused with dependence
It is hard to define, with little consensus of what it means In fact it is not
even defined as a condition in DSM IV When used it means psychological
dependence
 Abuse
Self administration of any drug in a culturally disapproved manner (illegal)
that causes adverse consequences

5. 5
Contd…
 Tolerance
A state of decreased responsiveness to the pharmacologic effect of a drug
as a result of prior exposure to that drug
 Cross tolerance
When exposure to drug A produces tolerance to it and also to drug B

6. 6
Contd…
 Withdrawal
The adverse psychological or physiological reactions to abrupt cessation of
a dependence producing drug
usually characterized by craving, dysphoria and signs of sympathetic
nervous system overactivity
 Reinforcement
The capacity of drugs to produce effects that make the user wish to take
them again

7. 7
ICD-10 Diagnostic guidelines
1. Strong desire or sense of compulsion to take the drug
2. Difficulties in controlling substance-taking behaviour
3. A physiological withdrawal state
4. Evidence of tolerance
5. Progressive neglect of alternative pleasures or interests
6. Persisting with substance use despite clear evidence of overtly harmful
consequences
A definite diagnosis of dependence should usually be made only if three
or more symptoms have been present together at some time during the
previous year

8. 8
Origins of substance dependence
Agent (drug)
Host
Environment
Reinforcement, availability,
cost, potency, purity, mode
of adm. speed of onset and
termination of effects
Social setting, community
standards, peer influence, role
models, employment &
educational opportunities,
environmental cues asso. with
drugs
Heredity, innate tolerance,
psychiatric symptoms, prior
experiences/ expectations,
propensity of risk taking
behaviour

9. 9
Genetic factors
 They contribute to 60% of an individuals susceptibility to most forms of
drug abuse
 Attempts to find drug abuse genes are not yet successful
 Polygenic disorder
 Innate tolerance to a drug increases vulnerability to dependence
 Individuals with mutation in ALDH2 gene have low propensity for
alcoholism

10. 10
Neurobiology of dependence
 Complex and chronic disease process
occurring in brain which is
modulated by genetic,
developmental and environmental
factors
 Most consistent and reproducible
finding is activation of mesolimbic
dopaminergic system
 Mesolimbic system consists of
dopaminergic neurons in ventral
tegmental area and their axonal
projections to nucleus accumbens
(NAc) and the prefrontal cortex

11. 11
Mechanism of tolerance
1. Innate tolerance - genetically determined insensitivity
2. Pharmacokinetic - changes in distribution or metabolism e.g. barbiturates
induce their own metabolism
3. Pharmacodynamic - adaptive changes in systems affected by drug
a. Receptor down regulation – decrease in number, internalization

12. 12
Contd…
b. Receptor desensitization – occupied receptors become less efficient in
activating subsequent steps e.g. due to functional uncoupling of G
proteins from receptor
c. Post receptor adaptive mechanisms - e.g. opiates act by decreasing cyclic
AMP. On chronic use the level of cAMP increases resulting in decrease
response to opiates
4. Conditioned tolerance – develops when environmental cues such as
sights, smell or situations consistently are paired with drug administration

13. 13
Classification of drugs of abuse
 The drugs producing dependence can be classified
1. Depending on their ability to produce psychological or physical
dependence
2. Depending on their characteristic effects
3. Depending on their mechanism of action

14. 14
Classification based on
dependence
Type of dependence Drugs
Severe Psychological + Physical Opiate or morphine type: Morphine,
Codeine, Pethidine, Heroin
Alcohol / barbiturate type: Ethyl
alcohol, Barbiturates, BZDs
Nicotine (tobacco)
Psychological with mild Physical
dependence
Opiate antagonists: Nalorphine,
Levallorphan
Amphetamines
Only Psychological Cocaine, LSD, Mescaline, Psilocybin,
Cannabinoids, Caffeine

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Classification based on effects
1. CNS stimulants: amphetamine, cocaine
2. CNS depressants: alcohol, barbiturates, BZDs
3. Narcotics: heroin, morphine, codiene
4. Psychotomimetic: LSD, mescaline, PCP
5. Volatile inhalants: benzene, amyl nitrite, petrol, kerosene

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RR, Relative risk of addiction; 1 = nonaddictive; 5 = highly addictive

17. 17
Contd…
G, Gi/o-coupled receptors;
i, ionotropic receptors/ ion channels;
T, monoamine transporters

18. 18
1. Opioids
 Derived from the juice of opium poppy, Papaver somniferum
 First reference to its use in 3rd century B.C.
 Contains more than 20 alkaloids
 Morphine was isolated by Serturner in 1806
 Endogenous opioid peptides were identified in early 1970’s
 Act on GPCR: the µ, κ and δ opioid receptors

19. 19
Opioid receptors
Opioid
receptors
Actions
µ (mu) Analgesia, respiratory depression,
sedation, euphoria, miosis, reduced g.i.
motility, physical dependence
Κ (kappa) Analgesia, respiratory depression,
dysphoria, hallucinations, miosis, sedation,
physical dependence
δ (delta) Analgesia, respiratory depression,
reinforcing actions, reduced g.i. motility

20. 20
Contd…
 µ receptors are selectively expressed on GABA neurons and are inhibited
inhibition of GABAergic inhibitory neurons disinhibition of
dopaminergic neurons
 Κ receptors are expressed on and inhibit dopamine neurons

21. 21
1. Analgesia
2. Anaesthesia
3. Acute left ventricular failure
4. Cough
5. Diarrhoea
 Most commonly abused- morphine, heroin, codeine, meperidine
(common among health professionals)
Opioids: Therapeutic uses

22. 22
Opioid overdose
 Accidental, suicidal or seen in drug abusers
 S/S: respiratory depression, cyanosis, fall in BP and shock, miosis, flaccidity,
stupor, coma, death due to respiratory failure
 Treatment:
 Respiratory support, maintenance of BP, gastric lavage
 Specific antidote: Naloxone 0.4-0.8 mg i.v.

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Opioid withdrawal
 Withdrawal is associated with marked drug seeking behaviour
 Physical manifestations include lacrymation, sweating, yawning, anxiety,
fear, restlessness, mydriasis, tremor, insomnia, abdominal colic, diarrhoea,
rise in BP, palpitation, rapid weight loss
 Treatment:
1. Substitution therapy with methadone

24. 24
Contd…
2. Clonidine: α2 agonist acts on presynaptic receptors & inhibit release of NE
3. Naltrexone + Clonidine: naltrexone induces withdrawal which is overcome
by clonidine, then naltrexone is used for maintenance
4. Other drugs: Levo alpha acetyl methadol (LAAM), buprenorphine,
propoxyphene, diphenoxylate, lofexidine (α2 agonist like clonidine)

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2. Cannabinoids
 Obtained from Cannabis indica (marijuana)
 Various forms in which it is used:
1. Bhang derived from dried leaves, taken orally
2. Ganja derived from dried female inflorescence, smoked
3. Charas resinous extract from flowering tops and leaves, smoked with
tobacco (hashish)
 Most important active principle is Δ9 tetrahydrocannabinol (Δ9 THC)

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Cannabinoid receptors
 CB1 receptors in CNS (hippocampus, cerebellum, SN, mesolimbic pathway)
and CB2 receptors in peripheral tissues
 Anandamide is the endocannabinoid synthesized in brain
 Subjective effects include feeling of relaxation & wellbeing, sharpened
sensory awareness
 Impaired short term memory, motor incoordination, catalepsy, analgesia,
antiemesis, increased appetite.

27. 27
Contd…
 Tolerance and physical dependence is of minor degree
 Withdrawal symptoms are mild and include nausea, agitation, irritability,
confusion, sweating, tachycardia, etc
 Psychological dependence may be mild to marked
 No compulsive urge to take the drug
 Supportive treatment suffice in withdrawal state

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Cannabinoid potential uses
 Cancer chemotherapy induced emesis
 Glaucoma
 As a bronchodilator
 As an appetite stimulant
 As a neuronal protective in head injury
 Anxiety
 Migraine
Dronabinol is the only FDA approved cannabinoid agonist currently
marketed

29. 29
3. Hallucinogens
 Psychedelics: subjective experience due to heightened sensory awareness
that ones mind is being expanded or that one is in unison with mankind or
the universe
 Psychotomimetic: means that the experience mimics the state of
psychosis
 Affect thought, perception and mood
 Include LSD, psilocybin, mescaline
 LSD derived from cereal fungus ergot, mescaline
from a Mexican cactus and psilocybin from a fungus

30. 30
Contd…
 Molecular target is 5-HT2A receptor
 They increase glutamate release in the cortex
 Produce shape and color distortion, depersonalization, hallucination,
slowing of time perception, sense
that colors are heard & sounds are seen
 Leads to rapid tolerance
 Their effects are not reinforcing hence they do not act via mesolimbic
dopaminergic pathway

31. 31
4. Nicotine and tobacco
 Apart from nicotine, tobacco smoke contains carcinogenic tar and carbon
monoxide and causes disease, responsible for many preventable deaths
 Acts on nicotinic acetylcholine receptors (nAChR) which are expressed on
dopaminergic neurons in VTA
 nAChR are α4β2 containing channels
 Shut down nicotinic receptors shortly after binding to it hence
dopaminergic stimulation stops (minirush)
 Then they again switch back on so that smoker takes the next puff or
smokes the next cigarette

32. 32
Contd…
 Produces mixture of inhibitory and excitatory effects
 Increased alertness and reduction of anxiety and tension
 Learning is facilitated
 Tachycardia, increased BP and reduced G.I. motility
 Nicotine withdrawal is mild & involves irritability and sleeplessness
 Highly addictive

33. 33
Harmful effects of smoking
 Accounts for 10% deaths worldwide & is expected to increase to 17% by
2030, mainly through
1. Cancers (lung, esophagus, pancreas, bladder)
2. Ischaemic heart disease
3. Chronic bronchitis
 Pregnancy: low birth weight babies, retarded childhood development,
increased abortion rates and perinatal mortality, preterm labour, placenta
praevia
 Only point in favor: protects against Parkinson's disease

34. 34
Treatment of nicotine dependence
 “To cease smoking is the easiest thing I ever did; I've done it a
thousand times” – Mark Twain
 Relapse is common, long term cessation in only 20%
 Combination of psychological and pharmacological treatment
 Nicotine replacement therapy: transdermal patch, chewing gum
 Bupropion
 Clonidine
 Nicotinic receptor antagonist: mecamylamine

35. 35
5. Alcohol (ethanol)
 Acts through several cellular mechanisms
1. Ionotropic receptors:
GABAA – enhances GABA mediated inhibition,
NMDA (glutaminergic) - inhibition
5-HT3 - activation
2. Ion channel: Kir3/GIRK
3. Transporter: (equilibrative nucleoside transporter, ENT1, related to
adenosine uptake)
 Not known which target is responsible for DA release
 Enhances euphoria by acting on opiate and endocannabinoid receptors

36. 36
Alcohol metabolism
 95% alcohol is metabolized by alcohol dehydrogenase (ADH), 5% excreted
unchanged in urine and breath
 85% occur in liver & 15% in stomach, women have 50% less stomach ADH
 Women are more vulnerable to acute intoxication and chronic effects

37. 37
Acute alcohol intoxication
 Occurs at blood levels of 150mg/dl
 Slurred speech, motor incoordination
 Increased self confidence, euphoria
 Highly labile mood
 Aggression
 Hypotension, gastritis, collapse, respiratory depression, coma, death
 Treatment is mainly supportive, dextrose infusion, insulin + fructose drip
hastens alcohol metabolism

38. 38
Alcohol withdrawal
 Treatment
Supportive, Benzodiazepines- chlordiazepoxide,
Propranolol blocks effect of sympathetic overactivity
chlormethiazole, carbamazepine are experimental drugs
used in some countries
Time (hrs) Withdrawal symptoms
6 -12 tremor, nausea, excessive sweating, agitation,
anxiety
12-24 visual, auditory and tactile hallucinations
24-48 generalized seizures
48-72 delirium tremens

39. 39
Alcohol addiction: treatment
1. Deterrent agents
 Disulfiram: inhibits aldehyde dehydrogenase
 Produces Disulfiram Ethanol reaction
 Use in the dose of 250-500 mg/day in first week followed by 250 mg/day
maintenance dose
 Should be coupled with psychotherapy
Ethanol Acetaldehyde
ADH ALDH Acetic acid

40. 40
Contd…
2. Anti-craving agents
 Naltrexone: interferes with alcohol induced reinforcement by blocking
opioid receptors
 Acamprosate: NMDA receptor antagonist
 Fluoxetine: used occasionally
 Others:
Topiramate, may provide a unique approach
Ondansetron, a 5 HT3 receptor antagonist reduced alcohol consumption
in lab animals & is being tested in humans

41. 41
6. Benzodiazepines
 Commonly prescribed as anxiolytics & sleep medications
 They facilitate opening of GABA activated Cl- channels
 Tolerance is common
 Produces dependence
 Withdrawal symptoms are- irritability, insomnia, phono & photophopia,
depression, cramps & even seizures
 Barbiturates were more abused, their prescription has declined after BZDs
have come into market

42. 42
7. Phencyclidine and ketamine
 Were developed as general anesthetics
 Noncompetitive antagonist at NMDA receptors: decreases calcium flux
into the cell and also act on σ opiate receptors which mediate dysphoria
 Cause intense analgesia, amnesia, delirium, stimulant as well as depressant
effects, staggering gait, slurred speech, vertical nystagmus
 Intoxicating doses can produce catatonia, hallucinations, delusions,
paranoia, disorientation & lack of judgement

43. 43
8. Cocaine
 Alkaloid found in leaves of Erythroxylon coca, a shrub indigenous to Andes
 Used as local anesthetic
 Blocks dopamine transporter thereby increasing dopamine concentration
in NAc
 Also blocks NE transporter sympathetic activation
increase BP, tachycardia, arrhythmias
 Tremors, paranoia, irritability, emotional lability
 Increases risk for I.C. hemorrhage, ischemic stroke, MI, seizures.

44. 44
Contd…
 Reverse tolerance or sensitization
Repeated cocaine users may produce complex adaptation of DA neuronal
system so that more and more DA is released
The dose of DA which previously only induced euphoria now create an
acute paranoid psychosis
Mechanism is unclear
 Till date no specific antagonist is available and treatment of overdose
remains supportive
 Chronic cocaine use can be treated with bromocriptine (DA agonist),
amantadine

45. 45
Contd…
 Route of administration is nasal or intravenous
 It is highly addictive
 Withdrawal is mild characterized by craving, agitation, anxiety, fatigue,
depression, exhaustion, hyper somnolence, hyperphagia
 Chronic signs of withdrawal are anhedonia, anergy, decreased drive, lack of
ambition, increased craving
 Use in pregnancy impairs fetal development and produces limb
malformations

46. 46
9. Amphetamines
 Indirectly acting sympathomimetic drugs that cause release of
endogenous biogenic amines, DA & NE
 Exert their effects by reversing the action of biogenic amine transporters at
the plasma membrane
 Clinical effects are very similar to cocaine but euphoria is less intense
 They are neurotoxic
 It is smoked, ingested or taken I.V.

47. 47
10. CART peptides
 Cocaine Amphetamine Regulated Transcript (CART) peptides is a recently
identified neurotransmitter system
 These are released after administration of cocaine and amphetamine
 May play a role in drug abuse, control of stress and feeding behaviour
 Potential target for future drug abuse therapies

48. 48
11. Ecstasy (MDMA)
 Like amphetamine they act by reversing action of transporters & causing
release of biogenic amines
 Affinity for serotonin transporter (SERT)
 Causes profound serotonin release, intracellular depletion can occur for 24
hrs after single dose
 ? Neurotoxic
 Acute toxic effects: hyperthermia, dehydration, serotonin syndrome,
seizures

49. 49
12. Inhalants
 Recreational exposure to chemical vapors such as nitrates, ketones and
aliphatic and aromatic hydrocarbons
 Sniffing, huffing, bagging
 Prevalent in children
 Leads to euphoria, excitement, dizziness, slurred speech, apathy, impaired
judgement, coma, death is due to respiratory depression, arrhythmias or
asphyxia
 No specific treatment, treat underlying psychiatric disorder, if any

50. 50
Principles of treatment
 Behaviour therapy: aversion therapies like sub threshold electric shock or
emetic like apomorphine
 Psychotherapy
 Group therapy e.g. alcoholics anonymous, narcotic anonymous
 Detoxification: Gradual tapering of drug that has caused dependence or
sudden withdrawal of drug followed by substitution therapy
 Specific drug therapy e.g. Disulfiram
 Correction of nutritional deficiencies
 Community treatment and rehabilitation

51. 51
Pharmacological approaches
Mechanism Examples
Substitution, to alleviate
withdrawal symptoms
Methadone-opiate, BZDs-alcohol
Long term substitution Methadone, nicotine patches or
chewing gum
Blocking response Naltrexone-opiate, mecamylamine-
nicotine
Aversive therapies Disulfiram
Modification of craving Bupropion, clonidine, acamprosate

52. 52
Health problems
 Among the injection drug users (IDU) worldwide, the prevalence of HIV
varies from <5% to >80%, with annual HIV incidence between <1% & 50%.
4 out of 10 people dying with AIDS are IDU
 HCV prevalence is more consistent with prevalence of 50%-90% &
incidence of 10%-30% per year
 Cardiovascular disease, Stroke, Cancer, Lung disease
 Hepatitis B, Obesity, Mental disorders
 Skin complications in IDU

53. 53
Animal models in addiction
research
 Animal models in the field of addiction are considered to be among
the best available models of neuropsychiatric disease
• Drugs of abuse are not only
rewarding but also reinforcing,
an animal will learn behaviour
(e.g. pressing a lever) when
paired with drug administration

54. 54
Significance of animal models
 Can predict abuse potential
 Factors involved in acquisition, maintenance, extinction, and reinstatement
of drug reinforcement can carefully be extracted in laboratory-controlled
situations
 Environmental, behavioral, and neurobiological factors that contribute to
individual differences in vulnerability to drug addiction can be explored
with animal models

55. 55
Reinstatement model
 Developed 25 yrs ago
Training for 12 days
Abstinence for 12 days
1. Environmental cues
2. Direct administration of the drug itself;
3. Exposure to a stressor
Lever pressing is reinstated

56. 56
Orange circles: pressing
lever delivering cocaine
Green circles: pressing lever
delivering no drug
Animals are first trained to self-administer an addictive drug in response
to pressing a lever. The animal then undergoes a period of drug
abstinence. Lever pressing can be reinstated using three modalities of
stimuli

57. 57
A. Self administration
B. Intracranial self stimulation
C. Place conditioning

58. 58
Model for physical dependence
 Morphine i.p. injection in rats starting dose (20mg/kg), increase in dose by
20mg/kg per day till 11 day, maintenance dose till 20 days. Test drug is
similarly administered with dose adjustment.
 On day 11 & 17, nalorphine (10mg/kg) i.p. injection
 Withdrawal symptoms are recorded during 30-60 min period
 10 point score recorded- writhing 3, squealing 2, diarrhoea 2, teeth
chattering 1, eyelid ptosis 1, wet dog type shaking 1

59. 59
Current research
 Active immunization (vaccine) with drug-protein conjugate vaccines has
been tested for cocaine, heroin, methamphetamine, and nicotine in animal,
with cocaine and nicotine vaccines in Phase II human trials
 Passive immunization with high affinity monoclonal antibodies has been
tested for cocaine, methamphetamine, nicotine, and phencyclidine in
preclinical animal models
 They can be used to treat overdose and to reduce relapse to drug use in
addicted patients

60. 60
Contd…
 Dronabinol phase II clinical trial for treatment of marijuana addiction
 Dynorphin phase II CT for opiate related disorders and withdrawal
 Piracetam phase I for cocaine related disorders
 Modafinil phase II for methamphetamine addiction
 Ondansetron and topiramate phase II for alcohol abuse
 Baclofen, a GABAB receptor agonist have shown a significant reduction in
craving