Psychopharmacology (Fourth Edition)

Jerry Meyer
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 Meyer
Farrar
Biezonski
Yates

Psychopharmacology

Psychopharmacology
Psychopharmacology 4e
by Meyer, Farrar, Biezonski and Yates

UNIQUE IN ITS BREADTH OF COVERAGE ranging from historical accounts of Drugs, the Brain, and Behavior
drug use to clinical and preclinical behavioral studies, Psychopharmacology Fourth Edition
is the ideal text for students studying disciplines from psychology to biology to
neuroscience, who are interested in the relationships between the behavioral
effects of psychoactive drugs and their mechanisms of action. This is a uniquely
engaging text, which provides the scientific depth, breadth, and rigor required
for the psychopharmacology course.

 Also available as an enhanced e-book, with interactive self-assessments

and embedded digital resources, in several formats including RedShelf,
VitalSource, and Chegg. All major devices are supported.

FOURTH
EDITION

ISBN 978-1-60535-987-8
1
www.oup.com/us/he
SINAUER
Jerrold S. Meyer ■ Andrew M. Farrar
Cover Photo: Courtesy Bethlem Museum of the Mind
Cover Design: Beth Roberge
9 781605 359878
2 Dominik Biezonski ■ Jennifer R. Yates

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 Psychopharmacology
Drugs, the Brain, and Behavior
FOURTH EDITION

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00_Meyer4e_FM.indd 2 12/15/21 12:49 PM
 Psychopharmacology
Drugs, the Brain, and Behavior
Fourth Edition

Jerrold S. Meyer Andrew M. Farrar

University of Massachusetts University of Massachusetts

Dominik Biezonski Jennifer R. Yates

Prevail Therapeutics, Lander University
a wholly owned subsidiary of Eli Lilly and Company

SINAUER ASSOCIATES

NEW YORK OXFORD

OXFORD UNIVERSITY PRESS

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About the cover
Anonymous, Mescaline Painting –
Blue and Red Abstract (c. 1938). This
striking painting was a product of a
1930s British psychiatric experiment
to study artistic self-expression
under the influence of mescaline,
which at the time was purported
to induce a schizophrenia-like state.
Courtesy Bethlem Museum of
the Mind.
00_Meyer4e_FM.indd 4
Psychopharmacology
Drugs, the Brain, and Behavior, Fourth Edition
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Library of Congress Cataloging-in-Publication Data
Names: Meyer, Jerrold S., 1947- author.
Title: Psychopharmacology: drugs, the brain, and behavior / Jerrold S. Meyer, Andrew
M. Farrar, Dominik Biezonski, and Jennifer R. Yates.
Description: Fourth edition. | Sunderland, Massachusetts, USA : Oxford University Press,
[2023] | Includes bibliographical references and index.
Identifiers: LCCN 2017049700 | (hardcover) ISBN 9781605359878, (ebook) ISBN
9781605359892.
Subjects: LCSH: Psychotropic drugs--Pharmacokinetics. | Psychotropic drugs--
Therapeutic use.
Classification: LCC RM315 .M478 2019 | DDC 615.7/88--dc23
LC record available at https://lccn.loc.gov/2017049700
The Diagnostic and Statistical Manual of Mental Disorders, DSM, DSM-IV, DSM-IV-TR,
and DSM-5 are registered trademarks of the American Psychiatric Association. Oxford
University Press is not associated with the American Psychiatric Association or with any
of its products or publications, nor do the views expressed herein represent the policies
and opinions of the American Psychiatric Association.
9 8 7 6 5 4 3 2 1
Printed in the United States of America
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 Jerrold Meyer dedicates his contribution to the book to his lovely wife and colleague,
Dr. Melinda Novak, for her unwavering patience and support during the countless
hours he was squirreled away in his home office working on the project.

Andrew Farrar dedicates his contribution to the book to his wife and partner in all
endeavors, Dr. Mariana Pereira, for her patience, dedication and support.

Dominik Biezonski dedicates his contribution to the book to his incredible wife,
Patty Biezonski, and to his loving parents, John and Margaret Biezonski.

Jennifer Yates dedicates her contribution to the book to Dr. James C. Walton,
for supporting her, always.

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 Brief Contents
CHAPTER 1 Principles of Pharmacology 1
CHAPTER 2 Structure and Function of the Nervous System 39
CHAPTER 3 Chemical Signaling by Neurotransmitters and Hormones 75
CHAPTER 4 Methods of Research in Psychopharmacology 107
CHAPTER 5 Catecholamines 148
CHAPTER 6 Serotonin 179
CHAPTER 7 Acetylcholine 203
CHAPTER 8 Glutamate and GABA 222
CHAPTER 9 Drug Misuse and Addiction 252
CHAPTER 10 Alcohol 289
CHAPTER 11 The Opioids 330
CHAPTER 12  sychomotor Stimulants: Cocaine, Amphetamine,
P
and Related Drugs 368
CHAPTER 13 Nicotine and Caffeine 406
CHAPTER 14 Marijuana and the Cannabinoids 445
CHAPTER 15  sychedelic and Hallucinogenic Drugs, PCP, and
P
Ketamine 483
CHAPTER 16 Inhalants, GHB, and Anabolic–Androgenic Steroids 513
CHAPTER 17  isorders of Anxiety and Impulsivity and the Drugs
D
Used to Treat Them 547
CHAPTER 18 Affective Disorders: Antidepressants and Mood Stabilizers 587
CHAPTER 19 Schizophrenia: Antipsychotic Drugs 619
CHAPTER 20 Neurodegenerative Diseases 654

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 Contents
1 Principles of Pharmacology 1
1.1 P
 harmacology: The Science BOX 1.3
■  PHARMACOLOGY IN ACTION
Interspecies Drug Dose Extrapolation 24
of Drug Action 2
Placebo effect 3 1.2 P
 harmacodynamics:
BOX 1.1
■  PHARMACOLOGY IN ACTION
Drug–Receptor Interactions 26
Naming Drugs 4 Extracellular and intracellular receptors have
several common features 26
Pharmacokinetic factors determining drug action 4
Methods of drug administration influence BOX 1.4
■  PHARMACOLOGY IN ACTION
the onset of drug action 5 Drug Categories 27

BOX 1.2
■  CASE STUDIES The Perils of Alcohol
Taken by an Unconventional Route
of Administration 7
Multiple factors modify drug absorption 11
Drug distribution is limited by selective barriers 14
Depot binding alters the magnitude and duration
of drug action 17
Biotransformation and elimination of drugs
contribute to bioavailability 18
Therapeutic drug monitoring 23
Dose–response curves describe receptor activity 29
The therapeutic index calculates drug safety 30
Receptor antagonists compete with agonists
for binding sites 30
Biobehavioral effects of chronic drug use 32
Repeated drug exposure can cause tolerance 32
Chronic drug use can cause sensitization 35
Pharmacogenetics and personalized medicine
in psychiatry 36

2 Structure and Function of the Nervous System 39

2.1 Cells of the Nervous System 40 Local potentials are small, transient changes
in membrane potential 52
BOX 2.1
■  THE CUTTING EDGE
Sufficient depolarization at the axon hillock
Embryonic Stem Cells 41
opens voltage-gated Na+ channels, producing
Neurons have three major external features 42 an action potential 54
Characteristics of the cell membrane are Drugs and poisons alter axon conduction 56
critical for neuron function 47
2.3 Organization of the Nervous System 57
Glial cells provide vital support for neurons 48
BOX 2.3
■  THE CUTTING EDGE Finding Your Way
BOX 2.2
■  OF SPECIAL INTEREST
in the Nervous System 57
Astrocytes 49
The nervous system comprises the central
2.2 E
 lectrical Transmission within and peripheral divisions 59
a Neuron 51 BOX 2.4
■  CASE STUDIES A Case of Toxic
Ion distribution is responsible for the cell’s Experimentation with a Garden-Variety
resting potential 51 Weed 62

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 viii Contents
CNS functioning is dependent on structural
features 62
The CNS has six distinct regions reflecting
embryological development 63
BOX 2.5
■  OF SPECIAL INTEREST
Neuroendocrine Response to Stress 69
3 Chemical Signaling by Neurotransmitters and Hormones 75
3.1 C
 hemical Signaling in the
Nervous System 76
Basic concepts 76
Neurotransmitter synthesis, release,
and inactivation 78
Neurotransmitters encompass several different
kinds of chemical substances 78
Neuropeptides are synthesized by a different
mechanism than other transmitters 80
Neuromodulators are chemicals that do not
act like typical neurotransmitters 80
Classical transmitter release involves exocytosis
and recycling of synaptic vesicles 81
Lipid and gaseous transmitters are not released
from synaptic vesicles 86
Several mechanisms control the rate of
neurotransmitter release by nerve cells 87
Mechanisms of neurotransmitter inactivation 88
Neurotransmitters outside of the CNS 89
4 Methods of Research in Psychopharmacology 107
4.1 T
 echniques in Behavioral
Pharmacology 108
Evaluating animal behavior 108
Animal testing needs to be valid and reliable to
produce useful information 108
A wide variety of behaviors are evaluated
by psychopharmacologists 111
BOX 4.1
■  CLINICAL APPLICATIONS
Drug Testing for FDA Approval 121
4.2 Techniques in Neuropharmacology 124
Multiple neurobiological techniques for assessing
the CNS 124
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The cerebral cortex is divided into four lobes, each
having primary, secondary, and tertiary areas 70
Rat and human brains have many similarities
and some differences 71
3.2 N
 eurotransmitter Receptors, Signaling
Mechanisms, and Synaptic Plasticity 90
Neurotransmitter receptor families 90
Ionotropic receptors consist of multiple subunits
that together form an ion channel 91
Metabotropic receptors consist of a single subunit
that works by activating G proteins 92
BOX 3.1
■  THE CUTTING EDGE Allosteric
Modulation of Neurotransmitter Receptors 94
Second-messenger systems 94
Tyrosine kinase receptors 96
Pharmacology of synaptic transmission 96
Synaptic plasticity 97
3.3 The Endocrine System 99
Endocrine glands and their respective hormones 99
Hormonal and neurotransmitter functions
of oxytocin and vasopressin 102
Mechanisms of hormone action 103
The endocrine system is important to
pharmacologists 104
Stereotaxic surgery is needed for accurate in vivo
measures of brain function 124
Neurotransmitters, receptors, and other proteins can
be quantified and visually located in the CNS 127
New tools are used for imaging the structure and
function of the brain 134
Genetic engineering helps neuroscientists to ask
and answer new questions 138
BOX 4.2
■  CASE STUDIES CRISPR Babies:
The case of Lulu and Nana 141
BOX 4.3
■  PHARMACOLOGY IN ACTION
Transgenic Model of Huntington’s Disease 142
Behavioral and neuropharmacological methods
complement one another 145
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 Contents ix

5 Catecholamines 148
5.1 C
 atecholamine Synthesis, Release,
and Inactivation 149
Catecholamines are synthesized by a multi-step
pathway in which tyrosine hydroxylase catalyzes
the rate-limiting step 149
Catecholamine storage and release are regulated by
vesicular uptake, autoreceptor activity, and cell
firing rate 151
Catecholamines are recycled after release by a process
of reuptake 153
Catecholamine levels are regulated by metabolizing
enzymes 155
5.2 O
 rganization and Function of the
Dopaminergic System 157
Two important dopaminergic cell groups are found
in the midbrain 157
Ascending dopamine pathways have been implicated
in several important behavioral functions 157
There are five main subtypes of dopamine receptors
organized into D1- and D2-like families 160
Dopamine receptor agonists and antagonists affect
locomotor activity, motor control, and other
behavioral functions 162
BOX 5.1
■  THE CUTTING EDGE Using Molecular
Genetics to Study the Dopaminergic System 164
5.3 O
 rganization and Function of the
Noradrenergic System 168
Norepinephrine is an important transmitter in both
the central and peripheral nervous systems 168
Norepinephrine and epinephrine act through α- and
β-adrenergic receptors 169
The central noradrenergic system plays a significant
role in arousal, cognition, and the consolidation of
emotional memories 170
Several medications work by stimulating or inhibiting
peripheral adrenergic receptors 174

6 Serotonin 179
6.1 S
 erotonin Synthesis, Release, The serotonergic system originates in the brainstem
and projects to all forebrain areas 188
and Inactivation 180
The firing of dorsal raphe serotonergic neurons varies
Serotonin synthesis is regulated by enzymatic activity with behavioral states 189
and precursor availability 180
There is a large family of serotonin receptors,
Similar processes regulate storage, release, and most of which are metabotropic 189
inactivation of serotonin and the catecholamines 183
BOX 6.1
■  OF SPECIAL INTEREST “Ecstasy”—
6.3 B
 ehavioral and Physiological Functions
Harmless Feel-Good Drug, Dangerous of Serotonin 192
Neurotoxin, or Miracle Medication? 184 Multiple approaches have identified several behavioral
and physiological functions of serotonin 192
6.2 B
 asic Features of the Serotonergic
System: Anatomical Organization,
Cell Firing, and Receptor Families 188

7 Acetylcholine 203
7.1 A
 cetylcholine Synthesis, Release, BOX 7.1
■  PHARMACOLOGY IN ACTION
Botulinum Toxin—Deadly Poison, Therapeutic
and Inactivation 204 Remedy, and Cosmetic Aid 206
Acetylcholine synthesis is catalyzed by the enzyme Several neuromuscular disorders are associated
choline acetyltransferase 204 with abnormal cholinergic functioning at the
Many different drugs and toxins can alter neuromuscular junction 209
acetylcholine storage and release 204
Acetylcholinesterase is responsible for acetylcholine
breakdown 205

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 x Contents
7.2 O
 rganization and Function of the
Cholinergic System 210
Cholinergic neurons play a key role in the functioning
of both the peripheral and central nervous
systems 210
8 Glutamate and GABA 222
8.1 G
 lutamate Synthesis, Release,
and Inactivation 223
Neurons generate glutamate from the precursor
glutamine 223
Glutamate packaging into vesicles and uptake
after release are mediated by multiple
transport systems 223
8.2 O
 rganization and Function of the
Glutamatergic System 226
Glutamate is the neurotransmitter used in many
excitatory pathways in the brain 226
Both ionotropic and metabotropic receptors mediate
the synaptic effects of glutamate 226
AMPA and NMDA receptors play a key role in
learning and memory 230
BOX 8.1
■  CLINICAL APPLICATIONS Fragile X
Syndrome and Metabotropic Glutamate
Receptor Antagonists: A Contemporary Saga
of Translational Medicine 231
High levels of glutamate can be toxic to nerve cells 236
9 Drug Misuse and Addiction 252
9.1 I ntroduction to Drug Misuse
and Addiction 253
Recreational drugs are widely consumed in our
society 253
Drug use in our society has increased and has become
more heavily regulated over time 254
9.2 F
 eatures of Drug Misuse
and Addiction 258
Drug addiction is considered to be a chronic,
relapsing behavioral disorder 258
BOX 9.1
■  OF SPECIAL INTEREST Should the
Term Addiction Be Applied to Compulsive
Behavioral Disorders That Don’t Involve
Substance Use? 260
There are two types of progression in drug use 261
Which drugs are the most addictive? 262
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BOX 7.2
■  THE CUTTING EDGE Acetylcholine
and Cognitive Function 212
There are two acetylcholine receptor subtypes:
nicotinic and muscarinic 214
8.3 G
 ABA Synthesis, Release,
and Inactivation 239
GABA is synthesized by the enzyme glutamic acid
decarboxylase 239
GABA packaging into vesicles and uptake after release
are mediated by specific transporter proteins 240
GABA is co-released with several other classical
neurotransmitters 241
8.4 O
 rganization and Function of the
GABAergic System 242
Some GABAergic neurons are interneurons, while
others are projection neurons 242
The actions of GABA are primarily mediated by
ionotropic GABAA receptors 243
BOX 8.2
■  THE CUTTING EDGE GABA A Receptor
Modulation by Neurosteroids 247
GABA also signals using metabotropic
GABAB receptors 249
9.3 F
 actors That Influence the Development
and Maintenance of Drug Misuse
and Addiction 263
The addictive potential of a substance is influenced
by its route of administration 264
Most recreational drugs exert rewarding and
reinforcing effects 264
Drug dependence leads to withdrawal symptoms
when abstinence is attempted 267
Discriminative stimulus effects contribute to
drug-seeking behavior 269
Genetic factors contribute to the risk for addiction 269
Psychosocial variables also contribute to addiction
risk 269
Sex differences in substance use, misuse,
and addiction 271
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Natural recovery from substance misuse
and addiction 271
The factors contributing to substance misuse
and addiction can be combined into a
biopsychosocial model 272
9.4 The Neurobiology of Drug Addiction 274
Drug reward and incentive salience drive the binge/
intoxication stage of drug use 274
The withdrawal/negative affect stage is characterized
by stress and by the recruitment of an antireward
system 277
10 Alcohol 289
10.1 Psychopharmacology of Alcohol 290
Alcohol has a long history of use 290
What is an alcohol and where does it come from? 291
The pharmacokinetics of alcohol determines its
bioavailability 292
Chronic alcohol use leads to both tolerance and
physical dependence 294
Alcohol affects many organ systems 297
BOX 10.1
■  CASE STUDIES The Case of
a Neurodegenerative Disease Disguised
by Alcohol Use Disorder 300
11 The Opioids 330
11.1 Narcotic Analgesics 331
The opium poppy has a long history of use 331
Minor differences in molecular structure determine
behavioral effects 332
Bioavailability predicts both physiological
and behavioral effects 333
Opioids have their most important effects on the
CNS and on the gastrointestinal tract 334
Opioid receptors and endogenous
neuropeptides 334
Receptor binding studies identified and localized
opioid receptors 335
Four opioid receptor subtypes exist 336
Several families of naturally occurring opioid
peptides bind to these receptors 338
BOX 11.1
■  THE CUTTING EDGE
Science in Action 339
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Contents xi
The preoccupation/anticipation stage involves
dysregulation of prefrontal cortical function and
corticostriatal circuitry 279
The persistence of addiction has been studied at both
the molecular and synaptic levels 280
Is addiction a brain disease? 280
BOX 9.2
■  THE CUTTING EDGE Epigenetic
Processes and Synaptic Plasticity as
Mechanisms for the Development and
Persistence of Drug Addiction 281
10.2 Neurochemical Effects of Alcohol 307
Animal models are vital for alcohol research 307
Alcohol acts on multiple neurotransmitters 309
10.3 Alcohol Use Disorder (AUD) 317
Defining AUD and estimating its incidence have
proved difficult 317
The causes of AUD are multimodal 319
Multiple treatment options provide hope for
rehabilitation 323
Opioid receptor–mediated cellular changes
are inhibitory 342
11.2 Opioids and Pain 344
The two components of pain have distinct
features 344
Opioids inhibit pain transmission at spinal and
supraspinal levels 347
11.3 O
 pioid Reinforcement, Tolerance,
and Dependence 352
Animal testing shows significant reinforcing
properties 353
Dopaminergic and nondopaminergic components
contribute to opioid reinforcement 354
Long-term opioid use produces tolerance,
sensitization, and dependence 355
BOX 11.2
■  OF SPECIAL INTEREST
The Opioid Epidemic 357
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 xii Contents
Several brain areas contribute to the opioid
abstinence syndrome 358
Neurobiological adaptation and rebound constitute
tolerance and withdrawal 359
Environmental cues have a role in tolerance,
drug abuse, and relapse 360
Treatment programs for opioid use disorder 361
12  sychomotor Stimulants: Cocaine, Amphetamine,
P
and Related Drugs 368
12.1 B
 ackground, Pharmacology, and
Mechanisms of Action of Cocaine
Background 369
Basic pharmacology 370
Mechanisms of action 372
12.2 A
 cute Behavioral and Physiological
Effects of Cocaine 375
Cocaine stimulates mood and behavior 375
Cocaine’s physiological effects are mediated
by the sympathetic nervous system 376
Dopaminergic pathways from the midbrain to the
striatum are critical for the behavioral effects
of cocaine and other psychostimulants 377
Brain imaging has revealed the neural mechanisms
of psychostimulant action in humans 378
Several DA receptor subtypes mediate the
functional effects of psychostimulants 378
12.3 C
 ocaine Use and the Effects
of Chronic Cocaine Exposure 380
Experimental cocaine use may escalate over time
to the development of a cocaine use disorder 380
Chronic cocaine exposure leads to significant
neurobiological and behavioral changes 382
Repeated or high-dose cocaine use can produce
serious health consequences 384
13 Nicotine and Caffeine 406
13.1 B
 ackground, History, and Basic
Pharmacology of Nicotine 407
Background and history 407
Nicotine pharmacokinetics related to
tobacco smoking 408
Nicotine pharmacokinetics related
to e-cigarette vaping 408
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Detoxification is the first step in the
therapeutic process 361
Treatment goals and programs rely on
pharmacological support and counseling 362
BOX 11.3
■  CASE STUDIES A Case of Neonatal
Abstinence Syndrome Following Maternal
Kratom Use 365
BOX 12.1
■  THE CUTTING EDGE
Neurochemical Mechanisms of Cocaine
369 Tolerance and Sensitization 385
Pharmacological, behavioral, and psychosocial
methods are used to treat cocaine use disorder 386
12.4 B
 ackground, History, and
Basic Pharmacology of the
Amphetamines 390
Background and history 390
Basic pharmacology 391
12.5 M
 echanisms of Action and
Neurobehavioral Effects
of Amphetamines 392
Mechanisms of amphetamine and
methamphetamine action 392
Neurobehavioral effects of amphetamines 392
Amphetamine and methamphetamine have
therapeutic uses 393
High doses or chronic use of amphetamines can
cause a variety of adverse effects 393
12.6 Methylphenidate and Modafinil 396
Methylphenidate 396
BOX 12.2
■  CLINICAL APPLICATIONS
Psychostimulants and ADHD 398
Modafinil 400
12.7 Synthetic Cathinones 401
Nicotine metabolism 410
Mechanisms of nicotine action 411
13.2 B
 ehavioral and Physiological Effects
of Nicotine 412
Smoking-related mood changes are related to
both pharmacological (nicotine) and non-
pharmacological factors 412
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 Contents xiii

Nicotine enhances cognitive function 412
Nicotine exerts both reinforcing and aversive
effects 414
Nicotine produces a wide range of physiological
effects 416
Nicotine is a toxic substance that can cause severe
distress or even death at high doses 417
Chronic exposure to nicotine induces tolerance
and dependence 417
13.4 Caffeine
13.3 Cigarette Smoking and Vaping 421
What percentage of the population are current users
of tobacco and/or e-cigarettes? 421
Nicotine users progress through a series of stages
in their pattern and frequency of use 422
Why do smokers smoke and vapers vape? 424
Smoking is a major health hazard and a cause
of premature death 426
BOX 13.1
■  THE CUTTING EDGE
How Safe Are E-cigarettes? 429
Behavioral and pharmacological strategies are used
to treat tobacco dependence 430
433
Basic pharmacology of caffeine 434
Behavioral and physiological effects of caffeine 434
BOX 13.2
■  OF SPECIAL INTEREST
Energy Drinks: Caffeine and More 436
Mechanisms of caffeine action 440

14 Marijuana and the Cannabinoids 445

14.1 B
 ackground, History, and Basic 14.3 A
 cute Behavioral and Physiological
Pharmacology of Cannabis Effects of Cannabinoids 462
and Marijuana 446 Cannabis consumption produces a dose-dependent
Forms of cannabis and their state of intoxication 462
chemical constituents 446 Marijuana use can lead to deficits in memory and
History of cannabis 447 other cognitive processes 464
Basic pharmacology of marijuana 448 Rewarding and reinforcing effects of cannabinoids
have been studied in both humans and
14.2 M
 echanisms of Cannabinoid animals 465
Action 450 14.4 C
 annabis Use, Misuse, and the Effects
Cannabinoid effects are primarily mediated by of Chronic Cannabis Exposure 466
cannabinoid receptors 450
Global cannabis/marijuana use, initiation of use,
Pharmacological and genetic studies reveal the and subsequent age-related changes in use are
functional roles of cannabinoid receptors 451 well documented 466
Cannabidiol is not a cannabinoid Chronic use of cannabis can lead to the development
receptor agonist 452 of a cannabis use disorder 467
Endocannabinoids are cannabinoid receptor agonists Chronic cannabis use can lead to adverse behavioral,
synthesized by the body 453 neurobiological, and health effects 471
BOX 14.1
■  CLINICAL APPLICATIONS BOX 14.2
■  OF SPECIAL INTEREST
Cannabinoid-Based Medications: Beyond Cannabis: The Rise of Synthetic
THC, CBD, and Medical Marijuana 458 Cannabinoids 477

15 Psychedelic and Hallucinogenic Drugs, PCP, and Ketamine 483

15.1 Psychedelic Drugs 484 15.2 PCP and Ketamine 501
Background 484 Background and history 501
BOX 15.1
■  HISTORY OF PHARMACOLOGY Pharmacology of PCP and ketamine 502
The Discovery of LSD 487 Recreational use, adverse effects, and therapeutic
Basic pharmacology of psychedelic drugs 491 applications 504
Neurobiology of psychedelic drugs: neural circuitry, BOX 15.2
■  PHARMACOLOGY IN ACTION
therapeutic applications, and adverse reactions 495 Getting High on Cough Syrup 507

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 xiv Contents

16 Inhalants, GHB, and Anabolic–Androgenic Steroids 513

16.1 Inhalants 514
Inhalants comprise a range of substances including
volatile solvents, fuels, halogenated hydrocarbons,
anesthetics, and nitrites 514
Effects of GHB are mediated by multiple
mechanisms 524
GHB is used therapeutically for the treatment
of narcolepsy and alcoholism 526

Inhalants are rapidly absorbed and readily enter GHB has significant dependence potential
the brain 514 when used recreationally 526

These substances are particularly favored by children 16.3 Anabolic–Androgenic Steroids 528
and adolescents 515 AAS are structurally related to testosterone 529
Many inhalant effects are similar to alcohol AAS were developed to help build muscle mass
intoxication 516 and enhance athletic performance 529
Chronic inhalant use can lead to tolerance AAS are currently taken by many adolescent
and dependence 516 and adult men 531
BOX 16.1
■  CASE STUDIES Dependence and AAS are taken in specific patterns and
Withdrawal in an Adolescent Inhalant User 517 combinations 532
Rewarding and reinforcing effects have been AAS enhance performance through multiple
demonstrated in animals 517 mechanisms of action 533
Inhalants have complex effects on central nervous Many adverse side effects are associated
system (CNS) function and behavioral activity 518 with AAS use 535
Health Risks Associated with Inhalant Use 519 Regular AAS use causes dependence in
some individuals 537
16.2 Gamma-Hydroxybutyrate 521
BOX 16.2
■  OF SPECIAL INTEREST Anabolic–
Background 521
Androgenic Steroids and “Roid Rage” 538
GHB produces behavioral sedation, intoxication,
and learning deficits 523 Testosterone has an important role in treating
hypogonadism 541
GHB and its precursors have reinforcing
properties 524

17  isorders of Anxiety and Impulsivity and the Drugs

D
Used to Treat Them 547
17.1 Neurobiology of Anxiety 548 17.2 C
 haracteristics of
What is anxiety? 548 Anxiety Disorders 568
The amygdala is important to emotion-processing Generalized anxiety disorder 568
circuits 549 Panic attacks and panic disorder with
Multiple neurotransmitters mediate anxiety 552 anticipatory anxiety 569
BOX 17.1
■  THE CUTTING EDGE Phobias 570
Toward Unraveling the Cellular and Molecular Social anxiety disorder 570
Mechanisms Underlying LC-NE Modulation
of Anxiety 554 Post-traumatic stress disorder 571
Obsessive–compulsive disorder 573
Genes and environment interact to
modulate anxiety 563
The effects of early stress are dependent
on timing 565
The effects of early stress vary with gender 566

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 Contents xv

17.3 D
 rugs for Treating Anxiety, OCD,
and PTSD 575
Barbiturates are the oldest sedative–hypnotics 576
BDZs are highly effective for anxiety reduction 578
Second-generation anxiolytics produce distinctive
clinical effects 583
Antidepressants relieve anxiety and depression 584
Many novel approaches to treating anxiety are
being developed 584

18 Affective Disorders: Antidepressants and Mood Stabilizers 587

18.1 C
 haracteristics of Norepinephrine and serotonin modulate
one another 601
Affective Disorders 588
Neurobiological models of depression 602
Major depression damages the quality of life 588
BOX 18.1
■  THE CUTTING EDGE
In bipolar disorder moods alternate between mania Epigenetic Modifications in Psychopathology
and depression 589 and Treatment 605
Risk factors for mood disorders are biological
and environmental 590 18.3 Therapies for Affective Disorders 608
Animal models of affective disorders 594 MAOIs are the oldest antidepressant drugs 608
Models of bipolar disorder 595 TCAs block the reuptake of NE and serotonin 610

18.2 N
 eurochemical Basis of Affective Second-generation antidepressants have different
side effects 610
Disorders 597
Third-generation antidepressants have distinctive
Serotonin dysfunction contributes to mechanisms of action 612
mood disorders 598
Drugs for treating bipolar disorder stabilize the highs
Norepinephrine activity is altered by and the lows 615
antidepressants 601

19 Schizophrenia: Antipsychotic Drugs 619

19.1 Characteristics of Schizophrenia 620 The neurodevelopmental model integrates
anatomical and neurochemical evidence 636
Schizophrenia is a heterogeneous disorder 621
Glutamate and other neurotransmitters contribute
Diagnosing schizophrenia can be challenging 621 to symptoms 637
19.2 Etiology of Schizophrenia 622 19.4 C
 lassic Neuroleptics and Atypical
Abnormalities of brain structure and function occur Antipsychotics 639
in individuals with schizophrenia 622
Phenothiazines and butyrophenones are
Genetic, environmental, and developmental classic neuroleptics 639
factors interact 626
Dopamine receptor antagonism is responsible
BOX 19.1
■  THE CUTTING EDGE for antipsychotic action 641
Epigenetic Modifications and Risk Side effects are directly related to neurochemical
for Schizophrenia 629 action 642
Preclinical models of schizophrenia 631 Atypical antipsychotics are distinctive in
BOX 19.2
■  PHARMACOLOGY IN ACTION several ways 646
The Prenatal Inflammation Model of Practical clinical trials help clinicians make
Schizophrenia 633 decisions about drugs 648
19.3 N
 eurochemical Models of There are renewed efforts to treat the
Schizophrenia 635 cognitive symptoms 649

Abnormal DA function contributes

to schizophrenic symptoms 635

00_Meyer4e_FM.indd 15 12/15/21 12:49 PM

 xvi Contents

20 Neurodegenerative Diseases 654

20.1 Parkinson’s Disease 655
The clinical features of PD are primarily
motor related 655
Patients with Parkinson’s may also
develop dementia 656
The primary pathology of PD is a loss of
dopaminergic neurons in the substantia nigra 656
Animal models of PD have strengths and
limitations 659
Pharmacological treatments for PD are primarily
symptomatic, not disease altering 659
There are several unmet needs in PD diagnosis
and treatment 661
BOX 20.1
■  PHARMACOLOGY IN ACTION
Can We Smell Parkinson’s Disease? 661
20.2 Alzheimer’s Disease 662
AD is defined by several pathological cellular
disturbances 663
There are several behavioral, health, and genetic risk
factors for AD 664
AD cannot be definitively diagnosed until
post-mortem analysis 665
Several different animal models contribute
to our understanding of AD 666
Symptomatic treatments are available,
and several others are under study for
slowing disease progression 667
BOX 20.2
■  THE CUTTING EDGE
Can Focused Ultrasound Help Treat
Alzheimer’s Disease? 668
20.3 H
 untington’s Disease, Amyotrophic
Lateral Sclerosis, and Multiple
Sclerosis 670
Huntington’s disease 670
Amyotrophic lateral sclerosis 672
Multiple sclerosis 673

Glossary G-1
References R-1
Index I-1

00_Meyer4e_FM.indd 16 12/15/21 12:49 PM

 Preface
Jerrold Meyer and Linda Quenzer were approached
by Sinauer Associates about 20 years ago to develop a
new undergraduate textbook on psychopharmacology.
We were already co-authors with Robert Feldman on a
massive, 900-page-long graduate level textbook entitled
Principles of Neuropsychopharmacology, but our Sinauer
editor wanted something more than just a condensed
and simplified version of the “big book.” Our charge
was to engage the interest of undergraduate students
in learning about psychoactive drugs and their mecha-
nisms of action, while maintaining the more advanced
textbook’s high standard of comprehensive and up-to-
date coverage. The fact that Sinauer has now published
the Fourth Edition of Psychopharmacology: Drugs, the
Brain, and Behavior, indicates that we have had some
success in fulfilling that charge.
In the preface to the first edition of this work, the
authors commented on the long history of human use
of mind-altering substances that eventually led to the
need for a science of psychopharmacology. This field
of study was already exploding by the late 20th and
early 21st centuries, and nothing has happened since
then to slow down this remarkable growth. However,
new trends are always emerging in any vibrant area
of scholarship, and psychopharmacology is no excep-
tion in that regard. One such trend particularly worth
noting is the impact of changing attitudes toward for-
merly disparaged substances, at least within Western
societies. This impact can be seen in two significant
developments. First, many countries or smaller po-
litical districts (i.e., states, provinces, or cities), espe-
cially within North America and Western Europe,
are decriminalizing the personal use of various rec-
reational drugs. Some drugs, like cannabis, have
even been fully legalized for such use. Although the
politics of decriminalization and legalization remain
contentious, a clear trend is in place. Second, we are
seeing a remarkable development of therapeutic ap-
plications using mind-altering drugs like psilocybin,
LSD, MDMA (ecstasy), and ketamine, that until re-
cently were deemed highly addictive and (except for
ketamine) without legitimate medical use. Again, this
development is not without controversy; however, we
are convinced that the growing empirical evidence
for therapeutic benefits derived from careful use of
psychedelic medications will cement their place in the
therapeutic domain.
00_Meyer4e_FM.indd 17
In accordance with pharmacology being a medical
discipline, this new edition continues to emphasize the
known or potential therapeutic applications of every
compound mentioned in the textbook. However, it’s
important for readers to recognize not only the advanc-
es being made in medications development for some
CNS disorders, but also the areas where progress has
been frustratingly slow. For example, the introduction
of new and exciting psychedelic medications promises
to benefit mood-, anxiety-, and trauma-related disor-
ders, but these drugs are less likely to help patients re-
cover from neurodegenerative disorders like Alzheim-
er’s disease, multiple sclerosis, or amyotrophic lateral
sclerosis. Drug addiction and autism spectrum disor-
ders are two other important areas where advances in
pharmacotherapy have lagged. Therefore, throughout
the book we have tried to identify the specific thera-
peutic benefits and limitations (where appropriate) of
each successful medication, failures of medications that
seemed promising at one time, and gaps where new
medications are sorely needed.
Every chapter in this Fourth Edition is fully up-
dated, with many citations from 2020 and 2021. Special
attention is given to recent developments and emerg-
ing trends in psychopharmacology while retaining the
same organization as in previous editions. The first
four chapters provide extensive foundation materials,
including the basic principles of pharmacology, neu-
rophysiology and neuroanatomy, cell signaling in the
nervous and endocrine systems, and current methods
in behavioral assessment and neuropharmacology. The
new Case Studies box feature is used in Chapter 1 (Prin-
ciples of Pharmacology) and in Chapter 2 (Structure and
Function of the Nervous System) to demonstrate how
the basic concepts of pharmacology and neuroscience
are applied in clinical practice. Among the highlights
of Chapter 3 (Chemical Signaling by Neurotransmit-
ters and Hormones) are expanded coverage of oxy-
tocin and vasopressin regulation of social behaviors
and current evidence on the use of oxytocin to treat
the social communication deficits present in autism
spectrum disorder. Chapter 4 (Methods of Research
in Psychopharmacology) is updated with examples of
state-of-the-art techniques, including examples from
genetic engineering and artificial intelligence, to illus-
trate how these technologies are being used to better
understand drug effects on behavior and the complex
12/15/21 12:49 PM
 xviii Preface
genetic basis of drug-organism interactions. The next
four chapters, Chapter 5 (Catecholamines), Chapter 6
(Serotonin), Chapter 7 (Acetylcholine), and Chapter
8 (Glutamate and GABA), describe the key features
of neurotransmitter systems that are particularly im-
portant to psychopharmacologists. Information about
the neurochemistry, anatomy, and behavioral func-
tions of these transmitters not only lays the ground-
work for the chapters that follow, but this new edition
places increased emphasis on clinical applications of
neurotransmitter-targeted drugs. The next eight chap-
ters focus on recreational drugs and their potential for
misuse. Chapter 9 (Drug Misuse and Addiction) covers
the current theories and mechanisms of drug addiction,
which is followed by seven chapters devoted to specific
recreational drugs. Chapter 10 (Alcohol) discusses the
pharmacology of alcohol, the features of alcohol use dis-
order (previously called alcoholism), and both current
and emerging treatments for this disorder. Chapter 11
(The Opioids) describes the features of the endogenous
opioid system, opioid use disorder, and novel treat-
ments for that disorder. The chapter has been updated
to reflect the increasing severity of the opioid epidemic
and the array of harm-reduction strategies being em-
ployed to combat it. This section of the book continues
with Chapter 12 (Psychomotor Stimulants: Cocaine,
Amphetamine, and Related Drugs), Chapter 13 (Nico-
tine and Caffeine), Chapter 14 (Marijuana and the Can-
nabinoids), Chapter 15 (Psychedelic and Hallucinogenic
Drugs, PCP, and Ketamine), and Chapter 16 (Inhalants,
GHB, and Anabolic-Androgenic Steroids). Among the
highlights of these chapters are greatly expanded cover-
age of e-cigarettes and vaping (Chapter 13), new discus-
sions of cannabis legalization and emerging therapeutic
applications of cannabidiol (CBD) and other cannabi-
noids (Chapter 14), and the mechanisms by which entac-
togens and psychedelic drugs (MDMA, psilocybin, and
LSD) are thought to work when used in drug-assisted
psychotherapy for mood- and trauma-related disorders
(Chapter 15). The final four chapters consider the neu-
robiology of neuropsychiatric and neurodegenerative
disorders and the drugs used to treat these disorders.
Chapter 17 (Disorders of Anxiety and Impulsivity and
the Drugs Used to Treat Them) and Chapter 18 (Affec-
tive Disorders: Antidepressants and Mood Stabiliz-
ers) cover not only classical pharmacotherapies such
as benzodiazepines and selective serotonin reuptake
inhibitors (SSRIs) but also novel approaches using
more “non-traditional” substances such as ketamine
and psilocybin, that are discussed in prior chapters on
recreational drugs. We highlight ongoing studies on
these substances that seek to determine optimal dos-
ing regimens, tolerability, durability, and mechanisms
of action, the latter which may lead to the generation
of novel compounds with reduced side effects. Chapter
00_Meyer4e_FM.indd 18
19 (Schizophrenia: Antipsychotic Drugs) has been up-
dated with examples of recent studies demonstrating
the promise of pharmacogenetics in optimizing treat-
ment efficacy while reducing side effects, such as tar-
dive dyskinesia. Finally, Chapter 20 (Neurodegenera-
tive Diseases) updates our discussion of the symptoms,
clinical trials, FDA-approved therapies, and diagnostic
tools, including advances in neuroimaging, for all dis-
orders covered in the chapter. It additionally introduces
novel developments such as a new symptom (unusual
body odor) that helps diagnose Parkinson’s disease and
a recently developed technology (focused ultrasound)
for treating Alzheimer’s disease.
Several features of Psychopharmacology: Drugs, the
Brain, and Behavior distinguish it from its many com-
petitors. Full-color photos depict pharmacologically
relevant plant species, drugs in crystalline form, and
drug-related paraphernalia. Beautifully rendered
four-color illustrations present data from important
experiments and portray models of drug action, in-
cluding neural pathways thought to mediate the psy-
chological and behavioral effects of specific substances.
Bulleted interim summaries highlight the key points
made in each part of the chapter, and study questions
are provided at the end of each chapter to assist stu-
dents in reviewing the most important material. A new
feature for this edition is the inclusion of learning ob-
jectives at the beginning of each section to help direct
students and instructors towards the main content to
be covered. Breakout boxes (printed and on the web)
categorized by the themes of Pharmacology in Action,
The Cutting Edge, Of Special Interest, Clinical Applica-
tions, Case Studies, and History of Psychopharmacol-
ogy highlight topics of particular importance. Finally,
the new Enhanced e-book offers access to Web Boxes,
study resources such as self assessment at the end of
each section, flashcards, weblinks and animations that
visually illustrate key neurophysiological and neuro-
chemical processes important for Psychopharmacology.
Finally, the new Enhanced e-book offers access to
Web Boxes, study resources such as self assessment
at the end of each section, flashcards, weblinks and
animations that visually illustrate key neurophysio­
logical and neurochemical processes important for
psychopharmacology.
Readers familiar with previous editions of this text-
book may notice that the long-standing co-author Linda
Quenzer was not involved in preparing this new edi-
tion. Although Linda has retired from textbook writing,
she has been ably replaced by new co-authors Andrew
Farrar and Dominik Biezonski. We are confident that
this new team, which includes previous contributor
Jennifer Yates, has produced a worthy successor to pre-
vious editions of the textbook. We hope that you, the
reader, will ultimately agree with that assessment.
12/15/21 12:49 PM

Acknowledgments
This book is the culmination of the efforts of many
dedicated people who contributed their ideas and
hard work to the project. We’d like to thank and ac-
knowledge the outstanding editorial team at Sinauer
Associates/Oxford University Press: Jessica Fiorillo
(Executive Editor), Johannah Walkowicz (Production
Editor), and Malinda Labriola (Editorial Assistant).
Thank you all for your help in putting together the
Fourth Edition, your guidance in making the transi-
tion to Oxford University Press, and not least your pa-
tience throughout the process of writing, revising, and
revising again when necessary. You had a vision for
this project that kept us moving forward in our goal
of producing the best possible psychopharmacology
textbook. Mark Siddall continues to do a fantastic job
of seeking out just the right photographs for the book.
We are indebted to other key staff members of Oxford
University Press who worked on this project, includ-
ing Joan Gemme, Meg Britton Clark, Michele Beckta,
Suzanne Carter, and Sean Hynd. We also thank Wendy
Walker and Danna Lockwood for their help with edit-
ing, and Melissa Flamson for assisting with permissions.
And we must acknowledge Dragonfly Media Group for
the beautiful job rendering the illustrations.
The following reviewers contributed many excellent
suggestions for improving the book:
Joel Alexander, Western Oregon University
Sage Andrew, University of Missouri
Chiye Aoki, New York University
Susan Barron, University of Kentucky
Ethan Block, University of Pittsburgh
Evan Caldbick, Simon Fraser University
Leighann R. Chaffee, University of Washington, Tacoma
Kirstein Cheryl, University of South Florida
Matt Clasen, American University
Patricia DiCiano, The Centre for Addiction and
Mental Health and Seneca College
00_Meyer4e_FM.indd 19
Preface xix
Henry Gorman, Austin College
Bill Griesar, Portland State University
Joshua Gulley, University of Illinois at
Urbana-Champaign
Matt Holahan, Carleton University
Phillip Holmes, University of Georgia
Adam Howorko, PhD; Athabasca University,
Concordia University Edmonton
Michael Kane, University of Pennsylvania
Thomas Lanthorn, Sam Houston State University
Jeffrey Lamoureux, Boston College
Lauren Liets, University of California, Davis
Ilyssa Loiacono, Queens College
Margaret Martinetti, The College of New Jersey
Janice McMurray, University of Nevada, Las Vegas
M. Foster, Olive Arizona State University
Robert Patrick, Brown University
Anna Rissanen, Memorial University, Newfoundland
Margaret Ruddy, The College of New Jersey
Jeffrey Rudski, Muhlenberg College
Lawrence Ryan, Oregon State University
Fred Shaffer, Truman State University
Marek Schwendt, University of Florida
Bob Stewart, Washington and Lee University
Evan Zucker, Loyola University
Lastly, we would like to acknowledge and thank the
many adopters of this textbook and their students.
To new adopters, we appreciate your selection and
trust that you will still be happy with that selection
after having used the book in your classroom. If you
are a previous adopter, we thank you for your con-
tinued loyalty that has made it possible to reach this
Fourth Edition of the book. Finally, if you are a stu-
dent, we hope that reading our book and studying
the field of psychopharma­cology might inspire you to
choose this exciting and dynamic field for your own
career so that in the years to come, your name might
be among the researchers cited in a future edition of
Psychopharmacology: Drugs, the Brain, and Behavior.
12/15/21 12:49 PM
 Digital Resources
for Psychopharmacology, Fourth Edition
For the Instructor
(Available at oup.com/he/meyer4e)
Instructors using Psychopharmacology, Fourth Edition,
have access to a wide variety of resources to aid in
course planning, lecture development, and student
assessment.
Content includes:
■ PowerPoint Presentations Two different
PowerPoint presentations are provided for each
chapter of the textbook:
■ Figures & Tables: All of the figures and tables
from the chapter, with figure numbers
and titles on each slide, complete captions
in the Notes field, and alt text embedded
for accessibility. All the artwork has been
reformatted and optimized for exceptional
image quality when projected in class.
■ Lecture: A complete lecture outline with
selected figures and tables.
■ Test Bank Revised and updated for the Fourth
Edition, the Test Bank consists of a broad range of
questions covering key facts and concepts in each
chapter. Both multiple-choice and short-answer
questions are provided. All questions are ranked
according to Bloom’s Taxonomy, aligned to new
Learning Objectives, and referenced to specific
textbook sections. Available in multiple formats,
including MS Word and Common Cartridge (for
import into learning management systems).
00_Meyer4e_FM.indd 20
Enhanced E-Book for the Student
(ISBN 9781605359892)
Ideal for self-study, the Psychopharmacology, Fourth
Edition, enhanced e-book delivers the full suite of
digital resources in a format independent from any
courseware or learning management system platform,
making Psychopharmacology’s online resources more
accessible for students.
The enhanced e-book is available via RedShelf,
VitalSource, and other leading higher education e-book
vendors and includes the following student resources:
■ Learning Objectives outline the important
takeaways of every major section.
■ Animations give students detailed, narrated
depictions of some of the complex processes
described in the textbook.
■ Self-Assessment Quizzes following each
major section allow students to gauge their
understanding of key concepts before proceeding.
NEW for this edition.
■ Web Boxes include coverage of novel and cutting-­
edge topics useful for special discussion.
■ Web Links list suggested websites and other online
resources related to each chapter.
■ Recommended Readings provide additional
references and readings for each chapter.
■ Flashcards help students master the hundreds of
new terms introduced in the textbook.
The Web Boxes are also available to students using
the print book. Go to oup.com/he/meyer4e.
12/15/21 12:49 PM
 Principles of Pharmacology 1
WILLIAM S. BAER (1872–1931) WAS AN ORTHOPEDIC SURGEON at Johns
Hopkins University, where he established the orthopedic department and led it for
most of his life, training many of the outstanding orthopedists of the day. During
World War I Baer observed that soldiers who had severe and deep flesh wounds
did not have the fever associated with infection and showed little of the expected
necrotic (dead) tissue damage if there was a significant presence of maggots (fly
larvae) in the wounds. Although it had been believed that early peoples (Australian
aborigines and Mayan Indian tribes) and others throughout history had used mag-
gots to clean wounds, it was Baer who once again recognized their importance,
especially in tense battlefield conditions where infection was especially hard to treat.
Apparently the maggots ingested the dying tissue but left healthy tissue intact. Baer,
upon doing further “pharmacological” experiments, showed that his hospitalized
patients with severe and chronic bone infections showed remarkable recovery after
being treated with maggots—the inflamed and dying tissue was ingested, leaving
wounds clean and healthy, and new tissue formed. As long as the maggots were
sterilized, secondary infections were avoided. After his research, “maggot therapy”
became popular and was used throughout the 1930s and 1940s until penicillin was
established as an easier treatment for infection. However, it has been suggested
that in modern times, maggot therapy will be reintroduced to treat those wounds
infected with antibiotic-resistant bacteria. At present in the European Union, Japan,
and Canada, maggots are considered “medicinal drugs,” and in 2005 the U.S. Food
and Drug Administration approved the use of maggots as a medical “device.”
What actually causes the amazing healing process is not entirely clear, but
pharmacologists are beginning to understand that maggot secretions suppress the
immune system and reduce inflammation, and they may also enhance cell growth
and increase oxygen concentration in the wound. This is certainly not the first time
pharmacology has returned to earlier forms of therapeutics, but the science now
can isolate and identify those components that lead to healing. ■
© PA Images/Alamy Stock Photo

Mutant mice produced by genetic engineering

(e.g., gene "knockout mice") may show pheno-
typic changes that emerge during development of
Maggot therapy
the pups. can Cavignaux/Photononstop/Alamy
(Bruno be used to clean wounds
andStock
prevent infection.
Photo.)

01_Meyer4e_CH01.indd 1 12/9/21 2:29 PM

 2 Chapter 1
1.1 P
 harmacology: The Science of
Drug Action
Pharmacology is the scientific study of the actions of
drugs and their effects on a living organism. Until the
beginning of the last century, pharmacologists studied
drugs that were almost all naturally occurring sub-
stances. The importance of plants in the lives of ancient
humans is well documented. Writings from as early
as 1500 BCE describe plant-based medicines used in
Egypt and in India. The Ebers Papyrus describes the
preparation and use of more than 700 remedies for ail-
ments as varied as crocodile bites, baldness, constipa-
tion, headache, and heart disease. Of course, many of
these treatments included elements of magic and in-
cantation, but there are also references to some modern
drugs such as castor oil and opium. The Chinese also
have a very long and extensive tradition in the use of
herbal remedies that continues today. World Health Or-
ganization estimates suggest that in modern times, as
many as 80% of the people in developing countries are
totally dependent on herbs or plant-derived medicinals.
And in 1999, in the United States, modern herbal medi-
cines and drugs based on natural products represented
half of the top 20 drugs on the market (Hollinger, 2008).
Many Americans are enamored with herbal medica-
tions despite limited clinical support for their effective-
ness, because they believe these treatments are more
“natural.” Nevertheless, serious dangers have been as-
sociated with some of them. WEB BOX 1.1 discusses the
benefits and dangers of herbal remedies.
When placed in historical context, it can be seen
that drug development in the United States is in its in-
fancy. The rapid introduction of many new drugs by
the pharmaceutical industry has forced the develop-
ment of several specialized areas of pharmacology. Two
of these areas are of particular interest to us. Neuro­
pharmacology is concerned with drug-induced changes
in the functioning of cells in the nervous system, and
psychopharmacology emphasizes drug-induced chang-
es in mood, thinking, and behavior. In combination, the
goal of neuropsychopharmacology is to identify chemi-
cal substances that act on the nervous system to alter
behavior that is disturbed because of injury, disease, or
environmental factors. Additionally, neuropsychophar-
macologists are interested in using chemical agents as
probes to gain an understanding of the neurobiology
of behavior.
When we speak of drug action, we are referring to the
specific molecular changes produced by a drug when it
binds to a particular target site or receptor. These mo-
lecular changes lead to more widespread alterations
in physiological or psychological functions, which we
consider drug effects. The site of drug action may be
very different from the site of drug effect. For example,
atropine is a drug used in ophthalmology to dilate the
01_Meyer4e_CH01.indd 2
pupil of the eye before eye examinations. Atropine has
a site of action (the eye muscles of the iris) that is close
to the site of its ultimate effect (widening the pupil), so it
is administered directly to the eye. In comparison, mor-
phine applied to the eye itself has no effect. Yet when it
is taken internally, the drug’s action on the brain leads to
“pinpoint” pupils. Clearly, for morphine, the site of effect
is far distant from the site of its initial action.
Keep in mind that because drugs act at a variety of
target sites, they always have multiple effects. Some
may be therapeutic effects, meaning that the drug–re-
ceptor interaction produces desired physical or behav-
ioral changes. All other effects produced are referred to
as side effects, and they vary in severity from mildly
annoying to distressing and dangerous. For example,
amphetamine-like drugs produce alertness and insom-
nia, increased heart rate, and decreased appetite. Drugs
in this class reduce the occurrence of spontaneous sleep
episodes characteristic of the disorder called narcolepsy,
but they produce anorexia (loss of appetite) as the prima-
ry side effect. In contrast, the same drug may be used as
a prescription diet control in weight-reduction programs.
In such cases, insomnia and hyperactivity are frequently
disturbing side effects. Thus therapeutic and side effects
can change, depending on the desired outcome.
It is important to keep in mind that there are no
“good” or “bad” drugs, because all drugs are just chem-
icals. It is the way a drug is procured and used that de-
termines its character. Society tends to think of “good”
drugs as those purchased at a pharmacy and taken at
the appropriate dosage for a particular medicinal pur-
pose, and “bad” drugs as those acquired in an illicit
fashion and taken recreationally to achieve a desired
psychological state. Even with this categorization, the
differences are blurred because many people consider
alcohol to be “bad” even though it is purchased legally.
Morphine and cocaine have legitimate medicinal uses,
making them “good” drugs under some conditions,
although they can, when misused, lead to dangerous
consequences and addiction, making the same drugs
“bad.” Finally, many “good” prescription drugs are ac-
quired illicitly or are misused by increasing the dose,
prolonging use, or sharing the drug with other indi-
viduals, leading to “bad” outcomes. As you will read
in later chapters, the ideas of Americans about appro-
priate drug use have changed dramatically over time
(see the sections on the history of the use of narcotics
in Chapter 11 and cocaine in Chapter 12).
Many of the drug effects we have described so far
have been specific drug effects, defined as those based
on the physical and biochemical interactions of a drug
with a target site in living tissue. In contrast, non­
specific drug effects are those that are based not on
the chemical activity of a drug–receptor interaction, but
on certain unique characteristics of the individual. It is
clear that an individual’s background (e.g., drug-taking
12/9/21 2:29 PM

experience), present mood, expectations of drug effect,
perceptions of the drug-taking situation, attitude to-
ward the person administering the drug, and other
factors influence the outcome of drug use. Nonspecific
drug effects help to explain why the same individual
self-administering the same amount of ethyl alcohol
may experience a sense of being lighthearted and
gregarious on one occasion, and depressed and mel-
ancholy on another. The basis for such a phenomenon
may well be the varied neurochemical states existing
within the individual at different times, with which
specific drug effects interact.
Placebo effect
Common examples of nonspecific effects are the multi-
ple outcomes that result from taking a placebo. Many of
you automatically think of a placebo as a “fake” pill. A
placebo is in fact a pharmacologically inert compound
administered to an individual; however, in many in-
stances it has not only therapeutic effects, but side ef-
fects as well. Just as many of the symptoms of illness
may have psychogenic or emotional origins, belief in a
drug may produce real physiological effects despite the
lack of chemical activity. These effects are not limited
to the individual’s subjective evaluation of relief but in-
clude measurable physiological changes such as altered
gastric acid secretion, blood vessel dilation, hormonal
changes, and so forth.
In a classic study, two groups of patients with ulcers
were given a placebo. In the first group, the medication
was provided by a physician, who assured the patients
that the drug would provide relief. The second group
also received the placebo, but it was administered by
a nurse, who described it as experimental in nature. In
group 1, 70% of the patients found significant relief, but
in group 2, only 25% were helped by the “drug” (Levine,
1973). Based on these results, it is clear that a sugar pill
is not a drug that can heal ulcers, but rather its effective-
ness depends on the ritual of the therapeutic treatment
that can have both neurobiological and behavioral ef-
fects that influence the outcome. It is a perfect example
of mind–body interaction, and there has been increasing
interest in understanding the mechanism responsible
for the placebo effect as a means to enhance the thera-
peutic effectiveness of drug treatments. Although some
consider deliberate prescription of placebos to patients
unethical because of the deception involved, other physi-
cians and ethicists have identified appropriate uses for
placebos that represent an inexpensive treatment that
avoids unnecessary medications.
Placebo effects may in part be explained by Pavlov-
ian conditioning in which symptom improvement in
the past has been associated with particular character-
istics of a medication, for example its taste, color, shape,
and size; a particular recommending clinician, with
her white coat, reassuring tone of voice, or attitude; or
01_Meyer4e_CH01.indd 3
Principles of Pharmacology 3
aspects of the medical facility. Since a placebo effect
has been demonstrated many times in animal models,
cues in the environment are apparently sufficient, and
verbal reassurances are not necessary. In fact, patients
have been shown to benefit even if they are told that the
medication is a placebo, so deception is apparently not
a necessity; however, verbal suggestion interacts with
conditioning (see Colagiuri et al., 2015).
A second possible explanation for the placebo effect
is that of conscious, explicit expectation of outcomes.
For example, those individuals who anticipate relief
may show an enhanced placebo response. Of great in-
terest are the placebo-induced neurobiological effects
within the brain. Research has shown that when place-
bos effectively reduce pain, those individuals who are
responders have significantly higher levels of natural
pain-relieving opioid neuropeptides in their cerebro-
spinal fluid than those individuals who do not show
a response to the placebo. Further, the subjects who
anticipate pain relief show reduced neural activity in
pain-related brain regions (see Benedetti et al., 2011).
While Pavlovian conditioning and conscious ex-
pectation both contribute to the placebo effect, other
factors may also have a part (see Murray and Stoessl,
2013; Carlino et al., 2016). Placebo effects may involve
social learning. That is, observing another individual
anticipating a positive outcome can be a more powerful
inducer of the placebo effect than direct conditioning or
verbal suggestions. Others have found that anticipating
a successful outcome reduces anxiety and activates re-
ward networks in the brain. Finally, a number of genet-
ic variants have been found that influence the placebo
effect. Understanding more about which genes identify
patients who will respond to placebo could allow treat-
ment to be adjusted to maximize outcome (Colagiuri et
al., 2015). This is one step toward personalized medi-
cine (see the last section of this chapter).
In contrast to placebos, negative expectations may in-
crease the level of anxiety experienced, which may also
influence the outcome of treatment. Expecting treatment
failure when an inert substance is given along with ver-
bal suggestions of negative outcome, such as increased
pain or another aversive event, would increase anxiety
as well as cause an accompanying change in neural
mechanisms, including increases in stress hormones.
This is the nocebo effect, and both the nocebo-induced
increase in pain reported and the hormonal stress re-
sponse can be reduced by treatment with an antianxiety
drug, demonstrating that expectation-induced anxiety
plays a part in the nocebo effect. Nocebos are important
to study because warnings about potential side effects
can lead to greater side-effect occurrence. Unfortunately,
because drug companies are required by law to provide
a comprehensive listing of all possible side effects, many
individuals have negative expectations, leading to in-
creased side effects.
12/9/21 2:29 PM
 4 Chapter 1
BOX 1.1 ■ PHARMACOLOGY IN ACTION
Naming Drugs
Drug names can be a confusing issue for many people
because drugs that are sold commercially, by pre-
scription or over the counter, usually have four or
more different kinds of names.
All drugs have a chemical name that is a complete
chemical description suitable for synthesizing by an
organic chemist. Chemical names are rather clumsy
and are rarely used except in a laboratory setting. In
contrast, generic or nonproprietary names are official
names of drugs that are listed in the United States
Pharmacopeia. The generic name is a much shorter
form of the chemical name but is still unique to that
drug. For example, one popular antianxiety drug has
the chemical name 7-chloro-1,3-dihydro-1-methyl-
5-phenyl-2H-1,4-benzodiazepin-2-one and the generic
In pharmacology, the placebo is essential in the de-
sign of experiments conducted to evaluate the effec-
tiveness of new medications, because it eliminates the
influence of expectation on the part of the experiment’s
participants. The control group is identical to the ex-
perimental group in all ways and is unaware of the
substitution of an inactive substance (e.g., sugar pill,
saline injection) for the test medication. Comparison
of the two groups provides information on the effec-
tiveness of the drug beyond the expectations of the
participants. Of course, drugs with strong subjective
effects or prominent side effects make placebo testing
more challenging because the experimental group will
be aware of the effects while those experiencing no ef-
fects will conclude they are the control group. To avoid
that problem, some researchers may use an “active”
placebo, which is a drug (unrelated to the drug being
tested) that produces some side effects that suggest to
the control participants that they are getting the active
agent. In other cases clinical researchers may feel that
it is unethical to leave the placebo group untreated if
there is an effective agent available. In that case the con-
trol group will be given the older drug, and effective-
ness of the new drug will be compared with it rather
than with a placebo.
The large contribution of nonspecific factors and
the high and variable incidence of placebo responders
make the double-blind experiment highly desirable. In
these experiments, neither the patient nor the observer
knows what treatment the participant has received.
Such precautions ensure that the results of any given
treatment will not be biased on the part of the partici-
pant or the observer. If you would like to read more
about the use of placebos in both clinical research and
01_Meyer4e_CH01.indd 4
name diazepam. The brand name, or trade name, of
that drug (Valium) specifies a particular manufacturer
and a formulation. A brand name is trademarked and
copyrighted by an individual company, which means
that the company has an exclusive right to advertise
and sell that drug.
Slang or street names of commonly abused drugs
are another way to identify a particular chemical.
Unfortunately, these names change over time and vary
with geographical location and particular groups of
people. In addition, there is no way to know the chemi-
cal characteristics of the substance in question. Some
terms are used in popular films or television and
become more generally familiar, such as “crack” or
“ice,” but most disappear as quickly as they appear.
therapeutics and the associated ethical dilemmas, refer
to the articles by Brown (1998) and Louhiala (2009).
Throughout this chapter, we present examples that
include both therapeutic and recreational drugs that af-
fect mood and behavior. Since there are usually several
names for the same substance, it may be helpful for you
to understand how drugs are named (BOX 1.1).
Pharmacokinetic factors determining
drug action
Although it is safe to assume that the chemical struc-
ture of a drug determines its action, it quickly becomes
clear that additional factors are also powerful con-
tributors. The dose of the drug administered is clearly
important, but more important is the amount of drug
in the blood that is free to bind at specific target sites
(bioavailability) to elicit drug action. The following sec-
tions of this chapter describe in detail the dynamic
factors that contribute to bioavailability. Collectively,
these factors constitute the pharmacokinetic compo-
nent of drug action; they are listed below and illus-
trated in FIGURE 1.1.
1. Routes of administration. How and where a drug is
administered determines how quickly and how
completely the drug is absorbed into the blood.
2. Absorption and distribution. Because a drug rarely
acts where it initially contacts the body, it must
pass through a variety of cell membranes and
enter the blood plasma, which transports the
drug to virtually all of the cells in the body.
3. Binding. Once in the blood plasma, some drug
molecules move to tissues to bind to active target
sites (receptors). While in the blood, a drug may
12/9/21 2:29 PM
 Principles of Pharmacology 5

(3) Binding Inactive storage FIGURE 1.1 Pharmacokinetic

Target site
Neuron receptor
(2) Absorption and
distribution
Membranes of oral
cavity, gastrointestinal
tract, peritoneum,
skin, muscles, lungs
depots factors that determine bioavailability
of drugs From the site of administra-
Bone and fat tion (1), the drug moves through cell
membranes to be absorbed into the
blood (2), where it circulates to all
cells in the body. Some of the drug
molecules may bind to inactive sites
Blood
plasma such as plasma proteins or storage
depots (3), and others may bind to
(5) Excretion receptors in target tissue. Bloodborne
Plasma drug molecules also enter the liver
protein Intestines, kidneys, (4), where they may be transformed
binding Metabolites lungs, sweat glands,
etc.
into metabolites and travel to the
kidneys and other discharge sites for
ultimate excretion (5) from the body.

(1) Drug administration

Oral, intravenous,
intraperitoneal,
subcutaneous,
intramuscular,
inhalation Liver, stomach, intestine,
kidney, blood plasma, brain
(4) Inactivation
also bind (depot binding) to plasma proteins or
may be stored temporarily in bone or fat, where
it is inactive.
4. Inactivation. Drug inactivation, or biotransforma­
tion, occurs primarily as a result of metabolic
processes in the liver as well as other organs and
tissues. The amount of drug in the body at any
one time is dependent on the dynamic balance
between absorption and inactivation. Therefore,
inactivation influences both the intensity and the
duration of drug effects.
5. Excretion. The drug metabolites are eliminated
from the body with the urine or feces. Some drugs
are excreted in an unaltered form by the kidneys.
Meyer 4e
Although these topics are discussed sequentially in
Psychopharmacology
the following pages, keep in mind that in the living
Dragonfly Media
organism, theseGroup
factors are at work simultaneously. In
Sinauer Associates
addition to bioavailability, the drug effect experienced
Meyer4e_1.01 7-21-21
will also depend on how rapidly the drug reaches its
target, the frequency and history of prior drug use (see
the discussion on tolerance later in the chapter), and
nonspecific factors that are characteristics of individu-
als and their environments.
Methods of drug administration influence
the onset of drug action
The route of administration of a drug determines how
much drug reaches its site of action and how quickly the
drug effect occurs. There are two major categories of ad-
ministration methods. Systemic routes of administration
Excretion refer to methods in which drugs
products
distribute throughout the entire
Feces, urine, body, thus reaching the target
water vapor, tissue through general circula-
sweat, saliva
tion. Within the broad category of
systemic administration, enteral
methods of administration use the
gastrointestinal (GI) tract (enteron
is the Greek word for “gut”); agents administered by these
methods are generally slow in onset and produce highly
variable blood levels of drug. The most common enteral
method of administration is oral, but rectal administra-
tion with the use of suppositories is another enteral route.
Other systemic routes of administration are parenteral
and include those that do not use the alimentary canal,
such as injection or pulmonary administration.
Oral administration (PO) is the most common-
ly used route for taking drugs, because it is safe,
self-administered, and economical, and it avoids the
complications and discomfort of injection methods.
Drugs that are taken orally come in the form of cap-
sules, pills, tablets, or liquid, but to be effective, the
drug must dissolve in stomach fluids and pass through
the stomach or intestine wall to reach blood capillaries.
In addition, the drug must be resistant to destruction
by stomach acid and stomach enzymes that are impor-
tant for normal digestion.
Movement of the drug from the site of adminis-
tration to the blood circulation is called absorption.
Although some drugs are absorbed from the stomach,
most drugs are not fully absorbed until they reach the
small intestine. Many factors influence how quickly
the stomach empties its contents into the small intes-
tine and hence determine the ultimate rate of absorp-
tion. For example, food in the stomach, particularly
if it is fatty, slows the movement of the drug into the
intestine, thereby delaying absorption into the blood.
The amount of food consumed, the level of physical
activity of the individual, and many other factors

01_Meyer4e_CH01.indd 5 12/9/21 2:29 PM

 6 Chapter 1
make it difficult to predict how quickly the drug will
reach the intestine. In addition, many drugs undergo
extensive first-pass metabolism. First-pass metabo­
lism is an evolutionarily beneficial function because
potentially harmful chemicals and toxins that are in-
gested pass via the portal vein to the liver, where they
are chemically altered by a variety of enzymes before
passing to the heart for circulation throughout the
body (FIGURE 1.2). Unfortunately, some therapeutic
drugs taken orally may undergo extensive metabo-
lism (more than 90%), reducing their bioavailability.
Drugs that show extensive first-pass effects must be
administered at higher doses or in an alternative man-
ner, such as by injection. Because of these many fac-
tors, oral administration produces drug plasma levels
that are more irregular and unpredictable and rise
Brain
Intravenous
injection (IV)
Inhalation
Lungs
Right side
of the heart
Liver
Intestine
Rest of the body
Intramuscular
Subcutaneous
injection (IM)
injection (SC)
FIGURE 1.2 Routes of drug administration First-pass
effect. Drugs administered orally are absorbed into the blood
and must pass through the liver before reaching the general
circulation. Some drug molecules may be destroyed in the
liver before they can reach target tissues. The arrows indicate
the direction of blood flow in the arteries (red) and veins (blue).
(Top inset) Pulmonary absorption through capillaries in the
Meyer 4e
01_Meyer4e_CH01.indd 6
Psychopharmacology
more slowly than those produced by other methods
of administration.
Rectal administration requires the placement of a
drug-filled suppository in the rectum, where the sup-
pository coating gradually melts or dissolves, releasing
the drug, which will be absorbed into the blood. De-
pending on the placement of the suppository, the drug
may avoid some first-pass metabolism. Drug absorbed
from the lower rectum into the hemorrhoidal vein by-
passes the liver. However, deeper placement means
that the drug is absorbed by veins that drain into the
portal vein, going to the liver before the general circula-
tion. Bioavailability of drugs administered in this way
is difficult to predict, because absorption is irregular
(BOX 1.2). Although rectal administration is not used
as commonly as oral administration, it is an effective
Bronchiole
Left side
of the heart
Alveoli Capillaries
Oral (PO) Subcutaneous
Intramuscular
Intravenous
Epithelium Muscle Blood
vessel
alveoli. Rapid absorption occurs after inhalation because
the large surface area of the lungs and the rich capillary
networks provide efficient exchange of gases to and from
the blood. (Bottom inset) Methods of administration by injec-
tion. The speed of absorption of drug molecules from admin-
istration sites depends on the amount of blood circulating to
that area.
12/9/21 2:29 PM

route in infants and in individuals who are vomiting,
unconscious, or unable to take medication orally.
Intravenous (IV) injection is the most rapid and ac-
curate method of drug administration in that a precise
quantity of the agent is placed directly into the blood
and passage through barriers such as the stomach wall
is eliminated (see Figure 1.2). However, the quick onset
of drug effect with IV injection is also a potential haz-
ard. An overdose or a dangerous allergic reaction to
the drug leaves little time for corrective measures, and
the drug cannot be removed from the body as it can be
removed from the stomach by stomach pumping.
For drug abusers, IV administration provides
a more dramatic subjective drug experience than
self-administration in other ways, because the drug
BOX 1.2 ■ CASE STUDIES
The Perils of Alcohol Taken by an Unconventional Route of Administration
As described in this chapter, pharmacokinetic factors
play a significant role in drug bioavailability and hence
drug effects. With respect to drugs of abuse, many
drug users experiment with alternative routes of ad-
ministration in order to avoid unpleasant side effects
or enhance the desired effects of a given drug. Ethyl
alcohol, or ethanol, is consumed almost exclusively
orally, in the form of a fermented drink, like beer or
wine, or as a distilled spirit, like vodka or whiskey.
When consumed by the oral route of administration,
ethanol has relatively high bioavailability. However,
because most ethanol is absorbed in the intestines,
the stomach contents, and thus the rate of gastric
emptying, can powerfully influence ethanol absorption
and bioavailability.
Even though nearly all ethanol is consumed orally,
even in cases of excessive consumption and abuse,
some individuals have engaged in the dangerous
practice of administering ethanol-containing drinks
rectally, as an alcohol enema. The practice of rec-
tally administering alcohol is highly risky for a couple
of notable reasons. Alcohol, particularly at higher
concentrations, is highly irritating to the sensi-
tive mucosa of the colon, and as such, exposure to
alcohol-containing drinks has resulted in numerous
cases of severe colitis, requiring hospitalization. More
seriously, the colon absorbs alcohol very rapidly,
and unlike the stomach, the colon does not contain
alcohol dehydrogenase (ADH), which normally begins
the biotransformation of ethanol in the stomach
before it is absorbed into the bloodstream. Moreover,
ethanol absorbed through the colon does not undergo
first-pass metabolism, further contributing to its el-
evated bioavailability. The more rapid absorption and
hence higher bioavailability of ethanol through rectal
administration can result in a blood-alcohol concen-
tration that is significantly higher than if the same
01_Meyer4e_CH01.indd 7
Principles of Pharmacology 7
reaches the brain almost instantly. Drug users report
that intravenous injection of a cocaine solution usually
produces an intense “rush” or “flash” of pure pleasure
that lasts for approximately 10 minutes. This experience
rarely occurs when cocaine is taken orally or is taken
into the nostrils (snorting; see the discussion on topical
administration). However, IV use of street drugs poses
several special hazards. First, drugs that are impure or
of unknown quality provide uncertain doses, and toxic
reactions are common. Second, lack of sterile injection
equipment and aseptic technique can lead to infec-
tions such as hepatitis, human immunodeficiency virus
(HIV), and endocarditis (inflammation of the lining of
the heart). Fortunately, many cities have implemented
free needle programs, which significantly reduce the
amount of ethanol were consumed orally. The higher
bioavailability and thus more pronounced intoxicating
effect of alcohol is likely chief among the reasons that
some individuals choose to administer alcohol rectal-
ly. Other reasons may include avoidance of vomiting
as well as the false belief that rectally administered
alcohol would be undetectable on the breath.
Peterson and colleagues (2014) present the case
of a 52-year-old man who was found deceased in his
home following rectal administration of wine. At the
time of autopsy, the decedent’s blood-alcohol con-
centration was 350 mg/dL, while the vitreous ethanol
concentration was 410 mg/dL. Determining post-
mortem alcohol content from the vitreous fluid of the
eye is thought to reflect alcohol concentration more
accurately at the time of death, since blood levels of
alcohol tend to vary quite widely and decrease in the
postmortem period. In any event, it is likely that the
blood-alcohol concentration in the decedent was at
least in the range of 350 to 410 mg/dL at the time of
death, which is well within the range at which most
people would suffer the fatal effects of ethanol.
While accidental ethanol overdoses resulting in
death are relatively common, it is unusual that these
fatal overdoses are the result of rectal administra-
tion. Given the high bioavailability of ethanol from
this route of administration and hence the elevated
potential for unintentional overdose, the small number
of fatal overdoses likely reflects the fact that while
dangerous, alcohol enema is a far less commonly
used method of administration than oral consumption.
As discussed in Chapter 10, alcohol overdose by any
route of administration represents a fraction of the
total number of alcohol-related fatalities, which can
include fatalities caused by other dangerous behav-
iors, including motor vehicle accidents.
12/9/21 2:29 PM
 8 Chapter 1
probability of cross-infection. Third, many drug abus-
ers attempt to dissolve drugs that have insoluble filler
materials, which, when injected, may become trapped
in the small blood vessels in the lungs, leading to re-
duced respiratory capacity or death.
An alternative to the IV procedure is intramuscular
(IM) injection, which provides the advantage of slower,
more even absorption over a period of time. Drugs ad-
ministered by this method are usually absorbed within
10 to 30 minutes. Absorption can be slowed down by
combining the drug with a second drug that constricts
blood vessels, because the rate of drug absorption is
dependent on the rate of blood flow to the muscle (see
Figure 1.2). To provide slower, sustained action, the drug
may be injected as a suspension in vegetable oil. For
example, IM injection of medroxyprogesterone acetate
(Depo-Provera) provides effective contraception for 3 to
6 months without the need to take daily pills. One dis-
advantage of IM administration is that in some cases,
the injection solution can be highly irritating, causing
significant muscle discomfort.
Intraperitoneal (IP) injection is rarely used with hu-
mans, but it is the most common route of administra-
tion for small laboratory animals. The drug is injected
through the abdominal wall into the peritoneal cav-
ity—the space that surrounds the abdominal organs.
IP injection produces rapid effects, but not as rapid as
those produced by IV injection. Variability in absorp-
tion occurs, depending on where (within the perito-
neum) the drug is placed.
In subcutaneous (SC) administration, the drug
is injected just below the skin (see Figure 1.2) and is
absorbed at a rate that is dependent on blood flow to
the site. Absorption is usually fairly slow and steady,
but there can be considerable variability. Rubbing the
skin to dilate blood vessels in the immediate area in-
creases the rate of absorption. Injection of a drug in a
nonaqueous solution (such as peanut oil) or implanta-
tion of a drug pellet or delivery device further slows
the rate of absorption. Subcutaneous implantation of
drug-containing pellets is most often used to adminis-
ter hormones. Implanon and Nexplanon are two con-
traceptive implants now available in the United States.
The hormones are contained in a single small rod about
40 mm (1.5 inches) long that is implanted through a
small incision just under the skin of the upper arm. A
woman is protected from pregnancy for a 3-year period
unless the device is removed. Recent technological ad-
vances allow drug solutions to be injected in a liquid
form, which, upon contact with subcutaneous tissue
fluid, forms a biodegradable solid or gel that slowly
releases active drug over a period of up to 1 month.
This technology has been used to administer buprenor-
phine, which acts as a partial agonist or antagonist at
opioid receptors. This mechanism of action is thought
to help individuals overcome opioid use disorder by
01_Meyer4e_CH01.indd 8
reducing drug withdrawal and promoting treatment
compliance due to the long duration of effect (see Ling
et al., 2019; Rosenthal, 2019, for detailed reviews of the
effectiveness of these novel formulations). Also, refer
to Chapter 11 for information about the endogenous
opioid system and drugs that act upon it.
Inhalation of drugs, such as those used to treat asth-
ma attacks, allows drugs to be absorbed into the blood
by passing through the lungs. Absorption is very rapid
because the area of the pulmonary absorbing surfaces is
large and rich with capillaries (see Figure 1.2). The effect
on the brain is very rapid because blood from the capil-
laries of the lungs travels only a short distance back to
the heart before it is pumped quickly to the brain via
the carotid artery, which carries oxygenated blood to the
head and neck. The psychoactive effects of inhaled sub-
stances can occur within a matter of seconds.
Inhalation is the method preferred for self-­
administration in cases when oral absorption is too
slow and much of the active drug would be destroyed
in the GI tract before it reached the brain. Nicotine re-
leased from the tobacco of a cigarette by heat into the
smoke produces a very rapid rise in blood level and
rapid central nervous system (CNS) effects, which peak
in a matter of minutes. Tetrahydrocannabinol (THC),
an active ingredient of marijuana, and crack cocaine are
also rapidly absorbed after smoking. In addition to the
inherent dangers of the drugs themselves, disadvantag-
es of inhalation include irritation of the nasal passages
and damage to the lungs caused by small particles that
may be included in the inhaled material.
Topical application of drugs to mucous membranes,
such as the conjunctiva of the eye, the oral cavity, na-
sopharynx, vagina, colon, and urethra, generally pro-
vides local drug effects. Because topically applied
drugs are typically intended to act locally, this method
of drug administration is generally not considered a
systemic route of administration. However, some topi-
cally administered drugs can nevertheless be readily
absorbed into the general circulation, leading to wide-
spread effects. A related delivery method is sublingual
administration, which involves placing the drug under
the tongue, where it contacts the mucous membrane
and is absorbed rapidly into a rich capillary network.
Sublingual administration has several advantages over
oral administration, because the drug is not broken
down by gastric acid or gastric enzymes. Further, its
absorption is faster because it is absorbed directly
into the blood and is not dependent on those factors
that determine how quickly the stomach empties its
contents into the small intestine. Additionally, since
the drug is not absorbed from the GI tract, it avoids
first-pass metabolism. Intranasal administration is of
special interest because it causes local effects such as
relieving nasal congestion and treating allergies, but it
can also have systemic effects, in which case the drug
12/9/21 2:29 PM

moves very rapidly across a single epithelial cell layer
into the bloodstream, avoiding first-pass liver metabo-
lism and producing higher bioavailability than if given
orally. The approach is noninvasive, painless, and easy
to use, and hence it enhances compliance. Even more
important is the fact that intranasal administration al-
lows the blood–brain barrier to be bypassed, perhaps
by achieving direct access to the fluid that surrounds
the brain (cerebrospinal fluid [CSF]) and moving from
there to extracellular fluid found in the intercellular
spaces between neurons. (For a discussion of the po-
tential mechanisms by which intranasal administra-
tion can bypass the blood–brain barrier, see Crowe et
al., 2018.) A large number of drugs, hormones, steroids,
proteins, peptides, and other large molecules are avail-
able in nasal spray preparations for intranasal delivery,
although not all drugs can be atomized. Hence, neu-
ropeptides such as the hormone oxytocin can be ad-
ministered by intranasal sprays to achieve significant
concentrations in the brain. WEB BOX 1.2 describes a
study that evaluated the effects of intranasal oxytocin
administration on social behavior in autistic adults.
Intranasal absorption can also be achieved without
dissolving the drug. Direct application of finely pow-
dered cocaine to the nasal mucosa by sniffing leads to
rapid absorption, which produces profound effects on
the CNS that peak in about 15 to 30 minutes. One side
effect of “snorting” cocaine is the formation of perfora-
tions in the nasal septum, the cartilage that separates
the two nostrils. This damage occurs because cocaine
is a potent vasoconstrictor. Reducing blood flow de-
prives the underlying cartilage of oxygen, leading to
necrosis. Additionally, contaminants in the cocaine act
as chemical irritants, causing tissue inflammation. Co-
caine addicts whose nasal mucosa has been damaged
by chronic cocaine “snorting” may resort to application
of the drug to the rectum, vagina, or penis.
Although the skin provides an effective bar-
rier to the diffusion of water-soluble drugs, certain
lipid-soluble substances (i.e., those that dissolve in fat)
are capable of penetrating slowly. Accidental absorp-
tion of industrial and agricultural chemicals such as
tetraethyl lead, organophosphate insecticides, and
carbon tetrachloride through the skin produces toxic
effects on the nervous system and on other organ sys-
tems. Transdermal (i.e., through the skin) drug ad-
ministration with skin patches provides controlled
and sustained delivery of drug at a preprogrammed
rate. The method is convenient because the individual
does not have to remember to take a pill, and it is pain-
less without the need for injection. It also provides the
advantage of avoiding the first-pass effect. In cases of
mass vaccination campaigns, transdermal delivery is
much quicker than other methods, and it reduces the
dangers of accidental needle sticks of health care work-
ers and unsafe disposal of used needles. Conventional
01_Meyer4e_CH01.indd 9
Principles of Pharmacology 9
patches consist of a polymer matrix embedded with
the drug in high concentration. Transdermal delivery
is now a common way to prevent motion sickness with
scopolamine, reduce cigarette craving with nicotine,
relieve angina pectoris with nitroglycerin, and pro-
vide hormones after menopause or for contraceptive
purposes. The major disadvantage of transdermal
delivery is that because skin is designed to prevent
materials from entering the body, a limited number
of drugs are able to penetrate. However, techniques
are continuing to be developed to increase skin per-
meability through a variety of methods. For instance,
handheld ultrasound devices that send low-intensity
sound energy waves through surrounding fluid in the
tissue temporarily increase the size of the pores in the
skin, allowing absorption of large molecules from a
skin patch. Other “active” patch systems that help to
move large molecules through the skin use iontopho-
resis, which involves applying a small electrical cur-
rent with tiny batteries to the reservoir or the patch.
The electrical charge repels drug molecules with a
similar charge and forces them through the skin at a
predetermined rate. If the amount and duration of cur-
rent are changed, drug delivery can be restricted to
the skin for local effects or can be forced more deeply
into the blood. This process is also capable of pulling
molecules out through the skin for monitoring. Such
monitoring might be used by diabetic individuals to
more frequently and painlessly evaluate levels of blood
glucose. An additional approach uses mechanical dis-
ruption of the skin. Small arrays of microneedles about
1 μm in diameter and 100 μm long and coated with
drug or vaccine are placed on the skin. The needles
penetrate the superficial layer of the skin—the stra-
tum corneum—where the drug is delivered without
stimulating underlying pain receptors. This method
provides the opportunity for painless vaccinations and
drug injections that can be self-administered. These
and other developing techniques have been described
by Langer (2003), Banga (2009), and Waghule and col-
leagues (2019).
Special injection methods must be used for some
drugs that act on nerve cells, because a cellular barrier,
the blood–brain barrier (discussed later in the chapter),
prevents or slows passage of these drugs from the blood
into neural tissue. To directly bypass the blood–brain
barrier, central routes of administration may be used.
For example, intrathecal injection is used when spinal
anesthetics are administered directly into the CSF in the
subarachnoid space surrounding the spinal cord, where-
as epidural infusion, in which a catheter is implanted
in the epidural space just outside of the dura mater, is
commonly used during childbirth, bypassing the blood–
brain barrier (FIGURE 1.3). In animal experiments, a mi-
crosyringe or a cannula enables precise drug infusion
into discrete areas of brain tissue (intracranial) or into
12/9/21 2:29 PM
 10 Chapter 1

FIGURE 1.3 Anatomical diagram Spinal Spinous Subarachnoid

of intrathecal and epidural routes of cord process space Ligamentum flavum
Arachnoid
administration (Left) Cross-section Interspinal ligament
Dura mater
of the lumbar spine, illustrating the L1 Supraspinous
typical spinal level selected for in- Spinal needle L2 ligament
trathecal and epidural routes of ad- L2
Intrathecal
ministration. (Right) The intrathecal route
route of administration requires that L3
the tip of the infusion catheter pen-
etrate the dura mater and arachnoid L4 L3
L3 Tuohy
membranes, allowing for drug to be
needles
infused directly into the subarach- L5
Filum
noid space. In contrast, the epidural terminale
route uses a flexible catheter that
targets the space outside of the dura Epidural
mater (epidural space). (After F. Cox route
Epidural L4
[Ed.]. 2009. Perioperative Pain Man- catheter
agement. Wiley-Blackwell: Oxford.)
Epidural
space

the CSF-filled chambers, the ventricles (intracerebro­ appropriate gene delivery system. Such a delivery sys-
ventricular). In this way, experimenters can study the tem, which is called a vector, is needed to carry the gene
electrophysiological, biochemical, or behavioral effects into the nuclei of target cells to alter protein synthesis.
of drugs on particular nerve cell groups. This method Administering gene therapy is clearly more challeng-
is described in Chapter 4. Animal research has evolved ing when disorders of the CNS, rather than disorders of
into potentially important treatment methods for human any other part of the body, are treated. Vectors are usu-
conditions such as cerebral meningitisSA/AU:
(inflammation of ally injected directly into the brain region targeted for
The scrap was busy with a lot of redundant labels. We
one of the protective membranes covering the brain). An modification. Viral vectors are frequently considered
simplified by using the bottom image in the scrap as a
infusion pump implanted under the skin of the
locator andscalp can important
then labeling for thisstructures
deliveryinsystem
the blow because of the special ability
be programmed to deliver a constantup (where
dose some of the details
of antibiotic of are clearer).toThis
viruses alsoto
bind helps
and enter cells and their nuclei,
to vary our figure more from the source.
into the cerebral ventricles; this device permits treat- where they insert themselves into the chromosomes to
ment of brain infection and is useful because
Note about antibiotics alterwant
fig legend - Au may DNA. Because
to swap viruses vary in terms of binding,
order of
are normally prevented from passing Top andblood–brain
the Bottom text and change Top andproteins,
cell entry Bottom to Right
and other properties, a variety of
barrier. These infusion pumps have and Left.
important uses in viruses are being evaluated.
delivering drugs systemically as well.AlsoWith appropriate
- I believe Lim and
the spelling of Touthy should colleagues
be Tuothy. (2010) provide a review of viral
software, it is possible to provide pulsed administration vector delivery as an approach to treating diseases of
Thanks,
of an agent that mimics the normal biological
Mike-DMG
rhythm, the CNS. Human trials have been increasing in num-
for example, of hormones. An exciting development has ber, but much research remains to be done before the
been the addition of feedback regulation of these pumps, safety and usefulness of gene therapy are fully demon-
which includes a sensor element that monitors
Meyer 4e a sub- strated. Concerns expressed by researchers include the
stance such as blood glucose in a diabetic individual and
Psychopharmacology following: that an immune response may be initiated
responds with an appropriate infusion of insulin
Dragonfly Mediadeliv-
Group by the introduction of foreign material, that the viral
ered from an implantable pump thatSinaueracts much like an
Associates vector may recover its ability to cause disease once it is
artificial pancreas. The downside to these pumps is the
Meyer4e_1.03 8-24-21 placed in the human cell, and that inserting the vector
risk of infection and frequent clogging, which reduces in the wrong place may induce tumor growth. Never-
their usefulness in maintaining stable drug concentra- theless, many animal studies are highly encouraging,
tions over prolonged periods. and gene therapy is believed to have enormous poten-
Many disorders of the CNS are characterized by ab- tial for the treatment of debilitating disorders of the
normal changes in gene activity, which alter the manu- nervous system such as stroke-induced damage, spinal
facture of an essential protein such as an enzyme or a cord injury, chronic pain conditions, and neurodegen-
receptor. Gene therapy refers to the application of de- erative disorders such as Alzheimer’s disease, Parkin-
oxyribonucleic acid (DNA), which encodes a specific son’s disease, and Huntington’s disease.
protein, to a particular target site. DNA can be used
to increase or block expression of the gene product to IMPACT ON BIOAVAILABILITY Because the route
correct the clinical condition. One significant difficulty of administration significantly alters the rate of ab-
in the application of gene therapy involves creating the sorption, blood levels of the same dose of a drug

01_Meyer4e_CH01.indd 10 12/9/21 2:29 PM

 Principles of Pharmacology 11

10.0 FIGURE 1.4 The time course of drug blood level depends
on route of administration The blood level of the same amount
5.0 of drug administered by different procedures to the same indi­
IV vidual varies significantly. Intravenous (IV) administration pro-
Drug concentration in blood (mg/kg)

duces an instantaneous peak when the drug is placed in the

blood, followed by a rapid decline. Intramuscular (IM) adminis-
tration produces rapid absorption and rapid decline, although
1.0
IM admin­istration in oil (IM-oil) shows slower absorption and
gradual decline. Slow absorption after subcutaneous (SC) ad-
0.5
ministration means that some of the drug is metabolized before
IM IM-oil absorption is complete. For this reason, no sharp peak occurs,
and overall blood levels are lower. Oral (PO) administration pro-
duces the lowest blood levels and a relatively short time over
0.10 threshold for effectiveness in this instance. (After R. R. Levine.
1973. Pharmacology: Drug Actions and Reactions. Little, Brown,
0.05 and Co.: Boston; D. F. Marsh. 1951. Outlines of Fundamental
SC Pharmacology. Charles C. Thomas: Springfield, IL.)
Threshold for effectiveness

0.01 PO Multiple factors modify drug absorption

0 6 12
Time (h)
administered by different routes vary significantly.
FIGURE 1.4 compares drug concentrations in blood
over time for various routes of administration. Keep
in mind that the peak level for each method reflects
not only differences in absorption rate, but also the fact
that slow absorption provides the opportunity for liver
metabolism to act on some of the drug molecules before
absorption is complete. Advantages and disadvantages
of selected methods of administration are summarized
in TABLE 1.1.
18 24 Once the drug has been administered, it is absorbed
from the site of administration into the blood to be
circulated throughout the body and ultimately to the
brain, which is the primary target site for psychoactive
drugs (i.e., those drugs that have an effect on think-
ing, mood, and behavior). We have already shown that
the rate of absorption is dependent on several factors.
Clearly, the route of administration alters absorption
because it determines the area of the absorbing surface,
the number of cell layers between the site of adminis-
tration and the blood, the amount of drug destroyed
by metabolism or digestive processes, and the extent of
binding to food or inert complexes. Absorption is also
dependent on drug concentration, which is determined

TABLE 1.1 Advantages and Disadvantages of Selected Routes of Drug Administration

Meyer 4e
Route of administration
Psychopharmacology Advantages Disadvantages
Dragonfly
Oral (PO) Media Group Safe; self-administered; economical; no Slow and highly variable absorption; subject to
Sinauer Associates needle-related complications first-pass metabolism; less-predictable blood
Meyer4e_1.04 7-21-21 levels
Intravenous (IV) Most rapid; most accurate blood Overdose danger; cannot be readily reversed;
concentration requires sterile needles and medical technique
Intramuscular (IM) Slow and even absorption Localized irritation at site of injection; needs
sterile equipment
Subcutaneous (SC) Slow and prolonged absorption Variable absorption depending on blood flow
Inhalation Large absorption surface; very rapid onset; Irritation of nasal passages; inhaled small
no injection equipment needed particles may damage lungs
Topical Localized action and effects; easy to May be absorbed into general circulation
self-administer
Transdermal Controlled and prolonged absorption Local irritation; useful only for lipid-soluble drugs
Epidural Bypasses blood–brain barrier; very rapid Not reversible; needs trained anesthesiologist;
effect on CNS possible nerve damage
Intranasal Ease of use; local or systemic effects; very Not all drugs can be atomized; potential irritation
rapid; no first-pass metabolism; bypasses of nasal mucosa
blood–brain barrier

01_Meyer4e_CH01.indd 11 12/9/21 2:29 PM

 12 Chapter 1

in part by individual differences in age, sex, and body
size. Finally, absorption is dependent on the solubility
and ionization of the drug.
TRANSPORT ACROSS MEMBRANES Perhaps the
single most important factor in determining plasma
drug levels is the rate of passage of the drug through
the various cell layers (and their respective membranes)
between the site of administration and the blood. To
understand this process, we need to look more care-
fully at cell membranes.
Cell membranes are made up primarily of complex
lipid (fat) molecules called phospholipids, which have a
negatively charged phosphate region (the head) at one
end and two uncharged lipid tails (FIGURE 1.5A). These
molecules are arranged in a bilayer, with their phosphate
ends forming two almost continuous sheets filled with
fatty material (FIGURE 1.5B). This configuration occurs
because the polar heads are attracted to the polar water
molecules. Hence, the charged heads are in contact with
both the aqueous intracellular fluid and the aqueous
extracellular fluid. Proteins that are found inserted into
the phospholipid bilayer have functions that will be de-
scribed later (see Chapter 3). The molecular characteris-
tics of the cell membrane prevent most molecules from
passing through unless they are soluble in fat.
LIPID-SOLUBLE DRUGS Drugs with high lipid solu-
bility move through cell membranes by passive diffu­
sion, leaving the water in the blood or stomach juices
and entering the lipid layers of membranes. Movement
across the membranes is always in a direction from
higher to lower concentration. The larger the concentra-
tion difference on each side of the membrane (called the
concentration gradient), the more rapid is the diffusion.
Lipid solubility increases the absorption of drug into the
blood and determines how readily a drug will pass the
lipid barriers to enter the brain. For example, the nar-
cotic drug heroin is a simple modification of the parent
compound morphine. Heroin, or diacetylmorphine, is
more soluble in lipid than is morphine, and it penetrates
into brain tissue more readily, thus having a quicker
onset of action and more potent reinforcing properties.
This occurs despite the fact that before the psychotropic
drug effects occur, the heroin must be converted to mor-
phine by esterase enzymes in the brain. That property
makes heroin a prodrug—that is, one that is dependent
on metabolism to convert an inactive drug to an active
one, a process called bioactivation. This strategy is one
used by pharmaceutical companies that develop pro-
drugs that cross the blood–brain barrier (see the section
Drug Distribution Is Limited by Selective Barriers) if the
active drug cannot penetrate easily.
IONIZED DRUGS Most drugs are not readily lipid sol-
uble, because they are weak acids or weak bases that
can become ionized when dissolved in water. Just as
common table salt (NaCl) produces positively charged
ions (Na+) and negatively charged ions (Cl−) when dis-
solved in water, many drugs form two charged (ion-
ized) particles when placed in water. Although NaCl is
a strong electrolyte, which causes it to almost entirely
dissociate in water, most drugs are only partially ion-
ized when dissolved in water. The extent of ionization

(A) (B)
Globular Phospholipid
protein charged region
Extracellular
Negatively charged
(hydrophilic) region

Bilayer

Uncharged
(hydrophobic) region
Intracellular Globular Fatty uncharged
protein tails

FIGURE 1.5 Cell membranes (A) Example of a phospholipid molecule with a negatively charged
group (PO4−) at one end (hydrophilic) and two fatty uncharged tails (hydrophobic). (B) The arrange-
ment of individual phospholipid molecules forms a bilayer, with negatively charged heads attracted to
the water molecules of both intracellular and extracellular fluids. The fatty tails of the molecules are
tucked within the two charged layers and have no contact with aqueous fluid. Embedded in the bilayer
are protein molecules that serve as receptors or channels.

01_Meyer4e_CH01.indd 12 12/9/21 2:29 PM

 Principles of Pharmacology 13

TABLE 1.2 pH of Body Fluids Non-ionized Non-ionized

Fluid pH COOH COOH

2
Stomach 1.35–3.5 OCOCH3 OCOCH3
Blood 7.35–7.4
Kidney urine 4.6–8.0
3 1
Cerebrospinal fluid (CSF) 7.3

Source: After G. K. Schwalfenberg. 2012. J Environ

COO– COO–
Public Health 2012: 727630.
OCOCH3 OCOCH3

depends on two factors: the relative acidity/alkalinity Ionized Ionized

(pH) of the solution, and an intrinsic property of the
molecule (pKa).
Acidity or alkalinity is expressed as pH, which is de-
scribed on a scale of 1 to 14, with 7 being neutral. Acidic
solutions have a lower pH, and alkaline (basic) solu-
tions have a pH greater than 7.0. Drugs are dissolved
in body fluids that differ in pH (TABLE 1.2), and these
differences play a role in drug ionization and move-
ment from one body fluid compartment to another, for
example from the stomach to the bloodstream, or from
the bloodstream into the kidney urine.
The second factor determining ionization is a char-
acteristic of the drug molecule. The pKa of a drug rep-
resents the pH of the aqueous solution in which that
drug would be 50% ionized and 50% non-ionized. In
general, drugs that are weak acids ionize more readily
in an alkaline environment and become less ionized in
an acidic environment. The reverse is true of drugs that
are weak bases. If we put the weak acid aspirin (acetyl-
salicylic acid) into stomach acid, it will remain primarily
in a non-ionized form (FIGURE 1.6). The lack of electri-
cal charge makes the drug more lipid soluble and hence
readily absorbed from the stomach to the blood. In the
intestine, where the pH is around 5.0 to 6.0, ionization
increases and absorption through that membrane is re-
duced compared with that of the stomach.
This raises the question of why aspirin molecules
Meyer 4e
do not move from the stomach to the blood and backPsychopharmacology
to
the stomach again. In our example, aspirin in the acid-Dragonfly Media Group
ic gastric fluid is primarily in non-ionized form and
Sinauer Associates
thus passes through the stomach wall into the blood.
Meyer4e_1.06
In blood (pH 7.4), however, aspirin becomes more ion-
ized; it is said to be “trapped” within the blood and
does not return to the stomach. Meanwhile, the circu-
lation moves the aspirin molecules away from their
concentrated site at the stomach to maintain a concen-
tration gradient that favors drug absorption. Hence, al-
though passive diffusion would normally cease when
drug concentration approached a 50:50 equilibrium,
the combination of ion trapping and blood circulation
of the drug away from the absorbing surface means
that absorption from oral administration can be quite
high. Keep in mind that although the acidic stomach
favors absorption of weak acids, much of the aspirin
Stomach (pH 2.0)
Blood (pH 7.4)
Non-ionized
COOH
OCOCH3
4
5
COO–
OCOCH3
Ionized
Intestine (pH 5.5)
FIGURE 1.6 Effect of ionization on drug absorption On the
right side of the cell barrier in stomach acid (pH 2.0), aspirin
molecules tend to remain in the non-ionized form (1), which
promotes the passage of the drug through the cell walls (2) to
the blood. Once the intact aspirin molecules reach the blood
(pH 7.4), they ionize (3) and are “trapped” in the blood to be cir-
culated throughout the body. In the lower portion of the figure,
when the aspirin has reached the intestine, it tends to dissoci-
ate to a greater extent (4) in the more basic pH. Its more ionized
form reduces passage (5) through the cells to the blood, so ab-
sorption from the intestine is slower than from the stomach.
is absorbed in the small intestine because absorption
is also determined
7-22-21 by the length of time the drug is in
contact with the absorptive membrane.
Drugs that are highly charged in both acidic and
basic environments are very poorly absorbed from
the GI tract and cannot be administered orally. This
explains why South American hunters readily eat the
flesh of game killed with curare-poisoned arrows. Cu-
rare is highly ionized in both the acidic stomach and
the alkaline intestine, so the drug does not leave the
digestive system to enter their blood.
OTHER FACTORS Factors other than ionization have
a significant influence on absorption as well. For in-
stance, the much larger surface area of the small

01_Meyer4e_CH01.indd 13 12/9/21 2:29 PM

 14 Chapter 1
intestine and the slower movement of material through
the intestine, as compared with the stomach, provide a
much greater opportunity for absorption of all drugs.
Therefore, the rate at which the stomach empties into
the intestine very often is the significant rate-limiting
factor. For this reason, medication is often prescribed to
be taken before meals and with sufficient fluid to move
the drug through the stomach and into the intestine.
Since drug absorption is closely related to the con-
centration of the drug in body fluids (e.g., stomach), it
should certainly be no surprise to you that the drug
dosage required to achieve a desired effect is directly re-
lated to the size of the individual. In general, the larger
the individual, the more diluted the drug will be in the
larger fluid volume, and less drug will reach target sites
within a given unit of time. The average dose of a drug is
typically based on the response of individuals between
the ages of 18 and 65 who weigh 150 pounds. However,
for people who are very lean or obese, the average dose
may be inappropriate because of variations in the ratio
of fat to water in the body. For these individuals, body
surface area, which reflects both size and weight, may
serve as a better basis for determining drug dose. The sex
of the individual also plays a part in determining plasma
drug level: in women, adipose tissue, relative to water,
represents a larger proportion of the total body weight.
Overall, the total fluid volume, which contains the drug,
is relatively smaller in women than in men, producing a
higher drug concentration at the target site in women. It
should be obvious also that in the smaller fluid volume
of a child, a standard dose of a drug will be more concen-
trated and therefore will produce a greater drug effect.
Drug distribution is limited
by selective barriers
Regardless of the route of administration, once the drug
has entered the blood, it is carried throughout the body
within 1 or 2 minutes and can have an action at any
number of receptor sites. In general, those parts of the
body in which blood flow is greatest will have the high-
est concentration of drug. Since blood capillaries have
numerous pores, most drugs can move from blood and
enter body tissues regardless of lipid solubility, unless
they are bound to protein (see the discussion on depot
binding later in this chapter). Quite rapidly, high concen-
trations of drugs will be found in the heart, brain, kid-
neys, and liver. Other tissues with less vasculature will
more slowly continue to absorb the drug from the plas-
ma, causing plasma levels to fall gradually. As plasma
levels fall, the concentration of drug in the highly vas-
cularized organs will be greater than that in the blood,
so the drug will move from those organs back into the
plasma to maintain equilibrium. Hence, those organs
will have an initial high concentration of drug, and then
drug redistribution will reduce drug concentration there.
Ultimately drug concentration will be in equilibrium in
01_Meyer4e_CH01.indd 14
all tissues. Drug redistribution may be responsible for
terminating the action of a drug, as in the case of the
rapid-acting CNS depressant thiopental. Thiopental, a
barbiturate used for intravenous anesthesia, is highly
lipid soluble; therefore, rapid onset of sedation is caused
by entry of the drug into the brain. Deep sedation does
not last very long, because the blood level falls rapidly
as a result of redistribution of the drug to other tissues,
causing thiopental to move from the brain to the blood
to maintain equilibrium. High levels of thiopental can
be found in the brain 30 seconds after IV infusion. How-
ever, within 5 minutes, brain levels of the drug drop to
threshold anesthetic concentrations. In this way, thio-
pental induces sleep almost instantaneously but is effec-
tive for only about 5 minutes, followed by rapid recovery.
Because the brain receives about 20% of the blood
that leaves the heart, lipid-soluble drugs are readily
distributed to brain tissue. However, the blood–brain
barrier limits the movement of ionized molecules from
the blood to the brain.
BLOOD–BRAIN BARRIER Blood plasma is supplied
by a dense network of blood vessels that permeate the
entire brain. This system supplies brain cells with oxy-
gen, glucose, and amino acids, and it carries away car-
bon dioxide and other waste products. Despite the vital
role that blood circulation plays in cerebral function,
many substances found in blood fluctuate significantly
and would have disruptive effects on brain cell activity
if materials were transferred freely between blood and
brain (and the brain’s associated CSF).
CSF is a clear, colorless liquid that fills the subarach-
noid space that surrounds the entire bulk of the brain
and spinal cord and also fills the hollow spaces (ven-
tricles) and their interconnecting channels (aqueducts),
as well as the centrally located cavity that runs longi-
tudinally through the length of the spinal cord (central
canal) (FIGURE 1.7A). CSF is manufactured by cells of
the choroid plexus, which line the cerebral ventricles.
In contrast to the wide fluctuations that occur in the
blood plasma, the contents of the CSF remain quite
stable. Many substances that diffuse out of the blood
and affect other organs in the body do not seem to enter
the CSF, nor do they affect brain tissue. This separa-
tion between brain capillaries and the brain/CSF con-
stitutes what we call the blood–brain barrier. FIGURE
1.7B shows an enlargement of the relationship between
the cerebral blood vessels and the CSF.
The principal component of the blood–brain barrier is
the distinct morphology of brain capillaries. FIGURE 1.8
shows a comparison between typical capillaries found
throughout the body (Figure 1.8A) and capillaries that
serve the CNS (Figure 1.8B). Because the job of blood ves-
sels is to deliver nutrients to cells while removing waste,
the walls of typical capillaries are made up of endothe-
lial cells that have both small gaps (inter­cellular clefts)
12/9/21 2:29 PM
 Principles of Pharmacology 15

FIGURE 1.7 Distribution of cerebrospinal fluid (A) Cerebral

(A) Cerebrospinal fluid (CSF; blue) is manufac- subarachnoid space Choroid plexus of
tured by the choroid plexus within the cerebral lateral ventricle
ventricles. In addition to filling the ventricles and Aqueduct
their connecting aqueducts, CSF fills the space Lateral of Sylvius
between the arachnoid membrane and the pia ventricle
mater (subarachnoid space) to cushion the brain
against trauma. (B) The enlarged diagram shows
detail of CSF-filled subarachnoid space and its
relationship to cerebral blood vessels. Note how
the blood vessels penetrate the brain tissue.

and larger openings (fenestrations) through

Third
which molecules can pass. In addition, gen-
ventricle
eral capillaries have pinocytotic vesicles
that envelop and transport larger molecules
through the capillary wall. In contrast, in
brain capillaries, the intercellular clefts
are closed because adjoining edges of the Fourth
endothelial cells are fused, forming tight Spinal subarachnoid space ventricle
junctions. Also, fenestrations are absent
and pinocytotic vesicles are rare. Although
lipid-soluble materials can pass through the (B) Dura mater
walls of the blood vessels, most materials are
moved from the blood of brain capillaries Cerebral
Arachnoid
by special transporters. Surrounding brain membrane subarachnoid
capillaries are numerous glial feet—exten- space filled
sions of the glial cells called astrocytes or with CSF
Pia mater
astroglia. It is becoming apparent that these
Cerebral
astrocytic glial feet contribute to both post- artery
natal formation and maintenance of the
blood–brain barrier throughout adulthood. Cerebral
vein
It has been shown that blood–brain barrier
characteristics depend on the CNS environ-
ment, because if the endothelial cells are Brain capillary
Cerebral with tight junctions
removed and cultured without astroglia, cortex
they lose their barrier function. Conversely,
blood–brain barrier characteristics can be in-
duced in non-CNS endothelial cells that are
cultured with astrocytes (see Alvarez et al.,
2013). By filling in the extracellular space around capil- other regions of the brain wherever a functional in-
laries and releasing secretion factors, these astroglia ap- teraction (e.g., blood monitoring) is required between
parently help maintain the endothelial tight junctions. blood and neural tissue. For example, the area pos-
Also, it is likely that the close interface of astrocytes with trema, or chemical trigger zone, is a cluster of cells in
both nerve cells and brain capillaries provides the astro- the brainstem that responds to toxins in the blood and
cytes with a unique opportunity to coordinate the deliv- induces vomiting.
ery of oxygen and glucose in the blood with the energy The limited permeability of the blood–brain bar-
required by activated neurons. There is more discussionMeyer 4e rier is important in psychopharmacology because
of the many functions of astrocytes in Chapter 2.Psychopharmacology we need to know which drugs remain non-ionized
Before we go on, we should emphasize that Dragonfly
the Media Group pH and readily enter the CNS, and which
at plasma
Sinauer Associates
blood–brain barrier is selectively permeable, not im- drugs only circulate throughout the rest of the body.
Meyer4e_1.07 7-22-21
permeable. Although the barrier does reduce diffusion Minor differences in drug molecules are responsible
of water-soluble (i.e., ionized) molecules, it does not im- for the relative selectivity of drug action. For example,
pede lipid-soluble molecules. physostigmine readily crosses the blood–brain barrier
Finally, the blood–brain barrier is not complete. and is useful for treating the intoxication caused by
Several brain areas are not isolated from materials in some agricultural pesticides. It does so by increasing
the blood, and a limited blood–brain barrier exists in the availability of the neurotransmitter acetylcholine.

01_Meyer4e_CH01.indd 15 12/9/21 2:29 PM

 16 Chapter 1
(A) Typical capillary
Cell nucleus
Lipid-soluble
transport
Blood
plasma
Intercellular
cleft
Pinocytotic
vesicle
Endothelial
cell
Fenestration
FIGURE 1.8 Cross-section of typical capillaries and brain
capillaries (A) Capillaries found throughout the body have
characteristics that encourage movement of materials between
the blood and surrounding cells. (B) Brain capillaries minimize
In contrast, the structurally related but highly ionized
drug neostigmine is excluded from the brain and in-
creases acetylcholine only peripherally. Its restriction
by the blood–brain barrier means that neostigmine can
be used to treat the muscle disease myasthenia gravis
without significant CNS side effects, but it would not be
effective in treating pesticide-induced intoxication. As
mentioned earlier in this section, because many drugs
that are ionized do not pass through the blood–brain
barrier, direct delivery of the drug into brain tissue by
intracranial injection may be necessary, although at
leastMeyer
some4edrugs can be atomized and delivered in-
tranasally to bypass the blood–brain barrier. A second
Psychopharmacology
Dragonfly
approach is toMedia Group
develop a prodrug that is lipid soluble
Sinauer Associates
and becomes bioactivated by brain enzymes.
Meyer4e_1.08 8-25-21
PLACENTAL BARRIER A second barrier, unique to
women, is found between the blood circulation of a
pregnant mother and that of her fetus. The placenta,
which connects the fetus with the mother’s uterine
wall, is the means by which nutrients obtained from
the digestion of food, O2, CO2, fetal waste products, and
drugs are exchanged. As is true for other cell mem-
branes, lipid-soluble substances diffuse easily, and
water-soluble substances pass less easily. The potential
for transfer of drugs from mother to fetus has very im-
portant implications for the health and well-being of
the developing child. Potentially damaging effects on
the fetus can be divided into two categories: acute tox-
icity and teratogenic effects.
The fetus may experience acute toxicity in utero after
exposure to the disproportionately high drug blood
level of its mother. In addition, after birth, any drug
remaining in the newborn’s circulation is likely to have
01_Meyer4e_CH01.indd 16
(B) Brain capillary
Cell nucleus Endothelial cell
Lipid-soluble Tight junction
transport
Carrier-mediated
transport
Blood
plasma
End foot
of astrocyte
movement of water-soluble molecules through the blood ves-
sel wall because there are essentially no large or small clefts
or pinocytotic sites. (After W. H. Oldendorf. 1977. Exp Eye Res
25: 177–190. © 1977. Reprinted with permission from Elsevier.)
a dramatic and prolonged action because of slow and
incomplete metabolism. It is well known that opiates
such as heroin readily reach the fetal circulation and
that newborn infants of heroin- or methadone-addicted
mothers experience many of the signs of opiate with-
drawal. Certain tranquilizers, gaseous anesthetics, al-
cohol, many barbiturates, and cocaine all readily pass
into the fetal circulation to cause acute toxicity. In ad-
dition, alcohol, cocaine, and the carbon monoxide in
cigarette smoke all deprive the fetus of oxygen. Such
drugs pose special problems because they are readily
accessible and are widely used.
Teratogens are agents that induce developmental ab-
normalities in the fetus. The effects of teratogens such as
drugs (both therapeutic and illicit), exposure to X-rays,
and some maternal infections (e.g., German measles) are
dependent on the timing of exposure. The fetus is most
susceptible to damaging effects during the first trimes-
ter of pregnancy, because it is during this period that
many of the fetal organ systems are formed. Each organ
system is maximally sensitive to damaging effects dur-
ing its time of cell differentiation (TABLE 1.3). Many
drugs can have damaging effects on the fetus despite
minimal adverse effects in the mother. For example,
the vitamin A–related substance isotretinoin, which
is a popular prescription acne medication (Accutane),
produces serious birth defects and must be avoided by
sexually active young women. Experience has taught us
that evaluation of drug safety must consider potential
fetal effects, as well as effects on adults. Furthermore,
because teratogenic effects are most severe during the
time before pregnancy is typically recognized, the use
of any drug known to be teratogenic in animals should
be avoided by women of childbearing age.
12/9/21 2:29 PM

TABLE 1.3 Critical Periods of Teratogenic
Sensitivity for Several Organ Systems in
the Human Fetus
Organ system Weeks after fertilization
Brain 3–16
Eye 4–8
Genitalia 7–9
Heart 3–6
Limbs 4–6
Depot binding alters the magnitude
and duration of drug action
We already know that after a drug has been absorbed
into the blood from its site of administration, it circu-
lates throughout the body. Thus, high concentrations
of drug may be found in all organs that are well sup-
plied with blood until the drug gradually redistributes
to all tissues in the body. Drug binding occurs at many
inactive sites, where no measurable biological effect is
initiated. Such sites, called drug depots or silent recep­
tors, include several plasma proteins, with albumin
being most important. Any drug molecules bound to
these depots cannot reach active sites, nor can they be
metabolized by the liver. However, the drug binding
is reversible, so the drug remains bound only until the
blood level drops, causing it to unbind gradually and
circulate in the plasma.
The binding of a drug to inactive sites—called depot
binding—has significant effects on the magnitude and
duration of drug action. Some of these effects are sum-
marized in TABLE 1.4. First, depot binding reduces
the concentration of drug at its sites of action because
only freely circulating (unbound) drug can pass across
membranes. Onset of action of a drug that binds read-
ily to depot sites may be delayed and its effects reduced
TABLE 1.4 Effects of Drug Depot Binding on Therapeutic Outcome
Depot-binding characteristics
Rapid binding to depots before reaching target tissue
Individual differences in amount of binding
Competition among drugs for depot-binding sites
Unmetabolized bound drug
Redistribution of drug to less vascularized tissues
and inactive sites
01_Meyer4e_CH01.indd 17
Principles of Pharmacology 17
because the number of drug molecules reaching the
target tissue is dependent on its release from inactive
sites. Individual differences in the amount of depot
binding explain in part why some people are more
sensitive than others to a particular drug.
Second, because binding to albumin, fat, and mus-
cle is rather nonselective, many drugs with similar
physiochemical characteristics compete with each
other for these sites. Such competition may lead to a
much-higher-than-expected free drug blood level of
the displaced drug, producing a drug overdose. For ex-
ample, the antiseizure drug phenytoin is highly protein
bound, but aspirin can displace some of the phenytoin
molecules from the binding sites because aspirin binds
more readily. When phenytoin is displaced from plas-
ma protein by aspirin, the elevated drug level may be
responsible for unexpected side effects. Many psycho-
active drugs, including the antidepressant fluoxetine
(Prozac) and the tranquilizer diazepam (Valium), show
extensive (more than 90% of the drug molecules) plas-
ma protein binding and may contribute to drug interac-
tions in some cases.
Third, bound drug molecules cannot be altered by
liver enzymes, because the drug is not free to leave the
blood to enter liver cells for metabolism. For this rea-
son, depot binding frequently prolongs the time that the
drug remains in the body. This phenomenon explains
why some drugs, such as THC, which is stored in fat
and is only slowly released, can be detected in urine
for many days after a single dose. Such slow release
means that an individual could test positive for urinary
THC (one active ingredient in marijuana) without ex-
periencing cognitive effects at that time. The prolonged
presence of drugs in body fat and inert depots makes
pre-employment and student drug testing possible.
Finally, as mentioned previously, redistribution of
a drug from highly vascularized organs (e.g., brain) to
tissues with less blood flow will reduce drug concentra-
tions in those organs. The redistribution occurs more
rapidly for highly lipid-soluble drugs that reach the
Therapeutic outcome
Slower onset and reduced effects
Varying effects:
High binding means less free drug, so some people
seem to need higher doses.
Low binding means more free drug, so these
individuals seem more sensitive.
Higher-than-expected blood levels of the displaced drug,
possibly causing greater side effects, even toxicity
Drug remaining in the body for prolonged action
Termination of drug action
12/9/21 2:29 PM
 18 Chapter 1
brain very quickly but also redistribute readily because
of the ease of movement through membranes. Those
drugs have a rapid onset but short duration of action.
Biotransformation and elimination of drugs
contribute to bioavailability
Amount of drug remaining
Drugs are eliminated from the body through the com-
bined action of several mechanisms, including bio-
transformation (metabolism) of the drug and excretion
of metabolites that have been formed. Drug clearance
reduces blood levels and in large part determines the
intensity and duration of drug effects. The easiest way
to assess the rate of elimination consists of intrave-
nously administering a drug to establish a peak plasma
drug level, then collecting repeated blood samples. The
decline in plasma drug concentration provides a direct
measure of the clearance rate without complication by
absorption kinetics.
DRUG CLEARANCE Drug clearance from the blood
usually occurs exponentially and is referred to as
first-order kinetics. Exponential elimination means that
a constant fraction (50%) of free drug in the blood is re-
moved during each time interval. The exponential func-
tion occurs because even at relatively high drug concen-
trations, surplus clearance sites are available, so the rate is
concentration-dependent. Hence, when blood levels are
high, clearance occurs more rapidly, and as blood levels
drop, the rate of clearance is reduced. The amount of time
required for removal of 50% of the drug in blood is called
the half-life, or t½. FIGURE 1.9 provides an example of
half-life determination for the stimulant dextroamphet-
amine (Dexedrine), a drug used to treat attention-deficit/
hyperactivity disorder (ADHD). Although all drugs are
essentially eliminated after six half-lives, many psycho-
active drugs have half-lives of several days, so clearance
may take weeks after even a single dose. A list of the
half-lives of some common drugs is provided in TABLE
1.5. Keep in mind that clearance from the blood is also
dependent on biotransformation rate as well as depot
binding and storage in reservoirs such as fat.
The principal goal of any drug regimen is to main-
tain the plasma concentration of the drug at a constant
desired level for a therapeutic period. The therapeutic
window is the range of plasma drug levels that are
high enough to be effective, but not so high that they
cause toxic or otherwise intolerable side effects. For
some drugs, such as stimulants used to treat ADHD,
or hypnotic drugs used to promote sleep, the thera-
peutic period is only part of each day, so a single daily
dose of a drug with a relatively short half-life would
be required to avoid disruptive effects at other times
of day. However, in many cases the target therapeu-
tic concentration is achieved only after multiple ad-
ministrations. For instance, as FIGURE 1.10 shows,
a predictable fluctuation in blood level occurs over
01_Meyer4e_CH01.indd 18
100
75
in plasma (%)
50
25
12
6
3
0 1 2 3 4 5 6
Time (in half-lives)
FIGURE 1.9 First-order kinetics of drug clearance Expo-
nential elimination of drug from the blood occurs when clear-
ance during a fixed time interval is always 50% of the drug
remaining in blood. For example, the half-life of orally admin-
istered dextroamphetamine (Dexedrine) is approximately 10
hours. Therefore, 10 hours (one half-life) after the peak plas-
ma concentration has been reached, the drug concentration is
reduced to about 50% of its initial value. After 20 and 30 hours
(i.e., two and three half-lives) have elapsed, the concentration
is reduced to 25% and 12.5%, respectively. After six half-lives,
the drug is essentially eliminated, with 1.6% remaining. The
curve representing the rate of clearance is steeper early on,
when the rate is more rapid, and becomes more shallow as
the rate of clearance decreases.
Meyer 4e
Psychopharmacology
time as a Media
Dragonfly result Group
of the dynamic balance between ab-
sorption
Sinauer and clearance. After oral administration at
Associates
time A, the plasma
Meyer4e_1.09 level of a drug gradually increases
7-22-21
to its peak (peak 1) followed by a decrease because
of drug biotransformation, elimination, or storage at
inactive sites. If first-order kinetics is assumed, after
one half-life (time B), the plasma drug level has fallen
to half its peak value. Half-life determines the time
needed to reach the steady state plasma level, which
is the desired blood concentration of drug achieved
when the absorption/distribution phase is equal to
the metabolism/excretion phase. For any given daily
dose of a drug, the steady state plasma level is ap-
proached after a period of time equal to five half-lives
(time C), at which point only 3.125% of the initial dose
theoretically remains, minimally contributing to the
total drug concentration achieved with subsequent
doses. Hence, for a given dosing interval, the shorter
the half-life of a drug, the more rapidly the therapeutic
level of the drug will be achieved. Drugs with longer
half-lives will take longer to reach consistent blood
12/9/21 2:29 PM
 Principles of Pharmacology 19

Although most drugs are cleared from the blood

TABLE 1.5 Half-Lives of Some by first-order kinetics, under certain conditions some
Common Drugs drugs are eliminated according to the zero-order
Drug Half-life model. Zero-order kinetics means that drug mole-
cules are cleared at a constant rate regardless of drug
Cocaine 0.7–1.5 hours a
concentration; this is graphically represented as a
Morphine 2–3.52 hours b straight line (FIGURE 1.11). It happens when drug lev-
Nicotine 2 hours c els are high and routes of metabolism or elimination
Methylphenidate 2–3 hours d are saturated (i.e., more drug molecules are available
THC 20–30 hours e
than sites). A classic example of a drug that is elimi-
nated by zero-order kinetics is high-dose ethyl alcohol.
Ibuprofen 1.8-2 hoursf
When two or more drinks of alcohol are consumed in
Sertraline 22-36 hours g a relatively short time, alcohol molecules saturate the
Sources: Based on data in a J. L. Zimmerman. 2012 Crit Care enzyme-binding sites, and metabolism occurs at its
Clin 28: 517–526; b C. E. Inturrisi. 2002. Clin J of Pain 18: S3; maximum rate of approximately 10 to 15 ml/hour, or
c
N. L. Benowitz et al. 1982. J Pharmacol Exp Ther 221: 368–372;
d
H. C. Kimko et al. 1999. Clin Pharmacokinet 37: 457–470; 1.0 ounce of 100-proof alcohol per hour regardless of
e
f
F. Grotenhermen. 2003. Clin Pharmacokinet 42: 327–360; concentration. This rate is determined by the number
R. Bushra and N. Aslam 2010. Oman Med J 25: 55–1661; and
g
C. L. DeVane et al. 2002. Clin Pharmacokinet 41: 1247–1266. of enzyme molecules. Any alcohol consumption that
occurs after saturation of the enzyme will raise blood
levels dramatically and produce intoxication. Although
levels. For example, if we needed the blood level of zero-order biotransformation occurs at high levels of
drug X with a half-life of 4 hours to be 1000 mg, we alcohol, the biotransformation rate shifts to first-order
might administer 500 mg at the outset. After 4 hours, kinetics as blood levels are reduced (see Figure 1.11).
the blood level would have dropped to 250 mg, at
which time we could administer another 500 mg, BIOTR ANSFORMATION BY LIVER MICROSOMAL
raising the blood level to 750 mg. Four hours later, an- ENZYMES Most drugs are chemically altered by the
other 500 mg could be added to the current blood level body before they are excreted. These chemical changes
of 375 mg, bringing the new value to 875 mg, and so
forth. The amount of drug would continue to rise until
a maximum of 1000 mg was reached because more 0.80
drug was given than was metabolized. However, as
we reached the steady state level after approximately 0.70
Concentration of ethanol in blood (mg/ml)

five half-lives, the amount administered would ap-

proximate the amount metabolized (500 mg). 0.60

0.50
Desired blood drug level
(steady state plasma level) 0.40

Peak 1
Blood drug level

0.30

0.20

0.10

0
A B C Time (h)
Time
FIGURE 1.10 Achieving steady state plasma levels of drug
The scalloped line shows the pattern of accumulation during
repeated administration of a drug. The arrows represent the
times of administration. The shape of the scallop is dependent
on both the rate of absorption and the rate of elimination. The
smooth line represents drug accumulation in the blood during
continuous intravenous infusion of the same drug.
0
20 21 22 23 24
FIGURE 1.11 Zero-order rate of elimination The curve
shows the decline of ethanol content in blood after intrave-
nous administration of a large dose to laboratory animals.
The x-axis represents the time beginning 19 hours after ad-
ministration. Plotted data show the change from zero-order
to first-order kinetics when low concentrations are reached
between 23 and 24 hours after administration. (After E. K.
Marshall, Jr. 1953. J Pharmacol Exp Ther 109: 431.)

01_Meyer4e_CH01.indd 19 12/9/21 2:29 PM

 20 Chapter 1
are catalyzed by enzymes and can occur in many tis-
sues and organs, including the stomach, intestine,
blood plasma, kidney, and brain. However, the great-
est number of chemical changes, which we call drug
metabolism or biotransformation, occur in the liver.
There are two major types of biotransformation.
Type I biotransformations are sometimes called phase
I because these reactions often occur before a second
metabolic step. Phase I changes involve nonsynthetic
modification of the drug molecule by oxidation, reduc-
tion, or hydrolysis. Oxidation is by far the most com-
mon reaction; it usually produces a metabolite that is
less lipid soluble and less active, but it may produce
a metabolite with equal or even greater activity than
the parent drug. Type II, or phase II, modifications are
synthetic reactions that require the combination (called
conjugation) of the drug with some small molecule such
as glucuronide, sulfate, or methyl groups. Glucuronide
conjugation is particularly important for inactivating
psychoactive drugs. These metabolic products are less
lipid soluble because they are highly ionized and are
almost always biologically inactive. In summary, the
two phases of drug biotransformation ultimately pro-
duce one or more inactive metabolites, which are water
soluble, so they can be excreted more readily than the
parent drug. Metabolites formed in the liver are re-
turned to the circulation and are subsequently filtered
out by the kidneys, or they may be excreted into bile
and eliminated with the feces. Metabolites that are ac-
tive return to the circulation and may have additional
action on target tissues before they are further metabo-
lized into inactive products. Obviously, drugs that are
converted into active metabolites have a prolonged du-
ration of action. TABLE 1.6 shows several examples of
the varied effects of phase I and phase II metabolism.
The sedative drug phenobarbital is rapidly inactivated
by phase I metabolism. In contrast, aspirin is converted
at first to an active metabolite by phase I metabolism,
but phase II action produces an inactive compound.
Morphine does not undergo phase I metabolism but
is inactivated by phase II reactions. Finally, diazepam
(Valium), a long-lasting antianxiety drug, has several
active metabolites before phase II inactivation. Further,
as mentioned previously, some drugs are inactive until
TABLE 1.6 Varied Effects of Phase I and Phase II Metabolism
Active drug Active metabolites and inactive metabolitesa
Phase I
Phenobarbital
Phase I
Aspirin Salicylic acid
Morphine Phase II
Phase I
Diazepam Desmethyldiazepam
a
Bold terms indicate active metabolites.
01_Meyer4e_CH01.indd 20
they are metabolized. For example, the inactive drug
codeine is metabolized in the body to the active drug
morphine, making codeine a prodrug.
The liver enzymes primarily responsible for metabo-
lizing psychoactive drugs are located on the smooth
endoplasmic reticulum, which is a network of tubules
within the liver cell cytoplasm. These enzymes are
often called microsomal enzymes because they exhibit
particular characteristics on biochemical analysis.
Microsomal enzymes lack strict specificity and can
metabolize a wide variety of xenobiotics (i.e., chemi-
cals that are foreign to the living organism), including
toxins ingested with food, environmental pollutants,
and carcinogens, as well as drugs. Among the most im-
portant liver microsomal enzymes is the cytochrome
P450 (CYP450) enzyme family. Members of this class of
enzyme, which number more than 50, are responsible
for oxidizing most psychoactive drugs, including anti-
depressants, morphine, and amphetamines. Although
they are primarily found in the liver, cytochrome en-
zymes are also located in the intestine, kidney, lungs,
and nasal passages, where they alter foreign molecules.
Enzymes are classified into families and subfamilies
by their amino acid sequences, as well as by the genes
encoding them, and they are designated by a number—
letter—number sequence such as 2D6. Among the cy-
tochrome enzymes that are particularly important for
psychotropic drug metabolism are CYP450 1A2, 3A4,
2D6, and several in the 2C subfamily.
FACTORS INFLUENCING DRUG METABOLISM The
enzymes of the liver are of particular interest to psycho-
pharmacologists because several factors significantly
influence the rate of biotransformation. These factors
alter the magnitude and duration of drug effects and are
responsible for significant drug interactions. These drug
interactions can either increase bioavailability, causing
adverse effects, or reduce blood levels, which may re-
duce drug effectiveness. Additionally, variations in the
rate of metabolism explain many of the individual dif-
ferences seen in response to drugs. Factors that modify
biotransformation capacity include (1) enzyme induc-
tion, (2) enzyme inhibition, (3) drug competition, and (4)
individual differences in age, gender, and genetics.
Hydroxy-phenobarbital
Phase II
Salicylic-glucuronide
Morphine-6-glucuronide
Phase II Phase II
Oxazepam Oxazepam-glucuronide
12/9/21 2:29 PM

Many psychoactive drugs, when used repeatedly,
cause an increase in a particular liver enzyme (called
enzyme induction). Increased numbers of enzyme mol-
ecules not only cause the drugs to speed up their own
rate of biotransformation two- to threefold but also
can increase the rate of metabolism of all other drugs
modified by the same enzyme. For example, repeated
use of the antiseizure drug carbamazepine (Tegretol)
increases the number of CYP450 3A4 enzyme mole-
cules, leading to more rapid metabolism of carbamaze-
pine and many other drugs, producing a lower blood
level and a reduced biological effect. Among the drugs
metabolized by the same enzyme are oral contracep-
tives. For this reason, if carbamazepine is prescribed
to a woman who is taking oral contraceptives, she
will need an increased hormone dose or an alterna-
tive means of birth control (Zajecka, 1993). When drug
use is terminated, there is a gradual return to normal
levels of metabolism.
Another common example is cigarette smoke, which
increases CYP450 1A2 enzymes. People who are heavy
smokers may need higher doses of drugs such as an-
tidepressants and caffeine that are metabolized by the
same enzyme. Such changes in drug metabolism and
elimination explain in part why some drugs lose their
effectiveness with repeated use, a phenomenon known
as tolerance (see the discussion on tolerance later in the
chapter); these changes also cause a reduced effect of
other drugs that are metabolized by the same enzyme
(cross-tolerance). Clearly, drug-taking history can have
a major impact on the effectiveness of the drugs that an
individual currently takes.
In contrast to drug-induced induction of liver
enzymes, some drugs directly inhibit the action of en-
zymes (enzyme inhibition); this reduces the metabolism
of other drugs taken at the same time that are metab-
olized by the same enzyme. In such cases, one would
experience a much more intense or prolonged drug
effect and increased potential for toxicity. Monoamine
oxidase inhibitors (MAOIs), used to treat depression,
act in the brain by preventing the destruction of certain
neurotransmitters by the enzyme monoamine oxidase
(MAO). The same enzyme is found in the liver, where it
normally metabolizes amines such as tyramine, which is
found in red wine, beer, some cheeses, and other foods.
When individuals who are taking these antidepressants
eat foods rich in tyramine, dangerous high blood pres-
sure and cardiac arrhythmias can occur, making normal
foods potentially life-threatening. Further detail on this
side effect of MAOIs is provided in Chapter 18.
In addition, because MAOIs are not specific for
MAO, they have the potential to cause adverse effects
unrelated to MAO function. They inhibit several mi-
crosomal enzymes of the CYP450 family, producing
elevated blood levels of many drugs and potentially
causing increased side effects or unexpected toxicity.
01_Meyer4e_CH01.indd 21
Principles of Pharmacology 21
A second drug–food interaction involves the inges-
tion of grapefruit juice, which significantly inhibits
the biotransformation of many drugs metabolized by
CYP450 3A4, including numerous psychiatric medi-
cations. A single glass (5 ounces) of grapefruit juice
elevates the blood levels of those drugs significantly
by inhibiting their first-pass metabolism. The effect is
caused by chemicals in grapefruit that are not found in
oranges, such as bergamottin. Inhibition persists for 24
hours and dissipates gradually after several days, but
it can be a hazard for those taking medications daily,
because it causes significant drug accumulation.
A second type of inhibition, based on drug com­
petition for the enzyme, occurs for drugs that share
a metabolic system. Because the number of enzyme
molecules is limited, an elevated concentration of either
drug reduces the metabolic rate of the second, causing
potentially toxic levels. CYP450 metabolism of alcohol
leads to higher-than-normal brain levels of other seda-
tive–hypnotics (e.g., barbiturates or Valium) when ad-
ministered at the same time, producing a potentially
dangerous drug interaction.
Finally, differences in drug metabolism due to ge-
netic and environmental factors can explain why some
individuals seem to be extremely sensitive to certain
drugs, but others may need much higher doses than
normal to achieve an effect. Over 40 years ago, the first
genetic polymorphisms (genetic variations among indi-
viduals that produce multiple forms of a given protein)
for drug-metabolizing enzymes were identified. Large
variations, for instance, were found in the rate of acety-
lation of isoniazid, a drug used to treat tuberculosis and
subsequently found to relieve depression. Acetylation
is a conjugation reaction in which an acetyl group is at-
tached to the drug. These genetic polymorphisms that
determine acetylation rate vary across populations. For
instance, 44% to 54% of American Caucasians and Afri-
can Americans, 60% of Europeans, 10% of Asians, and
only 5% of Inuit are slow inactivators (Levine, 1973).
The enzymes that have been studied most are in the
CYP450 family, and each has multiple polymorphisms.
In that family, CYP2D6 (i.e., CYP450 2D6) is of great in-
terest because it is responsible for metabolizing numer-
ous psychotropic drugs, including many antidepres-
sants, antipsychotics, antihistamines, muscle relaxants,
opioid analgesics, and others. In a recent study, swabs
of epithelial cells from the cheek linings of 31,563 in-
dividuals were taken and analyzed for the number of
copies of the gene for CYP2D6. FIGURE 1.12A shows the
distribution of samples based on the number (zero, one,
two, or three or more) of normal CYP2D6 genes (Beoris
et al., 2016; see Taylor et al., 2020, for review). A small
percentage of individuals (0.14%) are very poor metabo-
lizers and have multiple copies of a polymorphism that
is ineffective in metabolizing substrates for the CYP2D6
enzyme. Intermediary metabolizers make up 7.25% of
12/9/21 2:29 PM
 22 Chapter 1

(A) Potential adverse Nonresponders FIGURE 1.12 Four genetic populations based on the number of
response to medication normal CYP2D6 genes (A) Percentage of samples containing zero,
100 one, two, and three or more copies of the normal CYP2D6 gene
87.41% from 31,563 individuals. PM, poor metabolizers; IM, intermediary
90
80
metabolizers; EM, extensive metabolizers; UM, ultrarapid metabo-
Percentage of samples

lizers. (B) Percentage of samples containing one, two, and three

70
or more copies of the normal CYP2D6 gene in self-reported
60 ethnic groups: Caucasians (yellow), African Americans (no-fill),
50 Asians (red hatch marks), Hispanics (blue hatch marks). (After
40 M. Beoris et al. 2016. Pharmacogenet Genomics 26 [2]: 96–99.
30 doi.org/10.1097/FPC.0000000000000188)
20
7.25% 5.21%
10
0.14%
0
0 Copy 1 Copy 2 Copies ≥3 Copies
PM IM EM UM

(B)
100
88.87% 86.89% 88.39%
90 Caucasian
77.17% African American
Percentage of samples

80
Asian
70 Hispanic
60
50
40
30
20 13.40%
6.33% 6.52% 8.82% 9.09% 6.52%
10 4.69% 2.71%
0
1 Copy 2 Copies ≥3 Copies
IM EM UM

the population tested and have one deficient allele and
one normal allele. These two clusters of individuals
having poorer metabolism would be expected to have
greater bioavailability of those drugs, which may be re-
sponsible for adverse drug reactions or toxicity. These
individuals would benefit from a reduction in drug dos-
age. Approximately 87% of the individuals are exten-
sive metabolizers and have two normal alleles. They are
considered extensive metabolizers because the normal
enzyme is highly functional and efficient. The fourth
group (5.21% of the population tested) are ultrarapid
metabolizers and have multiple (three or more) normal
gene copies. The ultrarapid group would be expected to
have
Meyersignificantly
4e lower blood levels of drug than nor-
mal, which may make them nonresponders to the medi-
Psychopharmacology
cation. Hence,
Dragonfly Mediathese
Groupindividuals would benefit from
higher
Sinauer drug dosage. Such differences are significant
Associates
because there may
Meyer4e_1.12 be as much as a 1000-fold difference
9-16-21
in rate of metabolism for a particular drug among these
individuals. In addition, the data showed there are dif-
ferent distributions of these genotypes in different pop-
ulations. FIGURE 1.12B shows the data for one or more
copies of the normal gene (the samples with zero copies
are not shown) broken down by self-reported ethnicity
(about two-thirds of the individuals provided data on
ethnicity). The data show that the frequency of individ-
uals with two copies of CYP2D6 was significantly lower
in African Americans than in the other ethnic groups
and that the percentage of individuals with one copy
was 1.5 to 2.1 times higher in that group. Additionally,
the percentage of individuals with three or more copies
among African American was 1.4 to 3.4 times higher.
These differences indicate greater variation in CYP2D6
metabolism in African Americans, which puts some at
greater risk for adverse side effects and others at risk
for inadequate response to psychotropic medications.
Further discussion of this topic can be found at the end
of the chapter in the section Pharmacogenetics and Per-
sonalized Medicine.
Other enzymes also show wide genetic differences.
For example, approximately 50% of certain Asian groups
(Chinese, Japanese, and Koreans) have reduced capacity
to metabolize acetaldehyde, which is an intermediary
metabolic step in the breakdown of alcohol. The result-
ing elevation in acetaldehyde causes facial flushing,
tachycardia, a drop in blood pressure, and sometimes
nausea and vomiting. The reduced metabolic capacity is
caused by a specific mutation in the gene for aldehyde
dehydrogenase (Wall and Ehelers, 1995).
Along with variations in genes, other individual dif-
ferences may influence metabolism. Significant changes
in nutrition or in liver function, which accompany vari-
ous diseases, lead to significantly higher drug blood lev-
els and prolonged and exaggerated effects. Advanced

01_Meyer4e_CH01.indd 22 12/9/21 2:29 PM


age is often accompanied by a reduced ability to me-
tabolize drugs, while children under age 2 also have in-
sufficient metabolic capacity and are vulnerable to drug
overdose. In addition, both the young and the elderly
have reduced kidney function, so clearance of drugs for
them is much slower. Sex differences in drug metabo-
lism also exist. For example, the stomach enzymes that
metabolize alcohol before it reaches the bloodstream are
far less effective in women than in men. This means that
for an identical dose, a woman will have a much higher
concentration of alcohol reaching her blood to produce
biological effects. If you would like to read more about
some of the clinical concerns related to differences in
drug metabolism, see Applegate (1999).
RENAL EXCRETION Although drugs can be excret-
ed from the body in the breath, sweat, saliva, feces, or
breast milk, the most important route of elimination is
the urine. Therefore, the primary organ of elimination
is the kidney. The kidneys are a pair of organs, each
about the size of a fist. They are responsible for filtering
materials out of the blood and excreting waste products.
As filtered materials pass through the kidney tubules,
necessary substances such as water, glucose, sodium,
potassium, and chloride are reabsorbed into the blood.
Most drugs are readily filtered by the kidney unless
they are bound to plasma proteins or are of large molec-
ular size. However, because reabsorption of water from
the tubules makes the drug concentration greater in the
tubules than in the surrounding blood vessels, many
drug molecules are reabsorbed back into the blood. Ion-
ization of drugs reduces reabsorption because it makes
the drugs less lipid soluble. Liver biotransformation of
drugs into ionized (water-soluble) molecules traps the
metabolites in the kidney tubules, so they can be ex-
creted along with waste products in the urine.
Reabsorption from the tubules, similar to diffu-
sion across other membranes (discussed earlier), is
pH-dependent. When tubular urine is made more al-
kaline, weak acids are excreted more rapidly because
they become more ionized and are not reabsorbed as
well; that is, they are “trapped” in the tubular urine.
If the urine is acidic, the weakly acidic drug will be
less ionized and more easily reabsorbed; thus, excre-
tion will be less. The opposite is true for a weakly basic
drug, which will be excreted more readily when tubu-
lar urine is acidic rather than basic. This principle of
altering urinary pH is frequently used in the treatment
of drug toxicity, when it is highly desirable to remove
the offending drug from the body as quickly as pos-
sible. In the case of phenobarbital poisoning, for ex-
ample, kidney excretion of this weakly acidic substance
is greatly enhanced by alkalinization of the urine with
sodium bicarbonate. This treatment leads to ioniza-
tion and trapping of the drug within the tubules, from
whence it is readily excreted. Acidifying the urine by
01_Meyer4e_CH01.indd 23
Principles of Pharmacology 23
administering IV ammonium chloride increases the
percentage of ionization of weakly basic drugs, which
enhances their excretion. For example, acidifying the
urine increases the rate of excretion of amphetamine
and shortens the duration of a toxic overdose episode.
Therapeutic drug monitoring
For a drug to be clinically effective while producing
minimal side effects, optimal blood levels and hence
drug concentration at the target site must be main-
tained throughout the treatment period. The difficul-
ties in determining the appropriate drug dosage for
initial clinical trials with humans and for veterinary
medical treatment based on preclinical laboratory ani-
mal testing are described in BOX 1.3. Optimal blood
levels must be determined in clinical trials before Food
and Drug Administration (FDA) approval. However,
wide variation in rates of absorption, metabolism, and
elimination among individuals because of differences
in gender, age, genetic profile, disease state, and drug
interactions can lead to significant differences in blood
levels. Blood levels that are too low prevent desired clin-
ical outcomes, and for individuals with higher-than-
normal blood levels, unwanted side effects and toxicity
may occur. In the future, pharmacogenetic screening of
individuals (see the section Pharmaco­genetics and Per-
sonalized Medicine in Psychiatry) will allow personal-
ized prescription of drug doses, but at present, the ap-
propriate dosage of a drug is determined most often by
the clinical response of a given individual. Under some
conditions, such as for drugs with serious side effects,
multiple blood samples are taken after drug adminis-
tration to determine plasma levels of drug or to monitor
a biological process (i.e., biomarker) for a toxic response
(therapeutic drug monitoring). Short-term blood sam-
pling may be done to establish the optimal dosage for a
patient taking a new medication. After each dosage cor-
rection by the physician, it may take some time to reach
steady state (approximately five half-lives), so monitor-
ing may continue for several days or weeks, until the
optimal dosage has been deter­m ined. For drugs that
must be taken over the life span, periodic monitor-
ing may be performed regularly. Monitoring detects
changes in pharmacokinetics due to aging, hormonal
changes during pregnancy and menopause, stress,
changes in medical condition, or addition of new med-
ications. Many of the monitored psychotropic drugs,
such as antiepileptic drugs, including carbamazepine,
some antidepressants, and drugs used as mood stabi-
lizers such as lithium and valproic acid, are taken on a
long-term basis.
Therapeutic drug monitoring is especially important
for drugs that have a narrow therapeutic index (i.e., the
dose needed for effectiveness is very similar to the dose
that causes serious side effects; see section 1.2 Pharmaco-
dynamics). Because blood levels rise to a peak and then
12/9/21 2:29 PM
 24 Chapter 1

fall to a trough just before the next administration (see
Figure 1.10), drug monitoring can ensure that the peak
remains below the blood level associated with toxic ef-
fects, while the trough remains in the therapeutic range
to maintain adequate symptom relief. Modifying the
dosage for a given individual can optimize treatment.
In addition, drug monitoring can be used to determine
whether the individual is taking the drug according to
the prescribed regimen. Failure to comply with the drug
treatment protocol often can be corrected by further pa-
tient education. The American Association for Clinical
Chemistry (2020) provides additional information on
therapeutic drug monitoring at https://labtestsonline.
org/tests/therapeutic-drug-monitoring.

BOX 1.3 ■ PHARMACOLOGY IN ACTION

Interspecies Drug Dose Extrapolation
Interspecies drug dose extrapolation means
converting or scaling the appropriate dose in one
species to another species. It is vital not only in
veterinary medicine, but also in drug development
when the initial clinical trials with humans are
based on preclinical testing in laboratory animals.
It is also significant in the laboratory in order to
replicate results from one species in another. The
goal of dose extrapolation is to find the optimal

© iStock.com/Oppdowngalon
dose for effectiveness and safety. See Sharma and
McNeill (2009) for a full discussion.
Comparing the sizes of the animals is the most Meyer 4e
obvious approach to scaling a drug dose to a dif- Psychopharmacology
ferent species, but it is not the only factor. Using
size alone can have disastrous consequences, as Sinauer Associates
Meyer4e_Bx1.03 7-22-21
shown by the tragic outcome in Tusko, a 14-year-old
Asiatic elephant housed in the Lincoln Park Zoo in
Oklahoma City (West et al., 1962). The researchers
used only the difference in weight to scale the dose for drug. For example, there are major variations among
the elephant from previous experiments with cats. If species in the CYP450 enzyme family amino acid
the elephant’s sensitivity to the hallucinogenic lysergic sequences. The varied enzyme structures determine
acid diethylamide (LSD) resembled that of humans, which drug substrates are acted upon by the enzyme.
the 297 mg given to the elephant would have been an Another example of varied metabolism is conjugation
enormous overdose. Almost immediately after the with glucuronide, which is important and efficient in
drug was injected into the rump of the 3.5-ton elephant humans, while cats lack glucuronidation. Rats are
with a dart rifle, he stormed around his pen, appear- Meyer very4eefficient acetylators, but dogs lack acetylation,
ing uncoordinated before he collapsed, defecated, and Psychopharmacology
while humans are intermediate between the two. It is
had continuous seizures. His tongue turned blue and heDragonfly
clear that these
Media differences will lead to variations in
Group
struggled to breathe, dying shortly later of strangula- Sinauer
the blood
Associates of drug in different species.
levels
tion. There were efforts to save him, but the drugs usedMeyer4e_Bx1.03
In addition to8-30-21
differences in weight and pharmaco-
may have instead contributed to his death. One must kinetic factors, drug targets also contribute to varia-
conclude that the elephant’s sensitivity to LSD more tions in interspecies response to administered drugs.
closely resembled that of humans than of felines. CNS neurotransmitters are differentially distributed
There are many pharmacokinetic and pharmacody- in the brains of various species, and differences in
namic factors that are unrelated to size yet vary signif- the number, affinity, distribution, and regulation of
icantly among species. For example, protein binding at receptors likely explain dramatic differences in drug
silent depots varies greatly among species because of response. For example, opiate analgesics such as
differences in affinity to and number of binding sites. morphine cause CNS depression in primates, dogs,
Hence, for any drug that shows high depot binding in and rats but induce excitation in horses and cats.
one species, using weight alone to determine dose These pharmacodynamic factors are not related to the
would be ineffective, whereas correction for the extent size of the animal, so to adequately convert the drug
of protein binding would increase accuracy. Complex dose, one should have some understanding of the
interspecies differences in drug metabolism are also receptor characteristics of each species.
key factors in differences in bioavailability of a given

01_Meyer4e_CH01.indd 24 12/9/21 2:29 PM

Another random document with
no related content on Scribd:
abandonné, — Frontin était le nom du destrier. — Bradamante le
prit, et l’envoya à Montauban, avec recommandation expresse de ne
le laisser monter que rarement et de le conduire toujours au pas, de
sorte qu’il était plus brillant et plus gras que jamais.
Elle se met aussitôt à l’œuvre avec toutes ses dames, toutes ses
damoiselles, et, par un subtil labeur, elle fait tracer sur une soie
blanche et noire une broderie d’or fin ; elle en recouvre et en orne la
selle et la bride du bon destrier ; puis elle choisit une de ses
suivantes, fille de sa nourrice Callitrésie, et confidente de tous ses
secrets.
Elle lui avait raconté mille fois combien l’image de Roger était
empreinte dans son cœur ; elle avait exalté sa beauté, son courage,
ses grâces au-dessus des dieux. Elle la fait venir près d’elle et lui
dit : « — Je ne puis choisir un meilleur messager pour une telle
mission ; car je ne connais pas d’ambassadeur plus fidèle et plus
prudent que toi, ma chère Hippalque. — »
La donzelle s’appelait Hippalque. Bradamante lui apprend où elle
doit se rendre ; elle l’informe pleinement de tout ce qu’elle aura à
dire à son cher seigneur ; elle lui fera ses excuses de n’être point
allée elle-même au monastère ; ce n’est pas qu’elle songe à renier
sa promesse, mais elle en a été empêchée par la fortune plus forte
que la volonté humaine.
Elle la fait monter sur une haquenée et lui met à la main la riche
bride de Frontin. Elle lui dit que, s’il se trouve sur son chemin
quelqu’un d’assez lâche ou d’assez insensé pour vouloir le lui
enlever, elle n’a qu’à dire à qui appartient le destrier, car elle ne
connaît pas de chevalier, quelque hardi qu’il soit, qui ne tremble au
nom de Roger.
Elle la charge d’une foule d’autres recommandations pour Roger.
Après les avoir attentivement écoutées, Hippalque se met en route
sans plus de retard. Elle chevauche pendant plus de dix milles, à
travers les chemins, les champs et les forêts obscures et épaisses,
sans que personne vienne l’arrêter ou lui demander où elle va.
 Vers le milieu du jour, sur le penchant d’une montagne, et dans
un sentier étroit et malaisé, elle rencontre Rodomont, tout armé, qui
suivait à pied un tout petit nain. Le Maure lève sur elle un front
hautain et blasphème toute la hiérarchie des dieux, de ce qu’un si
beau destrier, si bien caparaçonné, ne se trouve pas entre les mains
d’un chevalier.
Il avait juré d’enlever de force le premier cheval qu’il rencontrerait
sur sa route. Or celui-ci est le premier qu’il ait rencontré, et il se
trouve justement qu’il n’en a jamais vu de plus beau. Mais l’enlever à
une damoiselle lui semble une félonie ; pourtant il brûle de l’avoir. Il
hésite ; il le regarde, il le contemple et s’écrie : « — Ah ! pourquoi
son maître n’est-il pas avec lui ? — »
« — S’il y était, — réplique Hippalque, — il te ferait peut-être
changer d’idée. Ce cheval appartient à quelqu’un qui vaut mieux que
toi, à un guerrier qui n’a point son pareil au monde. — » « — Quel
est donc celui qui dépasse ainsi tous les autres en valeur ? — » dit
le Maure. « — C’est Roger, — » lui répond-elle. Alors Rodomont : «
— Je veux ce destrier, puisque c’est à Roger, à un tel champion que
je le prends.
« S’il est vrai, comme tu le dis, qu’il soit si fort, et qu’il l’emporte
en vaillance sur tous les autres, ce n’est pas seulement le cheval,
mais la voiture que je devrai lui rendre et dont je lui payerai le prix
selon sa convenance. Tu peux lui dire que je suis Rodomont, et que,
s’il veut en venir aux mains avec moi, il me trouvera ; partout où je
vais, partout où je demeure, l’éclat de mon nom me fait assez
reconnaître.
« Partout où je vais, il reste de mon passage de telles traces, que
la foudre n’en laisse pas de plus grandes après elle. — » Ainsi
disant, il avait saisi les rênes dorées du coursier. Il saute sur son
dos, et laisse Hippalque tout en larmes et défaillante de douleur. Elle
menace Rodomont et lui fait honte ; mais il ne l’écoute pas, et gravit
la montagne.
Il suit le chemin par lequel le nain le conduit à la recherche de
Mandricard et de Doralice. Hippalque le suit de loin, l’accablant de
malédictions et de menaces. On verra plus loin ce qu’il advint de
cela. Turpin, qui a écrit toute cette histoire, fait ici une digression
pour retourner à l’endroit où le Mayençais avait été mis à mort.
La fille d’Aymon vient à peine de quitter ces lieux, que Zerbin y
arrive par un autre sentier, accompagné de la méchante vieille. Il voit
le corps d’un chevalier étendu au milieu du vallon et ne sait qui ce
peut être. Mais, comme il est sensible et courtois, il est ému de pitié
à ce triste spectacle.
Pinabel était étendu par terre, perdant son sang par tant de
blessures qu’il n’y en aurait pas eu davantage si plus de cent épées
se fussent réunies pour lui donner la mort. Le chevalier d’Écosse
s’empresse de suivre les traces toutes fraîches, pour tâcher de
savoir qui avait commis le meurtre.
Il dit à Gabrine de l’attendre et qu’il reviendra bientôt la retrouver.
Celle-ci s’approche du cadavre et l’examine attentivement de tous
côtés, pour voir s’il n’a pas sur lui quelque objet précieux dont il
serait inutile de laisser plus longtemps un mort se parer. La vieille,
parmi tous ses autres vices, était aussi avare qu’une femme peut
l’être.
Si elle pouvait dissimuler le vol de pareils objets, elle enlèverait
bien la riche soubreveste, ainsi que les belles armes. Mais elle doit
se contenter de dérober ce qui peut facilement se cacher, et elle
abandonne le reste à regret. Elle choisit, parmi les autres dépouilles,
une belle ceinture, et se l’attache autour de la taille, entre ses deux
jupons.
Peu après arrive Zerbin. Il a en vain suivi les pas de Bradamante,
car le sentier se divise en plusieurs branches qui montent ou
descendent. Le jour baisse, et il ne veut pas rester au milieu de ces
rochers en pleine obscurité ; suivi de la méchante vieille, il se hâte
donc de s’éloigner de la funèbre vallée pour chercher un logis.
Près de deux milles plus loin, ils trouvent un grand château
appelé Hauterive. Ils s’y arrêtent pour y passer la nuit, qui déjà
envahissait le ciel d’un vol rapide. Ils y sont à peine installés, que de
tous côtés les lamentations frappent leurs oreilles, et qu’ils voient les
pleurs couler de tous les yeux, comme s’il s’agissait d’une
catastrophe publique.
Zerbin en demande la cause. On lui dit qu’avis vient d’être donné
au comte Anselme que son fils Pinabel a été trouvé étendu sans vie
entre deux montagnes, dans un étroit sentier. Zerbin, pour éviter que
les soupçons ne se portent sur lui, feint d’apprendre une chose
nouvelle et baisse les yeux ; mais il pense bien que le cadavre qu’il a
trouvé sur sa route doit être celui de Pinabel.
Bientôt arrive le brancard funèbre, à la lueur des torches et des
flambeaux. Alors les cris redoublent, les battements de mains
retentissent jusqu’aux étoiles, et les larmes coulent plus abondantes
des paupières. Mais, plus que tous les autres, le visage du
malheureux père dénote un sombre désespoir.
Cependant on apprête de solennelles et pompeuses funérailles,
selon l’usage antique que chaque génération voit peu à peu se
perdre. Le châtelain fait publier un ban par lequel il promet une riche
récompense à celui qui lui fera connaître le meurtrier de son fils. Ce
ban interrompt un instant les lamentations du populaire.
De voix en voix, d’une oreille à l’autre, la promesse annoncée par
le ban se répand dans toute la contrée. Elle parvient jusqu’à la vieille
scélérate qui dépasse en férocité les tigres et les ours. Aussitôt elle
saisit cette occasion de perdre Zerbin, soit pour satisfaire sa haine,
soit pour montrer que tout sentiment humain est banni de son cœur,
Soit pour gagner la récompense promise. Elle s’en va trouver le
malheureux châtelain, et, après un préambule qu’elle tâche de
rendre le plus vraisemblable possible, elle lui dit que c’est Zerbin qui
a commis le crime. Elle lui montre la belle ceinture que le père
infortuné reconnaît sur-le-champ. Après ce témoignage et la
déclaration de l’horrible vieille, tout lui paraît clair.
Pleurant, il lève ses mains vers le ciel, et jure que son fils ne
restera pas sans vengeance. Il fait cerner l’appartement de son hôte
par ses vassaux, qui sont accourus en toute hâte. Zerbin est loin de
se croire entouré d’ennemis, et ne s’attend pas au traitement que lui
ménage le comte Anselme, qui se croit si outragé par lui ; il est
plongé dans le premier sommeil lorsqu’on le saisit.
On l’enchaîne, on le plonge dans un cachot ténébreux, et le soleil
n’a pas encore reparu que son injuste supplice est déjà ordonné ; il
est condamné à être écartelé dans le lieu même où a été commis le
crime qu’on lui impute. On ne se préoccupe pas d’examiner plus
attentivement s’il est coupable ou non ; il suffit que le châtelain le
croie ainsi.
Le lendemain, dès que la belle aurore vient colorer l’horizon de
couleurs blanches, rouges et jaunes, on se dispose à punir Zerbin
de son prétendu crime. La populace, aveugle et sanguinaire,
l’accompagne hors du château en criant : Qu’il meure ! qu’il meure !
Toute cette foule va sans ordre, les uns à pied, les autres à cheval.
Quant au chevalier d’Écosse, il s’avance la tête basse, lié sur un
petit roussin.
Mais Dieu, qui, la plupart du temps, vient en aide aux innocents
et n’abandonne jamais celui qui se fie en sa bonté, lui a déjà trouvé
un défenseur tel qu’il n’y a plus à craindre de le voir mourir en ce
jour. Roland arrive, conduit sur ce chemin par la Providence, afin de
sauver Zerbin. Roland aperçoit dans la plaine cette foule qui traîne à
la mort le dolent chevalier.
Avec lui est la jeune fille qu’il a trouvée dans une grotte sauvage,
Isabelle, la fille du roi de Galice, tombée au pouvoir des malandrins
après avoir échappé à la tempête et aux fureurs de la mer qui ont
brisé son navire. C’est celle que Zerbin porte dans son cœur et qui
lui est plus chère que sa propre vie.
Roland l’avait emmenée avec lui en quittant la caverne. Isabelle
demande à Roland quelle est cette foule qu’elle aperçoit dans la
campagne. « — Je ne sais pas, — » dit-il. Puis il la laisse sur la
colline et descend rapidement dans la plaine. Il regarde Zerbin, et à
première vue il le tient pour un chevalier de grande estime.
Il s’approche, il lui demande pourquoi il est enchaîné, et où on le
conduit. Le dolent chevalier lève la tête, et, après avoir écouté ce
que lui dit le paladin, il lui raconte la vérité ; il la lui expose avec un
tel accent de sincérité que le comte le juge digne de sa protection,
persuadé qu’il est innocent et qu’il n’a point mérité la mort.
Mais, quand il apprend que l’arrêt a été rendu par le comte
Anselme d’Hauterive, il ne doute plus de son injustice, car ce félon
n’a pas d’autres façons d’agir. En outre, il sent se réveiller l’antique
haine qui divise la maison de Mayence et celle de Clermont, et qui a
causé à toutes deux tant de sang, tant de ruines et tant de hontes.
« — Déliez ce chevalier, canaille, — crie le comte aux manants,
— ou je vous extermine. — » « — Quel est celui-ci qui se vante de
porter de tels coups ? — répond un des hommes d’armes qui veut
payer d’assurance. — Si nous étions de cire ou de paille et que lui-
même fût de feu, sa menace pourrait peut-être nous épouvanter. —
» Et il se précipite sur le paladin de France, qui abaisse sa lance
contre lui.
Le Mayençais avait sur son dos la brillante armure enlevée
pendant la nuit à Zerbin ; mais elle ne peut le défendre contre le
coup terrible porté par le paladin et qui le frappe à la joue droite. Le
casque n’est point entamé, car il est de fine trempe, mais le choc est
si grand, que le malheureux a le cou rompu et tombe mort.
Roland poursuit sa course ; sans déranger sa lance, il en
transperce un autre de part en part. Puis il la jette, tire Durandal et
se précipite au plus épais de la troupe ; à l’un, il fend la tête en deux ;
à l’autre il la coupe net au ras du buste ; il perce la gorge à plusieurs
autres ; en un clin d’œil, il en tue ou il en met en fuite plus de cent.
Plus du tiers est mort ; Roland chasse le reste ; il taille, il fend, il
transperce, il déchire ; les malheureux jettent pour fuir tout ce qui les
embarrasse : les écus, les épées, les épieux, les serpes ; les uns se
dispersent au loin, les autres courent le long du chemin ; d’autres se
cachent dans les bois et dans les cavernes. Roland, sans pitié ce
jour-là, ne veut pas en laisser échapper un seul vivant.
Sur cent vingt, — c’est Turpin qui a fait le compte, — quatre-
vingt-dix au moins périrent. A la fin, Roland revient vers Zerbin, dont
le cœur tressaille d’impatience dans la poitrine. Si celui-ci éprouva
une vive allégresse en voyant revenir Roland, cela ne se peut
raconter pleinement en ces vers ; il se serait prosterné pour
l’honorer, mais il se trouvait lié sur le roussin.
Roland le délie et l’aide à revêtir ses armes, qu’il a reprises au
capitaine de la troupe, auquel elles n’ont pas porté bonheur. Pendant
ce temps, Zerbin lève les yeux sur Isabelle, restée sur le sommet de
la colline, et qui, voyant le combat terminé, s’est avancée plus belle
que jamais.
Lorsque Zerbin voit s’approcher la dame qu’il a tant aimée, la
belle dame qu’il croyait, sur la foi d’une fausse nouvelle, engloutie
dans les flots, et qu’il a si longtemps pleurée, il sent un froid glacial
lui serrer le cœur ; tout son corps tremble ; mais bientôt le frisson fait
place aux feux ardents de l’amour.
La reconnaissance qu’il doit au seigneur d’Anglante l’empêche
de se jeter dans ses bras, car il pense que Roland est devenu
l’amant de la damoiselle. La joie qu’il a d’abord éprouvée dure peu,
et fait place à une peine plus amère ; il a moins souffert quand il a
appris qu’elle était morte, qu’en la voyant aux mains d’un autre.
Ce qui lui cause le plus de douleur, c’est qu’elle appartienne au
chevalier à qui il doit tant. Essayer de la lui enlever ne serait ni
honnête ni chose facile sans doute. Il ne laisserait certainement à
personne autre une telle proie sans la lui disputer ; mais une telle
reconnaissance le lie envers le comte, qu’il est forcé de courber la
tête.
Ils arrivent tous les trois, sans s’être dit une parole, près d’une
fontaine où ils descendent de cheval pour se reposer un instant. Le
comte, fatigué, enlève son casque et invite Zerbin à retirer aussi le
sien. La dame, qui reconnaît son amant, pâlit soudain de joie ; mais
elle se ranime vite, comme la fleur, après une grande pluie, au retour
du soleil.
Et, sans plus attendre, sans la moindre fausse honte, elle court à
son cher amant et lui jette les bras autour du cou. Elle ne peut
prononcer une parole, mais elle lui baigne de larmes le sein et la
figure. Roland, à la vue de ces transports, n’a pas besoin d’autre
explication pour comprendre que le chevalier qu’il a sauvé n’est
autre que Zerbin.
Dès que la voix lui est revenue, Isabelle, les joues encore
humides de pleurs, raconte à Zerbin tout ce qu’elle doit à la
courtoisie du paladin de France. Zerbin, qui chérit la damoiselle à
l’égal de sa vie, se jette aux pieds du comte, et lui rend grâce de lui
avoir deux fois rendu la vie en une heure.
Les remerciements et les offres de services auraient pu durer
longtemps entre les deux chevaliers, s’ils n’avaient entendu du bruit
à travers les arbres du feuillage épais et sombre. Ils s’empressèrent
de remettre leurs casques sur leurs têtes et de remonter à cheval. A
peine étaient-ils en selle, qu’ils virent arriver un chevalier
accompagné d’une damoiselle.
Ce guerrier était Mandricard, qui suivait les traces de Roland, afin
de venger Alzire et Manilard, que le paladin avait si vaillamment
renversés. Sa poursuite, d’abord fort active, s’était sensiblement
ralentie, du moment où il avait eu Doralice en son pouvoir, après
l’avoir enlevée avec un tronçon de lance, à plus de cent guerriers
bardés de fer.
Le Sarrasin ignorait que celui qu’il poursuivait fût le seigneur
d’Anglante, mais tout semblait indiquer que c’était un illustre
chevalier errant. Il ne fait pas attention à Zerbin ; ses yeux, au
contraire, examinent le comte de la tête aux pieds, et retrouvant tous
les indices qu’on lui en a donnés : « — Tu es celui que je cherche,
— » dit-il.
« — Voilà dix jours, — ajoute-t-il, — que je suis tes traces, excité
par le bruit de tes exploits, qui est parvenu jusqu’au camp devant
Paris. Le seul survivant des mille guerriers que tu as taillés en
pièces y est arrivé après de grandes fatigues, et a raconté le
carnage que tu as fait des soldats de Noricie et de ceux de
Trémisen.
« Dès que je l’appris, je m’empressai de me mettre à ta
poursuite, pour te connaître et me mesurer avec toi. Je m’informai
des insignes que tu portes sur tes armes, et c’est toi, je le sais. A
défaut de ces indications, je te reconnaîtrais au milieu de cent
autres, rien qu’à ta fière prestance. — »
« — On ne peut dire, — lui répond Roland, — que tu ne sois pas
un chevalier de grande vaillance, car, à mon avis, un dessein si
magnanime ne saurait naître en un cœur vil. Si c’est le désir de me
voir qui t’a fait venir, je veux que tu me voies à visage découvert,
comme tu as vu mes armes ; je vais ôter mon casque, afin que ton
envie soit satisfaite.
« Mais quand tu m’auras bien vu en face, il te restera encore à
satisfaire le second désir qui t’a fait suivre mon chemin, c’est-à-dire
à voir si ma valeur répond à cette fière prestance que tu admires
tant. — » « — Maintenant, — dit le païen, — que tu m’as satisfait
entièrement sur le premier point, venons au second. — »
Cependant le comte examine le païen des pieds à la tête ; il
regarde à la ceinture, à l’arçon, et n’y voit pendre ni masse d’armes
ni épée. Il lui demande de quelle arme il compte se servir, si sa lance
vient à se rompre. L’autre lui répond : « — Ne t’inquiète point de
cela. Avec cette seule lance j’ai déjà fait peur à beaucoup d’autres.
« J’ai juré de ne point ceindre d’épée que je n’aie enlevé
Durandal au comte. Je vais, le cherchant par tous les chemins, afin
qu’il ait à faire plus d’une pose avec moi. Je l’ai juré, si tu tiens à le
savoir, le jour où je plaçai sur mon front ce casque, lequel, ainsi que
toutes les autres armes que je porte, ont appartenu à Hector, mort il
y a déjà mille ans.
« L’épée seule manque à ces bonnes armes. Comment fut-elle
dérobée, je ne saurais te le dire. Il paraît que le paladin la possède
aujourd’hui, et c’est là ce qui lui donne une si grande audace. Je
compte bien, si je puis me mesurer avec lui, lui faire rendre un bien
mal acquis. Je le cherche aussi dans le but de venger mon père, le
fameux Agrican.
« Roland lui donna traîtreusement la mort ; sans cela, je sais bien
qu’il n’aurait pu le vaincre. — » Le comte ne peut se taire
davantage ; il s’écrie d’une voix forte : « — Toi, et quiconque dit cela,
en avez menti. Mais celui que tu cherches, le hasard l’a conduit vers
toi. Je suis Roland, et j’ai tué ton père en loyal combat. Voici l’épée
que tu cherches aussi. Elle t’appartiendra si tu la mérites par ta
vaillance.
« Bien qu’elle m’appartienne à bon droit, je consens à ce qu’elle
soit le prix de notre lutte. Mais je ne veux pas que, dans ce combat,
elle me serve plus qu’à toi. Je la suspends à cet arbre. Tu pourras la
prendre librement, s’il advient que tu me tues ou que tu me fasses
prisonnier. — » Ainsi disant, il prend Durandal et la suspend à un
arbre, au milieu du chemin.
Ils s’éloignent à une demi-portée de flèche, poussent leurs
destriers l’un contre l’autre, en leur lâchant les rênes, et se frappent
tous deux, en pleine visière, d’un coup terrible. Les lances se
rompent et volent en mille éclats vers le ciel.
Les deux lances sont forcées de se rompre, car les cavaliers ne
veulent plier ni l’un ni l’autre, et reviennent au combat avec les
tronçons qui sont restés intacts. Les deux adversaires, qui n’ont
jamais manié que le fer, font maintenant un terrible usage de leurs
tronçons de lance, semblables à deux paysans qui se battent pour la
possession d’un ruisseau ou la délimitation d’un pré.
Au quatrième choc, les tronçons mêmes viennent à leur
manquer ; mais leur colère n’en devient, à l’un comme à l’autre, que
plus bouillante. Il ne leur reste pour se frapper que leurs poings.
Partout où leurs doigts peuvent s’accrocher, ils ouvrent les cuirasses
ou déchirent les mailles. Les lourds marteaux et les fortes tenailles
ne feraient pas mieux.
Le Sarrasin cherche comment il pourra terminer à son honneur
ce combat acharné ; ce serait folie de perdre son temps à se frapper
de la sorte, car les coups sont plus douloureux pour celui qui les
donne que pour celui qui les reçoit. Ils se saisissent tous les deux
corps à corps. Le roi païen serre Roland à la poitrine ; il croit
l’étouffer comme le fils de Jupiter étouffa jadis Antée.
Il le prend impétueusement de côté, le heurte, l’attire à lui, et son
animosité est si grande, qu’il ne prend point garde à la bride de son
cheval. Roland, plus maître de lui, en fait son profit et en espère la
victoire ; il pose doucement la main sur les yeux du cheval de
Mandricard et fait tomber la bride.
Le Sarrasin fait tous ses efforts pour étouffer Roland ou pour
l’enlever de selle ; le comte tient les genoux serrés, et ne plie ni d’un
côté ni de l’autre. Enfin, sous les secousses du païen, la sangle de
sa selle vient à casser, et Roland tombe à terre sans s’en apercevoir,
car il a toujours les pieds aux étriers, et il serre encore la selle avec
ses cuisses.
Le comte, en touchant la terre, produit le même bruit que si
c’était un trophée d’armes qui serait tombé. Le destrier de
Mandricard, qui a la tête libre, et dont la bouche est débarrassée du
frein, fuit ventre à terre, à travers les bois et les halliers, poussé deçà
et delà, par une terreur aveugle, et emportant son maître.
Doralice, qui voit son compagnon s’éloigner du champ de
bataille, craint de rester abandonnée et court derrière lui de toute la
vitesse de son roussin. Le païen, furieux, crie après son destrier ; il
le frappe avec les pieds et avec les mains ; comme s’il n’avait point
affaire à une bête, il le menace, croyant l’arrêter, mais il ne fait
qu’accélérer sa fuite.
La bête, pleine d’épouvante, affolée, court à travers champs,
sans regarder devant elle. Déjà elle avait couru plus de trois milles,
et elle aurait continué, si un fossé ne se fût rencontré sur son
chemin ; cheval et cavalier tombent au plus profond, où ils ne
trouvent ni litière ni lit de plume. Mandricard éprouve une secousse
terrible, mais il ne se rompt point les os.
Enfin le coursier s’arrête ; mais son maître ne peut le guider, car il
n’a plus de mors. Le Tartare le tient par la crinière, plein de fureur et
de colère. Il ne sait quel parti prendre. « — Mets-lui la bride de mon
palefroi, — lui dit Doralice, — le mien n’est point fougueux, et l’on
peut facilement le conduire avec ou sans frein. — »
Le Sarrasin regarde comme peu courtois d’accepter l’offre de
Doralice ; mais, grâce au frein qu’elle lui propose, il pourra
poursuivre son chemin et trouver une occasion plus propice. Sur ces
entrefaites, ils sont rejoints par la scélérate, l’infâme Gabrine,
laquelle, après avoir trahi Zerbin, fuyait comme une louve qui entend
venir les chasseurs et les chiens.
Elle avait encore sur elle les vêtements et les riches parures qui
avaient été enlevés à la maîtresse de Pinabel et que Marphise lui
avait donnés, ainsi que le palefroi de la vicieuse donzelle, qui
pouvait compter parmi les meilleurs. La vieille arrive sur le Tartare
avant de s’apercevoir de sa présence.
Les vêtements de jeune fille qu’elle porte excitent le rire de la fille
de Stordilan et de Mandricard, car ils la font ressembler à une
guenon, à un babouin. Le Sarrasin imagine de lui enlever sa bride
pour la mettre à son destrier. Le mors enlevé, il effraye le palefroi par
ses menaces et ses cris, et le met en fuite.
Le palefroi fuit à travers la forêt, emportant la vieille quasi morte
de peur ; il franchit les vallées, les collines, les fossés et les ravins,
courant à l’aventure, à droite et à gauche. Mais il m’importe trop peu
de vous parler de Gabrine, pour que je ne m’occupe plus de Roland,
qui a bien vite réparé les dégâts faits à sa selle.
Il remonte sur son destrier, et attend un grand moment que
Mandricard revienne. Ne le voyant point reparaître, il se décide à le
chercher. Mais, en homme habitué aux manières courtoises, le
paladin ne s’éloigne pas avant d’avoir pris congé des deux amants,
et d’avoir échangé avec eux de douces et affectueuses paroles.
Zerbin s’afflige de son départ ; la tendre Isabelle verse des
larmes ; tous deux veulent le suivre. Mais le comte n’y consent pas,
bien que leur compagnie lui soit agréable et bonne. La raison qui le
fait se séparer d’eux, c’est qu’il n’y a pas d’action plus déshonorante
pour un guerrier à la recherche de son ennemi, que de prendre un
compagnon qui l’aide et le défende.
Il les prie seulement de dire au Sarrasin, s’ils le rencontrent avant
lui, que Roland restera encore trois jours dans les environs, et
qu’ensuite il reprendra son chemin pour rejoindre la bannière aux
beaux lys d’or et regagner l’armée de Charles. Ainsi, pour peu qu’il le
veuille, Mandricard saura où le trouver.
 Tous deux promettent de le faire volontiers, ainsi que tout ce qu’il
lui plaira de leur commander. Puis les chevaliers suivent chacun des
chemins divers, Zerbin d’un côté, le comte Roland de l’autre. Mais,
avant de se mettre en route, le comte reprend son épée suspendue
à l’arbre, et pousse son destrier du côté où il pense avoir le plus de
chances de rencontrer le païen.
La course désordonnée que le cheval du Sarrasin fournit à
travers le bois, sans suivre aucun chemin, fait que Roland le cherche
en vain pendant deux jours. Il ne peut retrouver ses traces. Enfin il
arrive sur le bord d’un ruisseau, au milieu d’un grand pré émaillé de
fleurs aux couleurs jeunes et vives, et ombragé par une multitude de
beaux arbres.
Là, pendant les chaleurs de midi, les troupeaux et les pasteurs à
moitié nus venaient goûter une agréable fraîcheur. Roland, bien qu’il
ait sur lui sa cuirasse, son casque et son écu, éprouve comme un
frisson. Il s’arrête pour s’y reposer un peu ; mais, hélas ! une cruelle
et terrible déception l’attend dans ce séjour, qui doit être plus funeste
que je ne saurais dire, et c’est en un jour de malheur qu’il y est venu.
En regardant tout autour de lui, il voit des inscriptions gravées sur
la plupart des arbres qui ombragent cette rive. Dès qu’il y a jeté un
peu plus attentivement les yeux, il les reconnaît pour être de la main
de sa déesse. C’était en effet un des endroits que j’ai déjà décrits, et
où la belle reine du Cathay venait souvent avec Médor, de la
chaumière du pasteur située non loin de là.
Il voit les noms d’Angélique et de Médor entrelacés de cent
nœuds et en plus de cent endroits. Chaque lettre dont ces noms
sont formés est comme un clou avec lequel Amour lui perce et lui
déchire le cœur. Il va roulant mille pensées en son esprit, et
cherchant à se persuader qu’il se trompe, que c’est une autre
qu’Angélique qui a gravé son nom sur l’écorce de ces arbres.
Puis il dit : « — Je connais pourtant bien ces caractères ; j’en ai
tant de fois vu et lu de semblables ! Elle a peut-être imaginé ce nom
de Médor pour me désigner sous un pseudonyme. — » Par ces
suppositions si éloignées de la vérité, et cherchant à se tromper lui-
même, le malheureux Roland conserve quelque espérance qu’il ne
tarde pas à chasser lui-même de son cœur.
Mais plus il cherche à étouffer ce soupçon mauvais, plus il le
rallume et plus il le renouvelle, tel que l’imprudent oiseau qui est
venu donner dans un filet ou qui s’est posé sur des gluaux, et qui
s’embarrasse ou s’englue de plus en plus à mesure qu’il bat des
ailes pour se délivrer. Roland arrive à un endroit où la montagne
surplombe en forme de grotte au-dessus de la claire fontaine.
Les lierres et les vignes grimpantes en tapissent l’entrée de leurs
lianes tordues. C’est là que les deux heureux amants avaient
coutume de passer les heures les plus chaudes de la journée,
enlacés dans les bras l’un de l’autre. Là, plus que dans aucun autre
lieu des environs, se voient leurs noms, à l’intérieur et à l’extérieur,
écrits tantôt au charbon, tantôt à la craie, ou gravés avec la pointe
d’un couteau.
Le comte, plein de tristesse, met pied à terre en cet endroit, et
voit sur l’entrée de la grotte des mots que Médor avait tracés de sa
propre main et qui paraissent fraîchement écrits. Le jeune homme
avait exprimé dans des vers le grand bonheur qu’il avait goûté dans
la grotte. Je pense que ces vers devaient être fort beaux dans sa
langue ; voici quel était leur sens dans la nôtre :
« Arbres joyeux, vertes herbes, eaux limpides, caverne obscure
aux fraîches ombres, où la belle Angélique, fille de Galafron, s’est
abandonnée si souvent nue en mes bras, après avoir été vainement
aimée par tant d’autres, comment moi, pauvre Médor, pourrai-je
vous remercier du bonheur qui m’a été donné ici, autrement qu’en
chantant à jamais vos louanges,
« Et qu’en priant tous les amoureux, nobles, chevaliers et
damoiselles, ainsi que tous ceux, paysans ou voyageurs, que le
hasard ou leur volonté conduira en ces lieux, de vous dire ceci : que
les rayons du soleil et de la lune vous soient doux, ô verte prairie,
frais ombrages, grotte, ruisseau, arbres touffus ; et que le chœur des
nymphes vous garde des pasteurs et des troupeaux ! »
 Ceci était écrit en arabe, que le comte comprenait aussi bien que
le latin. Des nombreuses langues qu’il connaissait, c’était celle-là
que le paladin possédait le mieux. Cela lui avait permis souvent
d’éviter les périls et les outrages, quand il se trouvait au milieu du
camp sarrasin ; mais il ne se vante plus des bénéfices qu’il en a
retirés jadis, car il éprouve maintenant une telle douleur, qu’elle
compense bien tous les avantages passés.
Trois, quatre et six fois, l’infortuné relit ces vers, s’efforçant en
vain d’y trouver autre chose que ce qui y est écrit ; il le voit, au
contraire, toujours plus clair et plus compréhensible. A chaque fois, il
sent son cœur comprimé dans sa poitrine comme par une main
glacée. Enfin il reste les yeux fixés sur le rocher, quoique son esprit
en soit bien loin.
Il est près de perdre la raison, tellement il se livre en proie à la
douleur. Croyez-en celui qui en a fait l’expérience, cette souffrance
surpasse toutes les autres. Le menton sur la poitrine, il courbe un
front privé d’audace. Sa douleur est si poignante, qu’il ne peut ni se
plaindre ni pleurer.
Sa douleur impétueuse, et qui veut sortir trop vite et toute à la
fois, reste concentrée dans son cœur. Ainsi nous voyons l’eau,
enfermée dans un vase au large ventre et au col resserré, rester
dans le vase quand celui-ci est renversé ; le liquide, qui voudrait
s’échapper, se presse tellement dans l’étroit goulot, que c’est à
peine si elle sort goutte à goutte au dehors.
Roland revient un moment à lui ; il pense encore que la chose
peut n’être pas vraie ; quelqu’un aura sans doute voulu diffamer le
nom de sa dame, ou lui inspirer à lui-même une telle dose de
jalousie, qu’elle le fasse mourir ; il le croit, il le désire, il l’espère.
Mais, quoi que ce soit, celui qui l’a fait a bien imité la main
d’Angélique.
Cette faible espérance ranime un peu ses esprits et rafraîchit sa
pensée. Il remonte sur Bride-d’Or. Déjà le soleil cède la place à sa
sœur. Le paladin ne chevauche pas longtemps sans apercevoir la
fumée s’échapper des toits, sans entendre aboyer les chiens et
mugir les troupeaux. Il arrive dans un village où il se décide à loger.
Il descend nonchalamment de cheval et confie Bride-d’Or aux
soins d’un garçon expérimenté. D’autres lui ôtent ses armes,
d’autres détachent ses éperons d’or, un autre enfin va fourbir sa
cuirasse. C’était justement la chaumière où l’on avait apporté Médor
blessé, et où il eut si douce aventure. Roland ne songe qu’à dormir ;
il ne demande pas à souper ; sa douleur le rassasie, et il n’a pas
besoin d’autre nourriture.
Plus il cherche le repos, plus sa peine le travaille. Il voit partout
l’odieuse inscription ; les murailles, les portes, les fenêtres en sont
couvertes ; il veut interroger son hôte, mais il retient ses questions,
car il craint de rendre trop évidente, trop claire la vérité qu’il s’efforce
de voiler, afin d’en moins souffrir.
Mais il ne lui sert de rien de ruser avec lui-même, car, sans qu’il
ait rien demandé, il trouve qui lui en parle. Le pasteur, qui le voit
accablé de tristesse, et qui voudrait le distraire, lui conte l’histoire
des deux amants. C’était un récit qu’il faisait souvent à qui voulait
l’entendre et que plusieurs avaient trouvé intéressant. Il commence,
sans en être prié, à raconter à Roland
Comment, à la prière de la belle Angélique, il avait transporté
dans sa chaumière Médor grièvement blessé ; comment elle avait
soigné sa blessure et l’avait guérie en peu de jours, et comment
Amour lui avait fait à elle-même une blessure bien plus profonde et
l’avait, avec une simple étincelle, embrasée d’un feu si cuisant
qu’elle en brûlait tout entière.
Il lui dit comment, sans souci de son rang, car elle était la fille du
plus grand roi de tout le Levant, elle fut amenée, par son ardent
amour, à devenir la femme d’un pauvre soldat. Il termine son histoire
en montrant le bracelet qu’Angélique lui a donné, en le quittant, pour
le remercier de son hospitalité.
Cette conclusion est pour Roland comme le coup de hache qui
lui détache la tête du cou. Il se voit accablé de tortures innombrables
par Amour, ce bourreau. Il s’efforce de cacher son désespoir, mais
sa peine est plus forte que lui, et il ne peut la celer. Qu’il le veuille ou
non, il faut qu’à la fin elle déborde de sa bouche et de ses yeux par
des larmes et des soupirs.
Resté seul, et n’étant plus retenu par la présence d’un témoin, il
peut lâcher le frein à sa douleur ; un fleuve de larmes lui coule des
yeux sur les joues et tombe sur sa poitrine. Il soupire, il gémit ; il se
tourne et se retourne sans cesse sur son lit, qui lui paraît plus dur
qu’un rocher et plus piquant que s’il était fait d’orties.
Au milieu de sa souffrance, la pensée lui vient que sur le même
lit où il s’agite, l’ingrate dame a dû plus d’une fois venir reposer près
de son amant. Alors il se lève précipitamment de cette couche
odieuse, comme le paysan qui s’était étendu sur l’herbe pour dormir
et qui voit un serpent à ses côtés.
Ce lit, cette maison, ce pasteur lui deviennent soudain si odieux,
que, sans attendre le lever de la lune ou celui de l’aurore avant-
courrière du jour, il prend ses armes et son destrier, et s’enfonce
dans la partie du bois la plus obscure. Puis, quand il croit être bien
seul, il ouvre les portes à sa douleur par des cris et des hurlements.
Il ne cesse de verser des pleurs, il ne cesse de pousser des cris ;
il ne goûte de repos ni la nuit ni le jour ; il fuit les bourgs et les cités,
couchant à découvert, en pleine forêt, sur la terre nue. Il s’étonne
d’avoir dans la tête une source de larmes si vivace, et qu’il puisse
pousser tant de soupirs. Souvent il se dit, à travers ses sanglots :
« — Ce ne sont plus des larmes que mes yeux répandent avec
tant d’abondance ; les larmes n’auraient pu suffire à ma douleur ;
elles ont cessé de couler alors que ma peine n’était pas même à la
moitié de sa course. Maintenant, chassé par le feu qui me dévore,
c’est le principe même de la vie qui s’enfuit et se fraye un chemin à
travers mes yeux. C’est là ce que mes yeux répandent ; c’est là ce
qui me débarrassera enfin, tout à la fois, de la douleur et de la vie.
« Ce ne sont point des soupirs par lesquels s’exhalent mes
souffrances ; les soupirs ne sont pas de cette nature ; ils s’arrêtent
parfois, et je ne sens pas que la peine s’exhale moins de ma
poitrine. Amour, qui me brûle le cœur, produit ce vent, pendant qu’il
agite ses ailes autour du feu. Amour, par quel miracle tiens-tu mon
cœur dans le feu sans le consumer jamais ?
« Et moi, je ne suis, je ne suis pas celui que je parais être. Celui
qui était Roland est mort, et la terre le recouvre. Son ingrate dame
l’a tué, tellement, dans son manque de foi, elle lui a fait une cruelle
guerre. Je suis l’âme de Roland, séparée de son corps, et qui erre
dans les tourments de cet enfer, afin que mon ombre lamentable
serve d’exemple à quiconque a placé son espérance dans Amour. —
»
Le comte erre toute la nuit par les bois ; quand pointent les
rayons de l’astre du jour, son destin le ramène vers la fontaine où
Médor a gravé la fatale inscription. La vue de sa propre honte
inscrite sur le roc l’embrase d’une telle colère, qu’il ne reste plus en
lui une seule pensée qui ne soit haine, rage ou fureur. Sans réfléchir,
il tire son épée ;
Il taille l’inscription et le rocher, dont il fait voler les éclats jusqu’au
ciel. Malheur à cette grotte et à tous les lieux où se lisent les noms
de Médor et d’Angélique ! A partir de ce jour, ils ne verseront plus
leurs ombres fraîches sur les pasteurs et sur les troupeaux. La
fontaine elle-même, naguère si claire et si pure, n’est pas à l’abri
d’une telle rage.
Il jette pêle-mêle dans ses belles eaux les branches, les troncs,
les racines, les fragments de rochers, les mottes de terre, afin de les
troubler si profondément, qu’elles ne puissent plus jamais reprendre
leur limpidité première. Enfin, harassé de fatigue, couvert de sueur,
et le souffle venant à manquer à sa haine, à sa fureur, à sa colère
ardente, il tombe sur la prairie et pousse des soupirs vers le ciel.
Brisé de douleur et de fatigue, il tombe enfin sur l’herbe. Ses
yeux regardent fixement le ciel ; il ne prononce pas une parole. Sans
manger et sans dormir, il voit ainsi le soleil disparaître et reparaître
trois fois. Sa peine amère ne fait que s’accroître, jusqu’à ce qu’elle
l’ait enfin privé de sa raison. Le quatrième jour, pris d’une grande
fureur, il s’arrache du dos et met en pièces plastron et cotte de
mailles.
 Ici reste le casque, et là reste l’écu ; au loin le harnais et plus loin
le haubert. En somme, je dois dire que toutes ses armes furent
dispersées çà et là dans le bois. Puis il déchire ses vêtements et
montre à nu son ventre velu, toute sa poitrine et son dos. Et alors
commence la grande folie, si horrible que jamais personne n’en
verra de semblable.
Sa rage, sa fureur arrivent à un tel paroxysme, qu’il ne conserve
plus la notion d’aucun sens. Il ne se souvient plus comment on tient
en main l’épée avec laquelle il aurait, je pense, pu faire encore
d’admirables choses. Mais son incomparable vigueur n’a besoin ni
d’épée ni de hache ; et il en donne de merveilleuses preuves en
déracinant, d’une seule secousse, un grand pin.
Il en arrache deux autres comme s’ils eussent été du fenouil, des
hièbles ou des aneths. Il en fait autant pour les hêtres, les ormes, les
chênes verts et les sapins. Aussi facilement que l’oiseleur, pour faire
place nette à ses filets, arrache les joncs, la paille et les orties,
Roland déracine les chênes et les vieux arbres séculaires.
Les pasteurs qui entendent un tel fracas, laissant leurs troupeaux
épars dans la forêt, accourent de tous côtés en grande hâte pour
voir ce que c’est. Mais me voici arrivé à un point que je ne dois pas
dépasser, sous peine de vous fatiguer avec mon histoire. J’aime
mieux la suspendre un instant, que de vous ennuyer par sa
longueur.
 CHANT XXIV.

Argument. — Roland donne des preuves de folie furieuse. —

Zerbin rencontre Odoric, qui avait trahi Isabelle. Il lui fait grâce de la
vie, mais, en punition de sa faute, il lui donne Gabrine à garder. Il va
à la recherche de Roland, suit ses traces et ramasse ses armes
éparses sur le sol. Survient Mandricard, accompagné de Doralice. Il
en vient aux mains avec Zerbin, pour avoir l’épée du paladin. Zerbin
est blessé à mort, et Isabelle se réfugie auprès d’un ermite. Arrive
ensuite Rodomont, qui s’attaque à Mandricard ; mais le combat est
arrêté par l’arrivée d’un messager d’Agramant qui rappelle les deux
guerriers sous les murs de Paris.

Que celui qui met le pied sur l’amoureuse glu s’empresse de le

retirer, et n’attende pas d’être englué jusqu’aux épaules. L’amour
n’est, en somme, qu’une folie, de l’avis universel des sages. Si,
comme Roland, tous ceux qui en sont atteints ne deviennent pas
furieux, leur égarement se traduit par quelque autre signe. Et quelle
marque plus évidente de folie que de s’annihiler soi-même devant la
volonté d’autrui ?
Les effets sont variés, mais la folie qui les produit est une. C’est
comme une grande forêt, où quiconque se hasarde doit
infailliblement s’égarer ; les uns vont en haut, les autres en bas,
ceux-ci d’un côté, ceux-là d’un autre. En résumé, et pour conclure,