DRUG ABUSE AND DRUG DEPENDENCE

RELATING TO PSYCHOTROPIC DRUGS

NEUROPHARMACOLOGY
[DR SITANIMEZI MWEENDA]

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Introduction

 Drugs of abuse generally act on the CNS:

 to modify the user’s mental state.
 Some are used for enhancing physical performance.
 Drug abuse is:
 the non-medical, self-administered use of a drug,
 that is outside the limits considered acceptable by society

Factors contributing to drug abuse

1. Reinforcing properties of drugs
• The drugs give the users some experience they find pleasurable e.g.
euphoria with cocaine, heroine
• Drugs can reduce the intensity of unpleasant experience e.g. ↓ the
sense of anxiety or stress e.g. benzodiazepines, alcohol
By ↑ pleasure or by ↓ unpleasant experience, drugs reinforce the reasons for
their use
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Factors contributing to drug abuse …. cont’d

2. Dependence
• Physical (physiological) dependence
• Psychological dependence
3. Social factors
Peer pressure: the desire for social status and approval is a common reason
for initiating drug use
4. Drug availability
When procurement of drugs is difficult, drug abuse is minimal
5. Vulnerability of the individual
Psychological factors associated with tendencies for drug abuse include
impulsive behaviour, low tolerance for frustration, rebellious attitude
towards social norms, depressive disorders, anxiety disorders and antisocial
personality. 3
Definitions of key concepts

Tolerance
Decrease in response to the drug effects thereby giving the need to
progressively increase the dose to produce the effects originally achieved
with smaller doses
Tolerance is closely associated with physical dependence
The degree of tolerance varies considerably among different classes of drugs
Tolerance occurs due to compensatory responses that reduce the drug’s
pharmacodynamic actions
• Metabolic tolerance: due to ↑ disposition of the drug after chronic use
• Behavioural tolerance: an ability to compensate for the drug’s effects
• Functional tolerance: due to compensatory changes in receptors,
effector enzymes, or membrane actions of the drug

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Dependence

Drug dependence: the compulsion to take a drug repeatedly with distress

(physical and/or psychological) being caused if this is prevented
Psychological dependence
• An intense subjective need for a drug: the phenomenon is manifested by
compulsive drug seeking behavior in which the individual uses the drug
repetitively for personal satisfaction often in the face of known risks to
health
• A sense of craving is felt when the drug is not available
• Psychological dependence almost always precedes physical dependence
• Psychological dependence is related to increased activity in the “brain
reward system” (which limbic structures in the brain): mediated by
dopamine

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Physical dependence [physiological dependence]

• An altered physiological state that requires continuous drug

administration to prevent the appearance of an abstinence or
withdrawal syndrome
• When medication is stopped, withdrawal or discontinuation
symptoms occur. Withdrawal of the drug produces symptoms and
signs that are frequently the opposite of those sought by the user.
• Withdrawal (abstinence) syndrome: the syndrome of effects
caused by stopping administration of a drug.
– The effects are often opposite to the short-term effects of the abused
drug and often include activation of the sympathetic nervous system.
• Cross-dependence: ability of one drug to substitute for another
drug in the same drug class (e.g. methadone for heroine)
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Drug addiction

A non-medical term that refers to the drug abuser’s

overwhelming preoccupation with the procurement and use of
a drug
Features of drug addiction
• Compulsive drug use (due to psychological and physiological
changes that occur in the body)
• Pre-occupation with securing a drug supply
• Tendency to relapse following withdrawal

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Psychotropic drugs with high potential for abuse

Drug class Examples

CNS stimulants Cocaine, amphetamines, methylene-dioxy-
methamfetamine (MDMA, Ecstacy), nicotine
CNS depressants Ethanol, benzodiazepines, barbiturates
Opioid analgesics Morphine, diamorphine (heroin), pethidine,
fentanyl
Cannabinoids Cannabis
Hallucinogens Lysergic acid diethylamide (LSD), mescaline,
psilocybin
Dissociative anaesthetics Ketamine, phencyclidine

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CNS stimulants
Amphetamine and methamphetamine
• MOA: ↑ release of dopamine and noradrenaline and inhibits their
reuptake
• Effects: increased motor activity, euphoria and excitement,
anorexia and insomnia, hypertension, stereotyped behavior
(repetitive or ritualistic movement, posture, or utterance)
and paranoid psychosis with prolonged use
• Clinical uses: narcolepsy(sleep disorder characterized by e.g
excessive sleepiness), attention deficit hyperactivity disorder
• Tolerance and psychological dependence develop, but cause
minimal physical dependence
• Withdrawal causes deep long sleep and the patient wakes up
feeling tired, depressed and hungry
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CNS stimulants …. cont’d

Cocaine
• Inhibits reuptake of catecholamines
• Has similar effects to amphetamine:
– with greater euphoria and less tendency for stereotypical behaviour and
paranoid delusions
• Acute toxicity: psychosis (mental disorder shows disconnection
from reality), cardiac arrhythmias, hypertension, stroke,
myocardial infarction
• Chronic toxicity: paranoid psychosis
• Causes strong psychological dependence but moderate physical
dependence
• Withdrawal causes marked deterioration in motor performance
and lethargy
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CNS stimulants …. cont’d

Methylenedioxymethamfetamine (MDMA, “ecstacy”)

• Derivative of amphetamine
• Potentiates serotonin
• Causes euphoria and hallucinations, and heightens response to
sensory stimuli
• Toxicity: hyperthermia, exhaustion and dehydration caused
indirectly by the repetitive locomotor behaviour induced
• Withdrawal syndrome is similar to that of amphetamine

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CNS stimulants …. cont’d

Nicotine
• Activates nicotinic Ach receptors
• ↑ alertness, improves psychomotor performance and
cognitive functions, causes euphoria, ↓ irritability and anxiety,
suppresses appetite and relaxes skeletal muscle tone.
• Peripheral effects: tachycardia, ↑blood pressure and ↓ GIT
motility
• Acute toxicity: nausea and vomiting

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Nicotine: tolerance and dependence

• Tolerance develops rapidly first to peripheral effects, but later

to central effects
• Nicotine causes strong physical and psychological dependence

• Withdrawal causes craving, irritability, restlessness, difficult in

concentration, anxiety, impaired performance of psychomotor
skills and ↑ appetite. Symptoms may persist for weeks or even
months.
• The withdrawal syndrome can be alleviated by nicotine and
amphetamine

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Treatment of nicotine dependence

a. Nicotine replacement therapy

• Pharmacological approach is based on replacing the nicotine derived from
smoking. Once the patient has stopped smoking, the nicotine is gradually
withdrawn over 10 – 12 weeks.
• Route of administration of nicotine: oral (chewing gum, sublingual tablets),
transdermal patches and nasal spray
• Benefit is maximal when combined with active counseling. Nicotine on its
own without counseling and support is ineffective.
b. Bupropion
• A selective inhibitor of the neuronal uptake of noradrenaline and dopamine
• ↓ nicotine craving and withdrawal symptoms
c. Other therapies
Clonidine, nortriptyline and selegiline (alleviate withdrawal symptoms and
reduce craving)
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CNS depressants
Ethanol (alcohol)
 MOA: ↑ inhibition of calcium entry and potentiation of GABA
 Acute alcohol toxicity causes: ataxia, nystagmus, coma, respiratory depression and death
 Chronic effects:
 Wernicke’s encephalopathy (confusion, nystagmus and abnormal ocular movements) and;
 Korsakoff’s psychosis (polyneuropathy, selective amnesia and confabulation (memory
error)).
 Due to a direct effects of alcohol on the CNS and the nutritional deficiencies (vitamin B)
resulting from chronic heavy consumption.
 Tolerance, physical and psychological dependence occur with alcohol (there is cross-tolerance
and cross dependence with benzodiazepines and barbiturates)
 Alcohol withdrawal syndrome occurs in two stages:
1. Early stage (6-8 hours after cessation of drinking): tremors, nausea, retching and sweating
2. Late stage (starts 48-72 hours after cessation of drinking): autonomic instability (excess
sympathetic nervous system activity), delirium, tremor, seizures, hallucinations and mental
confusion
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TREATMENT OF ALCOHOL WITHDRAWAL

A. BENZODIAZEPINES
Symptoms of alcohol withdrawal can be suppressed by benzodiazepines. The patient is
stabilized with long acting benzodiazepine (e.g. diazepam and chlordiazepoxide) and the
drug is gradually withdrawn over a period 2 weeks
B. NON-SELECTIVE BETA-ADRENERGIC BLOCKER
Propranolol is used as an adjunct to benzodiazepines during the withdrawal process.
The beta-blocker blocks the effects of excessive sympathetic activity that occurs during
withdrawal. It permits reduction in benzodiazepine dose and accelerates improvement
in vital signs.
C. CLONIDINE (AN ALPHA2-ADRENOCEPTOR AGONIST)
It acts inhibiting the exaggerated noradrenaline release that occurs during withdrawal
D. ANTI-PSYCHOTIC DRUGS
To control the agitation and hallucinations
E. ANTI-CONVULSANT DRUGS
Chlormethiazole and phenytoin for seizures not responding to benzodiazepines

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DRUGS USED IN THE MANAGEMENT OF ETHANOL ABUSE

1. NALTREXONE (AN OPIOID ANTAGONIST)

↓ craving for ethanol and ↓ the rate of relapse of alcoholism
2. ACAMPROSATE
↓ the incidence of relapse and prolongs abstinence from ethanol. Acts
as a competitive inhibitor at the glutamate receptor.
3. DISULFIRAM
Inhibits aldehyde dehydrogenase, resulting in accumulation of toxic
levels of acetaldehyde, with nausea, vomiting, flushing, headache,
sweating, hypotension and confusion lasting up to 3 hours.
Discourages the alcoholic from taking alcohol due to the unpleasant
symptoms experienced when he does so. It is given under supervision.
Compliance is low.

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CNS depressants …. cont’d
BENZODIAZEPINES
• Tolerance and dependence are common
• Cross-tolerance occurs with barbiturates and ethanol
• Features of withdrawal syndrome include: rebound anxiety and insomnia,
depression, nausea and perceptual changes, autonomic instability (↑ heart rate
and BP, tremors, diaphoresis), muscle cramps, confusion, seizures, irritability,
agitation, delirium and possible death
• Treatment of withdrawal: a long acting benzodiazepine (diazepam and
chlordiazepoxide) is given and then withdrawn gradually [over 10 to 14 days]
• Acute toxicity: hypotension, mental confusion, ataxia, respiratory depression.
Treated with flumazenil, a benzodiazepine receptor antagonist.
• Chronic toxicity: cognitive impairment occurs with chronic toxicity
• Barbiturates have similar effects with benzodiazepines but produce more
dependence and more respiratory depression.
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Cannabis

• The active ingredient is D9-tetrahydrocannabinol (THC) which binds on cannabinoid

receptors (CBD2) in the CNS (the endogenous agonist is anandamide)
• Effects: sedation, euphoria, uncontrolled laughter, mental relaxation, altered
perception, loss of sense of time, hypotension due to peripheral vasodilatation, ↓
intraocular pressure, ↑ appetite, and anti-emetic effects
• High dose effects: hallucinations, delusions, paranoia, anxiety, depersonalization and
dissociation, and psychosis
• Overdose: produces drowsiness and confusion. There are no respiratory or CVS
effects that threaten life.
• Psychological and physical dependence produced is mild, and cannabis have low
addictive potential
• Withdrawal effects: mild anxiety, dysphoria and sleep disturbances
• Uses: (1) suppression of emesis associated with cancer chemotherapy (2) glaucoma
(3) appetite stimulation in patients with AIDS and cancer patients
• Dronabinol (pharmaceutical preparation of THC) and nabilone (THC analogue) are
used for the above clinical purposes
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Opioid analgesics

Most commonly abused opioids are heroin, morphine and pethidine

Opioids produce feelings of euphoria
Acute toxicity
Vomiting, confusion, tremor, drowsiness, sedation, respiratory depression,
coma, pin-point pupils.
• Treated with the opioid antagonist, naloxone.
Tolerance
With prolonged use tolerance develops to many opioid effects (analgesia,
euphoria, sedation, respiratory depression, nausea). Little or no tolerance
develops to constipation and miosis (constricted pupils are characteristic of
addicts). Cross-tolerance occurs among opioids. No cross-tolerance occurs
with general CNS depressants (barbiturates, benzodiazepines, alcohol).
Dependence
Long-term opioid use produces physical and psychological dependence
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Opioids: abstinence syndrome

• The intensity and duration of the withdrawal symptoms depends:

– on the half-life of the drug used and the degree of physical
dependence.
• The symptoms with opioids that have relatively short half-lives (e.g.
morphine, heroin) are intense and of short duration.
• Symptoms are less intense but more prolonged with opioids that
have long half-lives (e.g. methadone).
• The symptoms begin 8-10 hours after the last dose
• The first symptoms are lacrimation, rhinorrhoea, yawning and sweating.
This is followed by restlessness, chills, gooseflesh, anorexia, nausea and
vomiting, muscle aches, involuntary movements (kicking movements),
hyperpnoea, hyperthermia and hypertension.
• The acute course of withdrawal may last 7-10 days. If the abstinence
continues a secondary phase that lasts 26-30 weeks occurs and is
characterized by hypotension, bradycardia, hypothermia, mydriasis and
decreased responsiveness of the respiratory center to carbon dioxide.
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Treatment of opioid dependence

(1) Methadone
• Principle: substitute a longer acting, orally active, pharmacologically
equivalent drug for the abused drug,
– stabilize the patient on that drug,
– and then gradually withdraw the substituted drug.
• Methadone is suitable for this purpose. It is long acting and orally
active. A single dose can be given each day.
• Methadone is substituted for the opioid the addict is dependent on.
Because opioids display cross-dependence with one another,
methadone will prevent the onset of an abstinence syndrome. Once
the patient is stabilized on methadone, it is withdrawn gradually.
– Withdrawal of methadone is associated with mild withdrawal symptoms.
The entire process of methadone substitution and withdrawal takes about
10 days to complete. 22
Treatment of opioid dependence …. cont’d

(2) Naltrexone (an opioid antagonist)

• Rationale for treatment (opioid addiction), prevents:
– euphoria when the addict takes an opioid.

– It therefore blocks the acute rewarding effect of opioids.

• Naltrexone can precipitate a withdrawal reaction in persons

physically dependent on opioids.
– used after the acute withdrawal phase has been overcome.

• Naltrexone does not prevent craving for opioids.

– As a result many addicts fail to comply with the treatment program.

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Hallucinogens (psychotomimetic drugs)

• Examples: lysergic acid diethylamide (LSD), mescaline and

psilocybin

• MOA: unclear (may be related to serotonin 5-HT 1A and 5-HT1C

receptors to which they are agonists)
• Effects: altered perception with vivid and unusual sensory
experiences, euphoria, hallucinations and delusions
• Acute toxicity: dysphoria, frightening delusions and
hallucinations (treatment include benzodiazepines for sedation)
• Tolerance develops to the behavioural effects
• No dependence and withdrawal with these drugs

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Phencyclidine (PCP) (“angel dust”)

A dissociative anaesthetic (similar to ketamine but more

hallucinogenic) used in veterinary medicine.
• MOA: antagonist on glutamate receptors
• Low doses: effects similar to ethanol intoxication (due to
blockade of glutamate receptor)
• High doses: euphoria, hallucinations, changed body image,
increased sense of isolation and loneliness, impaired judgment,
↑ aggressiveness (effects are due to activation of sigma
receptors)
• Overdose: seizures, respiratory depression, cardiac arrest and
coma
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THE END!!!

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