TOXOLOGY OF DRUGS OF ABUSE
• The terminology used in discussing drug dependence,
abuse, and addiction has long been confusing.
• Confusion stems from the fact that repeated use of
certain prescribed medications can produce neuroplastic
changes resulting in two distinctly abnormal states.
• The first is dependence, sometimes called "physical"
dependence, produced when there is progressive
pharmacological adaptation to the drug resulting in
tolerance.
1
TOXOLOGY OF DRUGS OF ABUSE
• In the tolerant state, repeating the same dose of drug
produces a smaller effect.
• If the drug is abruptly stopped:
• a withdrawal syndrome ensues in which the adaptive
responses are now unopposed by the drug.
• Thus, withdrawal symptoms are opposite to the original
drug effects.
2
TOXOLOGY OF DRUGS OF ABUSE
• The appearance of withdrawal symptoms is the cardinal
sign of "physical" dependence.
• As thus defined, dependence can occur with the use of:
•
- opioids
•
- β blockers
•
- antidepressants
•
- benzodiazepines
•
- stimulants
• even when these agents are used as prescribed for
therapeutic purposes.
3
TOXOLOGY OF DRUGS OF ABUSE
• The state of "physical" dependence is a normal response
• easily treatable by tapering the drug dose
• and is not in itself a sign of addiction.
• The second abnormal state that can be produced by
repeated drug use occurs in only a minority of those who
initiate drug use.
• It leads progressively to compulsive, out-of-control drug
use.
4
TOXOLOGY OF DRUGS OF ABUSE
• Unfortunately, in 1987 the American Psychiatric
Association (APA) chose to use the word "dependence“
• when defining the state of uncontrolled drug use more
commonly known as addiction
• The word "addiction" was at that time considered
pejorative and thus to be avoided.
5
TOXOLOGY OF DRUGS OF ABUSE
• The result, over the last two decades, is that
confusion has developed between dependence as
a normal response and dependence as addiction.
• The newest version of the Diagnostic and
Statistical Manual of Mental Disorders (DSM-V)
due to be released in 2012 will correct this
confusion.
6
TOXOLOGY OF DRUGS OF ABUSE
• This distinction between dependence and addiction is
important
• because patients with pain sometimes are deprived of
adequate opioid medication
• simply because they have shown evidence of tolerance
• or they exhibit withdrawal symptoms if the analgesic
medication is stopped or reduced abruptly.
7
TOXOLOGY OF DRUGS OF ABUSE
• Modern neuroscience has greatly increased our
understanding of the phenomenology of addiction.
• Using animal models as well as human brain imaging
studies and clinical observations, addiction can be
defined fundamentally as a form of maladaptive
memory.
• It begins with the administration of substances (e.g.,
cocaine) or behaviors (e.g., the thrill of gambling) that
directly and intensely activate brain reward circuits.
• Activation of these circuits motivates normal behavior
and most humans simply enjoy the experience without
8
being
compelled to repeat it.
TOXOLOGY OF DRUGS OF ABUSE
9
ADDICTION
• 1- Addiction involves progressive loss of frontal
cortical
• 2- behavioral control and increasing limbic
temporal lobe
• 3- negative feelings
• The loss of behavioral control that underlies
addiction has at least two components
10
ADDICTION
• decreased frontal cortical regulation of attention and
cognitive flexibility and increased limbic fearnegative feelings (Fig. 1).
• The frontal lobes of brain are involved in decision
• making and other executive functions such as
motivation
11
TOXOLOGY OF DRUGS OF ABUSE
•
CNS depressants, including:
•
•
•
•
•
•
- alcohol
- other sedatives hyponotics such as Barbiturates
- nicotine and tobacco
- opioids; cannabinoids
- psychedelic drugs;
- inhalants (volatile solvents, nitrous oxide, and
ethyl ether)
12
TOXOLOGY OF DRUGS OF ABUSE
• CNS Depressants
• Ethanol
- Experimentation
with is almost universal, and a high
proportion of users find the experience pleasant.
•
- Ethanol is classified as a depressant because it indeed •
produces sedation and sleep.
- However, the initial effects of alcohol, particularly at •
lower doses, often are perceived as stimulation owing to
a suppression of inhibitory systems in the brain.
13
TOXOLOGY OF DRUGS OF ABUSE
• CNS Depressants
• Those who perceive only sedation from alcohol
generally choose not to drink when evaluated in a test
procedure.
• Alcohol impairs recent memory
• in high doses, produces the phenomenon of "blackouts":
• the drinker has no memory of his or her behavior while
intoxicated.
14
TOXOLOGY OF DRUGS OF ABUSE
• CNS Depressants
•
The effects of alcohol on memory are unclear
• but evidence suggests that reports from patients about their
reasons for drinking and their behavior during a binge are not
reliable.
• Alcohol-dependent persons often say that they drink to relieve
anxiety or depression.
•
When allowed to drink under observation, however, alcoholics
typically become more dysphoric as drinking continues
• thus not supporting the idea that alcoholics drink to relieve
15
tension.
TOXOLOGY OF DRUGS OF ABUSE
• CNS Depressants
•
Tolerance, Physical Dependence, and
Withdrawal
• Mild intoxication by alcohol is familiar to almost
everyone, but the symptoms vary among individuals.
•
• Some simply experience motor incoordination and
sleepiness.
• Others initially become stimulated and garrulous.
• As the blood level increases, the sedating effects
increase, with eventual coma and death occurring at
16
high alcohol levels.
TOXOLOGY OF DRUGS OF ABUSE
• CNS Depressants
•
Tolerance, Physical Dependence, and Withdrawal
• The initial sensitivity (innate tolerance) to alcohol varies greatly
among individuals and is related to family history of alcoholism
• Experience with alcohol can produce greater tolerance (acquired
tolerance) such that extremely high blood levels (300-400 mg/dL)
can be found in alcoholics who do not appear grossly sedated.
•
In these cases, the lethal dose does not increase proportionately to
the sedating dose
• thus
the margin of safety (therapeutic index) is decreased.
17
TOXOLOGY OF DRUGS OF ABUSE
• CNS Depressants
• Tolerance, Physical Dependence, and Withdrawal
• Heavy consumers of alcohol not only acquire tolerance
but also inevitably develop a state of physical
dependence.
•
• This often leads to drinking in the morning to restore
blood alcohol levels diminished during the night.
• Eventually, they may awaken during the night and take
a drink to avoid the restlessness produced by falling
alcohol levels.
18
TOXOLOGY OF DRUGS OF ABUSE
• CNS Depressants
• Tolerance, Physical Dependence, and Withdrawal
• The alcohol-withdrawal syndrome generally depends on
the size of the average daily dose
• and usually is "treated" by resumption of alcohol
ingestion.
•
Withdrawal symptoms are experienced frequently but
usually are not severe or life-threatening until they occur
in conjunction with other problems
•
such as infection, trauma, malnutrition, or electrolyte imbalance.
•
In the setting of such complications, the syndrome of delirium
tremens becomes likely.
19
Signs and Symptoms of CNS Depressant Intoxication and Withdrawal
• Intoxication (similar to alcohol)
• Disinhibition (e.g., inappropriate sexual or aggressive behavior,
impaired judgment, mood lability)
• Somnolence, stupor, or coma
• Impaired attention or memory
• Slurred speech
• Incoordination
• Unsteady gait
20
• Nystagmus
Signs and Symptoms of CNS Depressant Intoxication and Withdrawal
• Alcohol or any CNS DEPRESSANTS Withdrawal
Syndrome
• Alcohol craving
• Tremor, irritability
• Nausea
• Sleep disturbance
• Tachycardia
• Hypertension
• Perceptual
distortion
21
• Continue …….Alcohol or any CNS DEPRESSANTS
Withdrawal Syndrome
• Seizures (6-48 hours after last drink)
• Visual (and occasionally auditory or tactile) hallucinations (12-48
hours after last drink)
• Delirium tremens (48-96 hours after last drink; rare in
uncomplicated withdrawal)
• Severe agitation
• Confusion
• Fever, profuse sweating
• Diarrhea
• Dilated pupils
22
• Continue …….Alcohol or any CNS DEPRESSANTS
Withdrawal Syndrome
• Delirium tremens Abbreviation: DT
- The most severe expression of alcohol withdrawal syndrome
marked by:
•
- visual, auditory, or tactile hallucinations •
- extreme disorientation •
- restlessness, and hyperactivity of the autonomic nervous system
(evidenced by such findings as pupillary dilation
- fever, tachycardia, hypertension, and profuse sweating). •
- About 15% of affected patients may die, usually as a result of
comorbid illnesses. In most affected patients, recovery occurs
within
3 to 5 days. SYN:alcoholicdelirium
23
•
•
24
• Alcohol addiction produces cross-tolerance to
other sedatives such as benzodiazepines.
• This tolerance is operative in abstinent
alcoholics,
• but while the alcoholic is drinking, the sedating
effects of alcohol add to those of other sedatives,
making the combination more dangerous.
• This is particularly true for benzodiazepines,
which are relatively safe in overdose when given
alone but potentially are lethal in combination
with alcohol.
25
• The chronic use of alcohol and other sedatives is associated with
the development of depression
• The risk of suicide among alcoholics is one of the highest of any
diagnostic category.
• Cognitive deficits have been reported in alcoholics tested while
sober.
• These deficits usually improve after weeks to months of
abstinence.
•
More severe recent memory impairment is associated with
specific brain damage caused by nutritional deficiencies common
in26 alcoholics due to thiamine deficiency).
• Alcohol is toxic to many organ systems.
• As a result, the medical complications of alcohol
abuse and dependence include liver disease
• cardiovascular disease,
• endocrine and GI effects, and malnutrition
• Alcohol crosses the placental barrier, producing
the fetal alcohol syndrome, a major cause of
mental retardation to the fetus
27
• Pharmacological Interventions
• Detoxification
• A patient who presents in a medical setting with
an alcohol-withdrawal syndrome should be
considered to have a potentially lethal condition.
• Although most mild cases of alcohol withdrawal
never come to medical attention
• severe cases require general evaluation;
attention to hydration and electrolytes; vitamins,
• especially high-dose tthiamine; and a sedating
medication that has cross-tolerance with alcohol.
28
• Pharmacological Interventions
• Detoxification
• To block or diminish the symptoms of alcohol toxicity, a shortacting benzodiazepine such as oxazepam can be used at a dose of
15-30 mg every 6-8 hours according to the stage and severity of
withdrawal
• A patient who presents in a medical setting with an alcoholwithdrawal syndrome should be considered to have a potentially
lethal condition.
• some authorities recommend a long-acting benzodiazepine unless
there is demonstrated liver impairment.
• Anticonvulsants such as carbamazepine have been shown to be
29
effective
in alcohol withdrawal
• Pharmacological Interventions
• Pharmacotherapy
• Detoxification is only the first step of treatment.
• Complete abstinence is the objective of long-term treatment, and
this is accomplished mainly by behavioral approaches.
•
Medications that aid in the prevention of relapse are under
development.
•
Disulfiram (ANTABUSE; has been useful in some programs that
focus behavioral efforts on ingestion of the medication
30
• Pharmacological Interventions
• Pharmacotherapy
• Disulfiram blocks aldehyde dehydrogenase, the second step in
ethanol metabolism, resulting in the accumulation of acetaldehyde
•
which produces an unpleasant flushing reaction when alcohol is
ingested.
• Knowledge of this unpleasant reaction helps the patient to resist
taking a drink.
• Although quite effective pharmacologically, disulfiram has not
been found to be effective in controlled clinical trials because so
many patients failed to ingest the medication.
31
• Pharmacological Interventions
• Naltrexone (REVIA) an opioid receptor antagonist that blocks the
reinforcing properties of alcohol, is FDA- approved as an adjunct
in the treatment of alcoholism.
•
•
Chronic administration of naltrexone resulted in a decreased rate
of relapse to alcohol drinking in the majority of published doubleblind clinical trials .
It works best in combination with behavioral treatment
programs that encourage adherence to medication and abstinence
from alcohol.
• A depot preparation with a duration of 30 days (VIVITROL) was
approved by the FDA in 2006; it greatly improves medication
adherence, the major problem with the use of medications in
alcoholism.
32
• Pharmacological Interventions
• A significant development in identifying a potential
endophenotype of alcoholism has grown out of the clinical
experience with naltrexone.
• Animal studies have demonstrated that alcohol causes the release
of endogenous opioids in brain reward systems
• disinhibition or activation of dopamine neurons, a condition
common to all drugs of abuse.
• Blocking opioid receptors prevents this dopaminergic effect and
results in less stimulation or reward from alcohol.
33
• Pharmacological Interventions
• A functional allele of the gene for the μ opioid receptor that
naltrexone blocks has been associated with alcohol stimulation
and with good response to naltrexone treatment among alcoholics.
• Acamprosate (campral), another FDA-approved medication for
alcoholism , is a competitive inhibitor of the N-methyl-D-aspartate
(NMDA)–type glutamate receptor.
•
The drug appears to normalize the dysregulated
neurotransmission associated with chronic ethanole intake and
thereby to attenuate one of the mechanisms that lead to relapse
34
• Pharmacological Interventions
• Barbiturates and Older Sedatives
The use of barbiturates and older non-benzodiazepine sedating
medications such as:
•
- chloral-hydrate
•
- meprobamatee
•
- glutethimide
•
•
has declined greatly in recent years owing to the increased safety
and to the efficacy of the benzodiazepines and the newer agents
ZOLPIDEM , ESZOPICLONE , AND ZALEPLON
• Abuse problems with barbiturates resemble those seen with
benzodiazepines in many ways
35
• Pharmacological Interventions
. Treatment of abuse and addiction should be handled similarly to
interventions for the abuse of alcohol and benzodiazepines.
• Because drugs in this category frequently are prescribed as
hypnotics for patients complaining of insomnia, physicians should
be aware of the problems that can develop when the hypnotic
agent is withdrawn.
• Insomnia rarely should be treated with medication as a primary
disorder except when produced by short-term stressful situations.
36
• Pharmacological Interventions
. . Insomnia often is a symptom of an underlying chronic problem,
such as:
- depression or respiratory dysfunction, or may be due simply to a
change in sleep requirements with age.
-
Prescription of sedative medications, however, can change the
physiology of sleep with subsequent tolerance to these medication
effects.
- When the sedative is stopped, there is a rebound effect with
worsened insomnia. This medication-induced insomnia requires
detoxification by gradual dose .
37
Pharmacological Treatment of Withdrawal
Syndromes from Substances of Abuse
Substance
Alcohol
Other CNS
depressants
38
Agent and Dosage
Other Treatment
Thiamine, 100 mg
Diazepam, 10–20 intramuscularly or
mg/1–2 hours
50 mg twice daily by
(typical dosage
mouth, and
required, 60 mg) multivitamin tablets
for 3 days
Phenobarbital,
120 mg/hour
(typical dosage,
900–1500 mg)
Opiates andOpioids
39
Opioid receptor subtypes, their functions
1- μ (mu)
• Supraspinal and spinal analgesia;
• sedation; inhibition of respiration
• slowed gastrointestinal transit
• modulation of hormone and neurotransmitter release
2- δ (delta)
• Supraspinal and spinal analgesia;
• modulation of hormone
• and neurotransmitter release
40
Opioid receptor subtypes, their functions
3- κ (kappa)
• Supraspinal and spinal analgesia
• Psychotomimetic effects
• slowed gastrointestinal transit
41
Opioids
• Opioid drugs are used primarily for the treatment of pain
•
Some of the CNS mechanisms that reduce the perception of pain
also produce a state of well-being or euphoria.
•
Thus, opioid drugs also are taken outside medical channels for
the purpose of obtaining the effects on mood.
• This potential for abuse has generated much research on
separating the mechanism of analgesia from that of euphoria
•
in the hope of eventually developing a potent analgesic that does
not activate the brain reward systems.
42
Opioids
•
options for the treatment of pain, but none of these
currently is available for clinical use.
• Progress in pain control stems from a greater
understanding of the mechanism of tolerance to μ opiate
receptor–mediated analgesia, which involves NMDA
receptors
• Experimentally, by combining morphine with
dextromethorphan
• , an NMDA- receptor antagonist, tolerance is impaired
and analgesia is enhanced without an increase in the
dose
of opioid.
43
•
Opioids
Tolerance, Dependence, and Withdrawal
• Injection of a heroin solution produces a variety of
sensations described as warmth, taste, or high and
intense pleasure ("rush") often compared with sexual
orgasm.
• There are some differences among the opioids in their
acute effects, with morphine producing more of a
histamine-releasing effect
• and meperidine producing more excitation or confusion.
44
•
Opioids
Tolerance, Dependence, and Withdrawal
• Heroin has high lipid solubility, crosses the blood-brain
barrier quickly
• and is deacetylated to the active metabolites 6monoacetyl morphine and morphine.
• After the intense euphoria, which lasts from 45 seconds
to several minutes,
• there is a period of sedation and tranquility ("on the
45
nod")
lasting up to an hour.
•
Opioids
Tolerance, Dependence, and Withdrawal
• The effects of heroin wear off in 3-5 hours, depending on
the dose.
• Experienced users may inject two to four times per day.
• Thus, the heroin addict is constantly oscillating between
being "high" and feeling the sickness of early
withdrawal
• This produces many problems in the homeostatic
46
systems
regulated at least in part by endogenous opioids.
• For example, the hypothalamic-pituitary-gonadal
axis and the hypothalamic-pituitary-adrenal axis
are abnormal in heroin addicts.
• Women on heroin have irregular menses,
• and men have a variety of sexual performance
problems.
• Mood also is affected. Heroin addicts are
relatively docile and compliant after taking
heroin,
• but during withdrawal, they become irritable and
aggressive.
47
• Based on patient reports, tolerance develops early to the
euphoria-producing effects of opioids.
• There also is tolerance to the respiratory depressant,
analgesic, sedative, and emetic properties.
• Heroin users tend to increase their daily dose, depending
on their financial resources and the availability of the
drug.
• If a supply is available, the dose can be increased
progressively 100 times.
48
OPIOIDS
• Heroin users commonly acquire:
• bacterial infections producing skin abscesses;
• endocarditis;
• pulmonary infections, especially tuberculosis; and viral
infections producing hepatitis C and acquired immune
deficiency syndrome (AIDS).
49
OPIOIDS
The opioid-withdrawal syndrome is very unpleasant but not
life-threatening.
It begins within 6-12 hours after the last dose of a short-acting
opioid and as long as 72-84 hours after a very long-acting
opioid medication.
Heroin addicts go through early stages of this syndrome
frequently when heroin is scarce or expensive
50
Signs and Symptoms of Opioid Intoxication
and Withdrawal
Intoxication
Withdrawal
Activation or “rush” (early or with
low dosages) and sedation/apathy or Depressed mood and anxiety
“nod” (late or with high dosages)
Dysphoria
Euphoria or dysphoria
Craving
Feelings of warmth, facial flushing, or
Piloerection (“goose flesh”)
itching
Lacrimation or rhinorrhea
Impaired judgment, attention, or
51
memory
OpioidIntoxication Opioid-Withdrawal
Analgesia
Hyperalgia, joint and muscle aches
Constipation
Diarrhea and gastrointestinal cramping,
nausea, or vomiting
Pupillary constriction
Pupillary dilation and photophobia
Drowsiness
Insomnia
Respiratory depression,
areflexia, hypotension,
tachycardia
Autonomic hyperactivity (e.g.,
tachypnea, hyperreflexia,
tachycardia, hypertension, sweating,
hyperthermia)
Apnea,
cyanosis, coma
52
Yawning
Pharmacological Treatment of Withdrawal
Syndromes from Substances of Abuse
Substance
Agent and Dosage
Other
Treatment
3–5 days of clonidine 0.1–0.3 mg every 4–6
hours (check BP prior to each dose, hold for
BP ≤90/60)
Opioids
53
Alternatively, methadone dosed at 10–20 mg Ibuprofen for muscle
by mouth every 12 hours initially, or
cramps, loperamide
buprenorphine dosed at 4–12 mg under
for loose stools, and
tongue daily initially, both taper over a 5– promethazine for
10-day period to reduce withdrawal
nausea or vomiting
symptoms (1 mg buprenorphine is
equivalent to 5 mg methadone, 5 mg of
heroin, 15 mg of morphine, 100 mg of
meperidine)
Pharmacological Maintenance Strategies for
Substance
afterand
Detoxification
SubstanceDependenceAgent
Dosage
Completed
Methadone by mouth at
30–140 mg per day
Opioids
54
Buprenorphine 4–32 mg
under the tongue
(available as
buprenorphine/naloxone
[4/1] to prevent diversion)
Cannabinoids
• Marijuana is the common name for the plant Cannabis
sativa.
• Other names for the plant or its products include hemp,
hashish, chasra, bhang, ganja, and daga.
• The highest concentrations of the psychoactive
cannabinoids are found in the flowering tops of both
male and female plants.
• The primary psychoactive constituent of marijuana is
delta-9-tetrahydrocannabinol
55
Cannabinoids
• Cannabinoid receptors CB1 (mainly CNS) and CB2
(peripheral) have been identified and cloned.
• An arachidonic acid derivative, anandamide, has been
proposed as an endogenous ligand for CB receptors.
• While the physiological function of these receptors and
their endogenous ligands are incompletely understood
• they are likely to have important functions because they
are dispersed widely with high densities in the cerebral
cortex,
hippocampus, striatum, and cerebellum .
56
Cannabinoids
•
Specific CB1 antagonists have been developed and tested in
controlled clinical trials.
•
One of these, rimonabant, was found to reduce:
•
1 - relapse in cigarette smokers
•
2- to produce weight loss in obese patients
•
however, its development has been abandoned because of
depressive and neurologic side effects.
57
Cannabinoids
• Intoxication
• The subjective effect of marijuana intoxication varies from
individual to individual.
•
It is determined in part by highly variable pharmacokinetics,
dosage, route of administration, setting, experience and
expectation,
•
and individual vulnerability to certain psychotoxic effects.
• Typically, intoxication is characterized by an initial period of
“high” that has been described as a sense of well-being and
happiness .
58
Cannabinoids
• Intoxication
• This euphoria is followed frequently by a period of drowsiness or
sedation.
• The perception of time is altered and hearing and vision distorted.
•
The subjective effects of intoxication often include dissociative
reactions.
• Impaired functioning occurs in a variety of cognitive and
performance tasks,
• including memory, reaction time, concept formation, learning,
perception, motor coordination, attention, and signal detection.
59
Cannabinoids
• Intoxication
At dosages equivalent to one or two “joints” (marijuana
cigarettes), processes involved in the operation of motor
vehicles or airplanes are impaired.
The impairment persists for 4–8 hours, long after the user
perceives the subjective effects of the drug.
The impairment produced by alcohol is additive to that
produced by marijuana.
Tolerant individuals may exhibit somewhat less
performance
decrement.
60
Cannabinoids
• . Signs
and Symptoms of Cannabis Intoxication
• Euphoria, drowsiness, or sedation
• Sensation of slowed time
• Auditory or visual distortions, dissociation
• Impaired judgment, motor coordination, attention, or memory
• Slowed reaction time
• Conjunctival injection (dilation of blood vessel of conjuctiva)
• Tachycardia
• Increased appetite
• Anxiety, acute panic reactions, paranoia, illusions, or agitation
61
Cannabinoids
• . Signs
and Symptoms of Cannabis Intoxication
• Physically, dilation of conjunctival blood vessels and tachycardia
may be noted.
• Blood pressure remains relatively unchanged unless high dosages
are used, in which case orthostatic hypotension ensues.
•
Increased appetite is often attributed to marijuana but has not
been observed consistently in controlled studies.
62
Cannabinoids
• . Signs
and Symptoms of Cannabis Intoxication
• At higher dosages,
• acute panic reactions, paranoia,
•
hallucinations, illusions, thought disorganization, and agitation
have been observed.
•
With extremely high dosages, an acute toxic psychosis is
accompanied by:
•
depersonalization and loss of insight.
63
Cannabinoids
• One of the most controversial of the reputed effects of
marijuana is the production of
• an "amotivational syndrome.“
• It has anti-emetic properties that relieve side effects of
anticancer chemotherapy.
• It also has muscle-relaxing effects, anticonvulsant
properties,
• and the capacity to reduce the elevated intraocular
pressure of glaucoma.
64
Cannabinoids
• These medical benefits come at the cost of the psychoactive effects
that often impair normal activities.
• Thus, there is no clear advantage of marijuana over conventional
treatments for any of these indications.
• An oral capsule containing Δ-9-THC (dronabinol; MARINOL,
others) is approved for :
•
- anorexia associated with weight loss in patients with HIV
infection and
•
- for cancer chemotherapy-induced nausea and vomiting.
65
Cannabinoids
• With the cloning of cannabinoid receptors, the discovery
of endogenous ligands, and the synthesis of specific
agonists and antagonists,
• it is likely that new orally effective medications will be
developed without the undesirable properties of smoked
marijuana and
• without the deleterious effects of inhaling smoke
particles and the chemical products of high-temperature
combustion.
66
Cannabinoids
• . Signs
and Symptoms of Cannabis Withdrawal
• Cannabinoid withdrawal does not produce wellcharacterized withdrawal symptoms,
• perhaps because cannabinoids are so lipophilic
that they are very slowly eliminated from the
body.
• The DSM-IV does not include cannabis
withdrawal, but there is an impetus to include the
condition in future versions of DSM.
67
Cannabinoids
• . Signs
and Symptoms of Cannabis Withdrawal
• a withdrawal syndrome consistently follows
discontinuation of chronic heavy use of cannabis,
• or treatment with cannabinoid receptor antagonists.
• Some patients report:
• insomnia, irritability, dysphoria, anorexia, weight loss,
hand tremor, mild fever, or slight nausea with
discontinuation of use.
• These symptoms occur primarily in patients who smoke
68
very
potent preparations.
Pharmacological Treatment of Withdrawal
Syndromes from Substances of Abuse
Substance
Cannabinoids
69
Agent and
Dosage
Not
usually
needed
Other Treatment
Anxiolytics or
neuroleptics
acutely for
agitation or
severe anxiety
Animal Models of Substance Abuse and Addiction
• The reinforcing effects of drugs of abuse are believed to play
• a key role in substance abuse and addiction.
• Early demonstrations that drugs could serve as reinforcers
maintaining operant behavior in laboratory animals led to the
development of a model of human drug abuse.
• the paradigms used for establishing drugs as reinforcers in
• Animals focusing on:
1- drug self-administration
2- conditioned place preference
3- drug discrimination paradigms.
70
Animal Models of Substance Abuse and Addiction
• focused on modeling different phases of the addiction process
• In Animal models often focus on the ability of the drugs to directly
control the animal’s behavior
• an outcome that is consistent with the behavioral definition of
addiction.
• animal studies have demonstrated that the rewarding effect is not
dependent on preexisting conditions; that is, exposure to the drug
is sufficient to motivate drug-taking behavior.
• Self-administration by laboratory animals of drugs abused by
humans also supports the concept that drugs act as universal
reinforcers.
71
• Drug self-administration paradigm.
• The traditional animal models of drug abuse are framed by the
behaviorist view that emphasizes
• the action of drugs as positive reinforcers, much like food,
• water, and other ‘natural’ reinforcers.
• The fundamental principle is that aspects of behavior are
controlled by their consequences.
• A drug is said to be functioning as a reinforcer if responding
• for it is maintained above responding for saline or other control
• conditions.
72
• Drug self-administration paradigm.
•
• The traditional model entails training an animal
to
• self-administer a drug during a short daily
session, typically 1
• to 3 h.
• Figure shows a rat in a typical operant chamber
with an
• intravenous catheter for chronic selfadministration.
•
73
74
• Drug self-administration paradigm.
• Rodents are most often used in these studies
•
this model has been used with a variety of species including
nonhuman primates,
• dogs, and cats.
•
In rodents, a low-ratio requirement typically is used, such as a
fixed-ratio 1
• where each operant response produces a drug delivery.
•
In addition, a variety of operant responses have been used.
• Typically they depend on the species studied (for
• example, a lever press or a nose poke response typically is used for
rodents,
• whereas a panel press response typically is used for nonhuman primates).
75
• The most common routes of administration are intravenous
• and oral, but intracerebroventricular, intracranial, inhalation,
intragastric,and intramuscular routes have also been used
•
some of these other routes (for example, smoked) are used relatively
infrequently
• because of practical and logistical difficulties.
•
•
Generally, these studies use the route of administration that is most
similar to the route used in humans for that particular drug.
For example, animal studies with alcohol typically use an oral route
of administration,
• whereas an intravenous route is used for drugs like cocaine,
• heroin, and nicotine, to mimic the rapid onset produced
76
• by intravenous or inhalational administration in
•
• Taste factors must often be considered with the oral route, given
that these often limit consumption of pharmacologically active
doses
• however, use of intragastric self-administration or sweetening an
• alcohol solution with saccharin are 2 methods used to avoid the
• influence of taste.
•
Results from animal drug self-administration studies have
revealed that drugs can serve as positive reinforcers
• and there appears to be good correspondence between humans
• and animals in terms of drugs that are self-administered
• and patterns of drug intake.
77
• For example, drugs that are abused by humans generally
maintain responding in animals
•
whereas drugs that do not maintain responding in animals
typically are not abused by humans
•
In addition, similar patterns of drug intake have been reported in
humans and animals for ethanol, opioids, nicotine, and cocaine
self-administration.
•
These parallel results between the human and animal drug
literature validate the animal model of drug abuse
• and suggest that the use of this model may lead to a better
understanding of human drug-taking behavior.
78
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
The traditional self-administration procedure has been instrumental
in characterizing the brain regions and signaling pathways
that are responsible for rewarding behaviors. This ‘reward
pathway’ is comprised of several brain regions, the most prominent
being the ventral tegmental area, nucleus accumbens, and
Vol 60, No 3
Comparative Medicine
June 2010
180
ence 83). Early studies with monkeys and rats showed that, like
those in humans, patterns of self-administration in laboratory
animals that are given unlimited access conditions (that is, 24-h
sessions wherein each response was reinforced under a fixedratio
1 schedule) were characterized by dysregulated and binge
patterns of use. Under these conditions, toxicity can develop rapidly,
particularly with unlimited access to psychostimulant drugs
and opiates, thereby necessitating the use of procedures that limit
access to these drugs in some way.
Recent studies have attempted to capture these features—dysregulated
patterns of use and excessive consumption—without
the toxicity. For example, dysregulated and excessive drug intake
without serious toxicity has been observed to occur under 24-h
access conditions with low-unit doses of drug18 and under continuous
access conditions that limit the number of hours of access
each day (that is, 6 to 12 h daily1) or each period of continuous
access (that is, 72 h).101 Another method that has been used with
limited toxicity is to give animals 24-h access to a drug in discrete
trials throughout the light:dark cycle.27 This method has been
used for cocaine self-administration, and the results have shown
that
79the regularity of patterns of use break down and intake progressively
increases as access conditions increase. Under shortaccess
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Drug self-administration paradigm. The traditional animal models
of drug abuse are framed by the behaviorist view that emphasizes
the action of drugs as positive reinforcers, much like food,
water, and other ‘natural’ reinforcers. The fundamental principle
is that aspects of behavior are controlled by their consequences.
A drug is said to be functioning as a reinforcer if responding
for it is maintained above responding for saline or other control
conditions. The traditional model entails training an animal to
self-administer a drug during a short daily session, typically 1
to 3 h. Figure 2 shows a rat in a typical operant chamber with an
intravenous catheter for chronic self-administration. Although
rodents are most often used in these studies, this model has been
used with a variety of species including nonhuman primates,
dogs, and cats. In rodents, a low-ratio requirement typically is
used, such as a fixed-ratio 1, where each operant response produces
a drug delivery. In addition, a variety of operant responses
have been used. Typically they depend on the species studied (for
example, a lever press or a nose poke response typically is used
for rodents, whereas a panel press response typically is used for
nonhuman primates).
The most common routes of administration are intravenous
and oral, but intracerebroventricular, intracranial, inhalation, intragastric,
and intramuscular routes have also been used; some of
these other routes (for example, smoked) are used relatively infrequently,
because of practical and logistical difficulties. Generally,
these studies use the route of administration that is most similar
to the route used in humans for that particular drug. For example,
animal studies with alcohol typically use an oral route of administration,
whereas an intravenous route is used for drugs like cocaine,
heroin,
80 and nicotine, to mimic the rapid onset produced
by intravenous or inhalational administration in humans.19 Taste
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Drug self-administration paradigm. The traditional animal models
of drug abuse are framed by the behaviorist view that emphasizes
the action of drugs as positive reinforcers, much like food,
water, and other ‘natural’ reinforcers. The fundamental principle
is that aspects of behavior are controlled by their consequences.
A drug is said to be functioning as a reinforcer if responding
for it is maintained above responding for saline or other control
conditions. The traditional model entails training an animal to
self-administer a drug during a short daily session, typically 1
to 3 h. Figure 2 shows a rat in a typical operant chamber with an
intravenous catheter for chronic self-administration. Although
rodents are most often used in these studies, this model has been
used with a variety of species including nonhuman primates,
dogs, and cats. In rodents, a low-ratio requirement typically is
used, such as a fixed-ratio 1, where each operant response produces
a drug delivery. In addition, a variety of operant responses
have been used. Typically they depend on the species studied (for
example, a lever press or a nose poke response typically is used
for rodents, whereas a panel press response typically is used for
nonhuman primates).
The most common routes of administration are intravenous
and oral, but intracerebroventricular, intracranial, inhalation, intragastric,
and intramuscular routes have also been used; some of
these other routes (for example, smoked) are used relatively infrequently,
because of practical and logistical difficulties. Generally,
these studies use the route of administration that is most similar
to the route used in humans for that particular drug. For example,
animal studies with alcohol typically use an oral route of administration,
whereas an intravenous route is used for drugs like cocaine,
heroin,
81 and nicotine, to mimic the rapid onset produced
by intravenous or inhalational administration in humans.19 Taste
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
in characterizing the brain regions and signaling pathways
that are responsible for rewarding behaviors. This ‘reward
pathway’ is comprised of several brain regions, the most prominent
being the ventral tegmental area, nucleus accumbens, and
Vol 60, No 3
Comparative Medicine
June 2010
180
ence 83). Early studies with monkeys and rats showed that, like
those in humans, patterns of self-administration in laboratory
animals that are given unlimited access conditions (that is, 24-h
sessions wherein each response was reinforced under a fixedratio
1 schedule) were characterized by dysregulated and binge
patterns of use. Under these conditions, toxicity can develop rapidly,
particularly with unlimited access to psychostimulant drugs
and opiates, thereby necessitating the use of procedures that limit
access to these drugs in some way.
Recent studies have attempted to capture these features—dysregulated
patterns of use and excessive consumption—without
the toxicity. For example, dysregulated and excessive drug intake
without serious toxicity has been observed to occur under 24-h
access conditions with low-unit doses of drug18 and under continuous
access conditions that limit the number of hours of access
each day (that is, 6 to 12 h daily1) or each period of continuous
access (that is, 72 h).101 Another method that has been used with
limited toxicity is to give animals 24-h access to a drug in discrete
trials throughout the light:dark cycle.27 This method has been
used for cocaine self-administration, and the results have shown
that the regularity of patterns of use break down and intake progressively
increases
as access conditions increase. Under shortaccess
82
conditions (that is, 1 to 2 discrete trials per hour, 1.5 mg/