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Contents
Preface xvii
1 Principles of Pharmacology 3
Pharmacology: The Science of Drug Action 4
Placebo effect 5
Box 1.1 Pharmacology in Action Naming Drugs 6
Pharmacokinetic Factors Determining Drug
Action 7
Methods of drug administration influence the onset of drug
action 8
Multiple factors modify drug absorption 12
Drug distribution is limited by selective barriers 15
Depot binding alters the magnitude and duration of
drug action 18
Biotransformation and elimination of drugs contribute
to bioavailability 19
Therapeutic Drug Monitoring 25
Box 1.2 Pharmacology in Action Interspecies Drug Dose
Extrapolation 25
2 Structure and Function of the Nervous System 45
Cells of the Nervous System 46
Neurons have three major external features 46
Box 2.1 The Cutting Edge Embryonic Stem Cells 47
Characteristics of the cell membrane are critical for
neuron function 54
Glial cells provide vital support for neurons 55
Box 2.2 Of Special Interest Astrocytes 56
Electrical Transmission within a Neuron 58
Ion distribution is responsible for the cell’s resting
potential 58
Pharmacodynamics: Drug–Receptor
Interactions 27
Box 1.3 Pharmacology in Action Drug Categories 28
Extracellular and intracellular receptors have several
common features 30
Dose–response curves describe receptor activity 31
The therapeutic index calculates drug safety 32
Receptor antagonists compete with agonists for
binding sites 33
Biobehavioral Effects of Chronic Drug Use 34
Repeated drug exposure can cause tolerance 35
Chronic drug use can cause sensitization 38
Pharmacogenetics and Personalized Medicine
in Psychiatry 39
Local potentials are small, transient changes in
membrane potential 60
Sufficient depolarization at the axon hillock opens voltage-
gated Na+ channels, producing an action potential 61
Drugs and poisons alter axon conduction 63
Organization of the Nervous System 65
Box 2.3 The Cutting Edge Finding Your Way in the
Nervous System 65
The nervous system comprises the central and peripheral
divisions 66
CNS functioning is dependent on structural features 68
viii Contents
The CNS has six distinct regions reflecting embryological
development 70
Box 2.4 Of Special Interest Neuroendocrine Response to
Stress 76
3 Chemical Signaling by Neurotransmitters and Hormones 83
Chemical Signaling between Nerve Cells 84
Neurotransmitter Synthesis, Release,
and Inactivation 86
Neurotransmitters encompass several different
kinds of chemical substances 86
Box 3.1 Clinical Applications Orexin-Based
Medications: New Approaches to the Treatment
of Sleep Disorders 87
Neuropeptides are synthesized by a different mechanism
than other transmitters 90
Neuromodulators are chemicals that don’t act like typical
neurotransmitters 91
Classical transmitter release involves exocytosis and
recycling of synaptic vesicles 91
Lipid and gaseous transmitters are not released from
synaptic vesicles 95
Several mechanisms control the rate of neurotransmitter
release by nerve cells 96
Neurotransmitters are inactivated by reuptake and by
enzymatic breakdown 97
4 Methods of Research in Psychopharmacology 117
Research Methods for Evaluating the Brain
and Behavior 118
Techniques in Behavioral Pharmacology 118
Evaluating Animal Behavior 118
Animal testing needs to be valid and reliable to
produce useful information 118
A wide variety of behaviors are evaluated by
psychopharmacologists 120
Box 4.1 Pharmacology in Action Using the Three-
Chamber Social Interaction Test 125
Box 4.2 Clinical Applications Drug Testing for
FDA Approval 131
Techniques in Neuropharmacology 134
The cerebral cortex is divided into four lobes, each
having primary, secondary, and tertiary areas 76
Rat and human brains have many similarities and
some differences 79
Neurotransmitter Receptors and Second-Messenger
Systems 98
There are two major families of neurotransmitter
receptors 99
Second messengers work by activating specific
protein kinases within a cell 102
Tyrosine kinase receptors mediate the effects of
neurotrophic factors 104
Pharmacology of Synaptic Transmission 104
Synaptic Plasticity 105
The Endocrine System 107
Endocrine glands can secrete multiple hormones 107
Mechanisms of hormone action vary 109
Why is the endocrine system important to
pharmacologists? 111
Box 3.2 Pharmacology in Action Sex Hormones and
Drug Abuse 112
Multiple Neurobiological Techniques for Assessing
the CNS 134
Stereotaxic surgery is needed for accurate in vivo
measures of brain function 134
Neurotransmitters, receptors, and other proteins can
be quantified and visually located in the CNS 138
New tools are used for imaging the structure and
function of the brain 145
Genetic engineering helps neuroscientists to ask
and answer new questions 150
Box 4.3 Pharmacology in Action Transgenic Model
of Huntington’s Disease 153
Behavioral and neuropharmacological methods
complement one another 155

5 Catecholamines 159
Catecholamine Synthesis, Release, and
Inactivation 160
Tyrosine hydroxylase catalyzes the rate-limiting step
in catecholamine synthesis 160
Catecholamines are stored in and released from
synaptic vesicles 161
Catecholamine inactivation occurs through the
combination of reuptake and metabolism 164
Organization and Function of the
Dopaminergic System 166
Two important dopaminergic cell groups are found
in the midbrain 166
Ascending dopamine pathways have been implicated
in several important behavioral functions 167
Box 5.1 Clinical Applications Mutations That Affect
Dopamine Neurotransmission 168
6 Serotonin 189
Serotonin Synthesis, Release, and Inactivation 190
Serotonin synthesis is regulated by enzymatic activity and
precursor availability 190
Similar processes regulate storage, release, and
inactivation of serotonin and the catecholamines 192
Box 6.1 History of Psychopharmacology “Ecstasy”—
Harmless Feel-Good Drug, Dangerous Neurotoxin, or
Miracle Medication? 193
Organization and Function of the
Serotonergic System 196
7 Acetylcholine 213
Acetylcholine Synthesis, Release, and
Inactivation 214
Acetylcholine synthesis is catalyzed by the enzyme
choline acetyltransferase 214
Many different drugs and toxins can alter acetylcholine
storage and release 214
Acetylcholinesterase is responsible for acetylcholine
breakdown 215
Box 7.1 Pharmacology In Action Botulinum Toxin—
Deadly Poison, Therapeutic Remedy, and Cosmetic Aid 216
Contents ix
There are five main subtypes of dopamine receptors
organized into D1- and D2-like families 171
Dopamine receptor agonists and antagonists affect
locomotor activity and other behavioral functions 172
Box 5.2 The Cutting Edge Using Molecular Genetics to
Study the Dopaminergic System 174
Organization and Function of the
Noradrenergic System 177
Norepinephrine is an important transmitter in both
the central and peripheral nervous systems 177
Norepinephrine and epinephrine act through α- and
β-adrenergic receptors 178
The central noradrenergic system plays a significant
role in arousal, cognition, and the consolidation of
emotional memories 179
Several medications work by stimulating or inhibiting
peripheral adrenergic receptors 183
The serotonergic system originates in the brainstem
and projects to all forebrain areas 196
The firing of dorsal raphe serotonergic neurons varies
with behavioral state and in response to rewards and
punishments 197
There is a large family of serotonin receptors, most of which
are metabotropic 198
Multiple approaches have identified several behavioral and
physiological functions of serotonin 200
Box 6.2 The Cutting Edge Serotonin and
Aggression 203
Organization and Function of the Cholinergic
System 219
Cholinergic neurons play a key role in the functioning of
both the peripheral and central nervous systems 219
Box 7.2 The Cutting Edge Acetylcholine and Cognitive
Function 220
There are two acetylcholine receptor subtypes: nicotinic and
muscarinic 222
x Contents
8 Glutamate and GABA 231
Glutamate 232
Glutamate Synthesis, Release,
and Inactivation 232
Neurons generate glutamate from the precursor
glutamine 232
Glutamate packaging into vesicles and uptake after release
are mediated by multiple transport systems 232
Organization and Function of the
Glutamatergic System 235
Glutamate is the neurotransmitter used in many excitatory
pathways in the brain 235
Both ionotropic and metabotropic receptors mediate the
synaptic effects of glutamate 236
Box 8.1 Clinical Applications Fragile X Syndrome
and Metabotropic Glutamate Receptor Antagonists:
A Contemporary Saga of Translational Medicine 239
AMPA and NMDA receptors play a key role in learning and
memory 239
High levels of glutamate can be toxic to nerve cells 245
9 Drug Abuse and Addiction 265
Introduction to Drug Abuse and Addiction 266
Drugs of abuse are widely consumed in our society 266
Drug use in our society has increased and has become more
heavily regulated over time 267
Features of Drug Abuse and Addiction 270
Drug addiction is considered to be a chronic, relapsing
behavioral disorder 270
There are two types of progression in drug use 272
Box 9.1 Of Special Interest Should the Term Addiction
Be Applied to Compulsive Behavioral Disorders That Don’t
Involve Substance Use? 273
Which drugs are the most addictive? 275
Factors That Influence the Development
and Maintenance of Drug Abuse and
Addiction 276
The addiction potential of a substance is influenced by
its route of administration 277
Most abused drugs exert rewarding and reinforcing
effects 277
GABA 251
GABA Synthesis, Release, and Inactivation 251
GABA is synthesized by the enzyme glutamic acid
decarboxylase 251
GABA packaging into vesicles and uptake after release
are mediated by specific transporter proteins 251
GABA is coreleased with several other classical
neurotransmitters 253
Organization and Function of the
GABAergic System 254
Some GABAergic neurons are interneurons, while others are
projection neurons 254
The actions of GABA are primarily mediated by ionotropic
GABAA receptors 254
Box 8.2 Clinical Applications GABA and Epilepsy 255
GABA also signals using metabotropic GABAB
receptors 260
Drug dependence leads to withdrawal symptoms when
abstinence is attempted 280
Discriminative stimulus effects contribute to drug-seeking
behavior 282
Genetic factors contribute to the risk for addiction 283
Psychosocial variables also contribute to addiction risk 285
The factors contributing to drug addiction can be
combined into a biopsychosocial model 287
The Neurobiology of Drug Addiction 289
Drug reward and incentive salience drive the binge–
intoxication stage of drug use 289
The withdrawal/negative affect stage is characterized
by stress and by the recruitment of an antireward
circuit 292
The preoccupation/anticipation stage involves
dysregulation of prefrontal cortical function and
corticostriatal circuitry 294
Molecular neuroadaptations play a key role in the
transition to an addicted state 296
Is addiction a disease? 299

10 Alcohol 307
Psychopharmacology of Alcohol 308
Alcohol has a long history of use 308
What is an alcohol and where does it come from? 309
The pharmacokinetics of alcohol determines its
bioavailability 310
Chronic alcohol use leads to both tolerance and
physical dependence 313
Alcohol affects many organ systems 315
Box 10.1 Pharmacology in Action The Role of
Expectation in Alcohol-Enhanced Human Sexual
Response 315
11 The Opioids 351
Narcotic Analgesics 352
The opium poppy has a long history of use 352
Minor differences in molecular structure determine
behavioral effects 353
Bioavailability predicts both physiological and behavioral
effects 354
Opioids have their most important effects on the CNS and
on the gastrointestinal tract 354
Box 11.1 Clinical Applications Saving a Life: Naloxone
for Opioid Overdoses 355
Opioid Receptors and Endogenous
Neuropeptides 357
Receptor binding studies identified and localized
opioid receptors 357
Four opioid receptor subtypes exist 358
Several families of naturally occurring opioid peptides bind
to these receptors 360
Box 11.2 The Cutting Edge Science in Action 361
Opioid receptor–mediated cellular changes are
inhibitory 365
Opioids and Pain 366
The two components of pain have distinct features 367
Opioids inhibit pain transmission at spinal and
supraspinal levels 369
Other forms of pain control depend on opioids 371
Contents xi
Neurochemical Effects of Alcohol 325
Animal models are vital for alcohol research 325
Alcohol acts on multiple neurotransmitters 327
Alcohol Use Disorder (AUD) 335
Defining alcohol use disorder and estimating its incidence
have proved difficult 335
The causes of alcohol use disorder are multimodal 338
Multiple treatment options provide hope for
rehabilitation 342
Opioid Reinforcement, Tolerance,
and Dependence 374
Animal testing shows significant reinforcing
properties 376
Dopaminergic and nondopaminergic components
contribute to opioid reinforcement 376
Long-term opioid use produces tolerance, sensitization,
and dependence 377
Box 11.3 Of Special Interest The Opioid
Epidemic 379
Several brain areas contribute to the opioid abstinence
syndrome 381
Neurobiological adaptation and rebound constitute
tolerance and withdrawal 381
Environmental cues have a role in tolerance, drug abuse,
and relapse 382
Treatment Programs for Opioid Use Disorder 383
Detoxification is the first step in the therapeutic
process 383
Treatment goals and programs rely on pharmacological sup-
port and counseling 384
xii Contents

12 Psychomotor Stimulants: Cocaine, Amphetamine, and Related Drugs 391

Cocaine 392 Repeated or high-dose cocaine use can produce serious

health consequences 409
Background and History 392 Pharmacological, behavioral, and psychosocial methods are
Basic Pharmacology of Cocaine 393 used to treat cocaine abuse and dependence 409

Mechanisms of Cocaine Action 395 The Amphetamines 412

Acute Behavioral and Physiological Effects Background and History 412
of Cocaine 397 Basic Pharmacology of the Amphetamines 413
Cocaine stimulates mood and behavior 398
Mechanisms of Amphetamine and
Cocaine’s physiological effects are mediated by the Methamphetamine Action 414
sympathetic nervous system 399
Dopamine is important for many effects of cocaine and Behavioral and Neural Effects of
other psychostimulants 399 Amphetamines 415
Brain imaging has revealed the neural mechanisms of Amphetamine and methamphetamine have
psychostimulant action in humans 401 therapeutic uses 415
Several DA receptor subtypes mediate the functional High doses or chronic use of amphetamines
effects of psychostimulants 402 can cause a variety of adverse effects 415
Cocaine Abuse and the Effects of Chronic Cocaine Methylphenidate, Modafinil, and
Exposure 403 Synthetic Cathinones 418
Experimental cocaine use may escalate over time to a
Methylphenidate 418
pattern of cocaine abuse and dependence 403
Chronic cocaine exposure leads to significant behavioral Box 12.2 Clinical Applications Psychostimulants
and neurobiological changes 405 and ADHD 420
Box 12.1 The Cutting Edge Neurochemical Mechanisms Modafinil 422
of Cocaine Tolerance and Sensitization 406
Synthetic Cathinones 423

13 Nicotine and Caffeine 429

Nicotine 430 Nicotine exerts both reinforcing and aversive effects 436
Nicotine produces a wide range of physiological
Background and History 430 effects 438
Basic Pharmacology of Nicotine and Its Relationship Nicotine is a toxic substance that can be fatal at high
to Smoking 431 doses 439
Features of tobacco smoking and nicotine Chronic exposure to nicotine induces tolerance and
pharmacokinetics 431 dependence 440
Features of e-cigarette vaping and nicotine Cigarette Smoking and Vaping 443
pharmacokinetics 431
What percentage of the population are current users of
Nicotine metabolism 432 tobacco and/or e-cigarettes? 443
Mechanisms of Action 432 Nicotine users progress through a series of stages in their
pattern and frequency of use 444
Behavioral and Physiological Effects 433 Box 13.1 The Cutting Edge How Safe Are
Nicotine elicits different mood changes in smokers E-cigarettes? 446
compared with nonsmokers 434 Why do smokers smoke and vapers vape? 447
Nicotine enhances cognitive function 434 Smoking is a major health hazard and a cause of
premature death 450
 Contents xiii

Behavioral and pharmacological strategies are Acute subjective and behavioral effects of caffeine
used to treat tobacco dependence 451 depend on dose and prior exposure 456

Caffeine 455 Caffeine consumption can enhance sports

performance 457
Background 455 Regular caffeine use leads to tolerance and
dependence 458
Basic Pharmacology of Caffeine 456
Caffeine and caffeine-containing beverages pose
Behavioral and Physiological Effects 456 health risks but also exert therapeutic benefits 459
Mechanisms of Action 460

14 Marijuana and the Cannabinoids 467

Background and History of Cannabis Acute Behavioral and Physiological Effects

and Marijuana 468 of Cannabinoids 480
Forms of cannabis and their chemical constituents 468 Cannabis consumption produces a dose-dependent
History of cannabis 468 state of intoxication 480
Marijuana use can lead to deficits in memory and
Basic Pharmacology of Marijuana 470 other cognitive processes 481
THC 470 Rewarding and reinforcing effects of cannabinoids
Cannabidiol 471 have been studied in both humans and animals 482

Mechanisms of Action 472
Cannabinoid effects are mediated by cannabinoid
receptors 472
Pharmacological and genetic studies reveal the
functional roles of cannabinoid receptors 473
Endocannabinoids are cannabinoid receptor agonists
synthesized by the body 474
Cannabis Abuse and the Effects of Chronic Cannabis
Exposure 484
Chronic use of cannabis can lead to the development
of a cannabis use disorder 485
Chronic cannabis use can lead to adverse behavioral,
neurobiological, and health effects 489
Box 14.1 Of Special Interest Beyond Cannabis:
The Rise of Synthetic Cannabinoids 495

15 Hallucinogens, PCP, and Ketamine 501

Hallucinogenic Drugs 502 Pharmacology of Hallucinogenic Drugs 507

Mescaline 502 Different hallucinogenic drugs vary in potency
and in their time course of action 507
Psilocybin 502 Hallucinogens produce a complex set of psychological
and physiological responses 508
Dimethyltryptamine and Related
Tryptamines 504 Most hallucinogenic drugs share a common
indoleamine or phenethylamine structure 509
LSD 504 Indoleamine and phenethylamine hallucinogens
Box 15.1 History of Pharmacology are 5-HT2A receptor agonists 510
The Discovery of LSD 505 Salvinorin A is a κ-opioid receptor agonist 511
NBOMes 506 The neural mechanisms underlying hallucinogenesis
are not yet fully understood 511
Salvinorin A 507 Hallucinogenic drug use leads to adverse effects
in some users 511
Can hallucinogenic drugs be used therapeutically? 513
xiv Contents
PCP and Ketamine 515
Background and History 515
Pharmacology of PCP and Ketamine 516
PCP and ketamine produce a state of dissociation 516
PCP and ketamine are noncompetitive antagonists of
NMDA receptors 517
16 Inhalants, GHB, and Anabolic–Androgenic Steroids 527
Inhalants 528
Background 528
Inhalants comprise a range of substances including
volatile solvents, fuels, halogenated hydrocarbons,
anesthetics, and nitrites 528
Abused inhalants are rapidly absorbed and readily
enter the brain 528
These substances are particularly favored by children and
adolescents 529
Behavioral and Neural Effects 530
Many inhalant effects are similar to alcohol
intoxication 530
Chronic inhalant use can lead to tolerance and
dependence 530
Rewarding and reinforcing effects have been
demonstrated in animals 530
Inhalants have complex effects on central nervous
system (CNS) function and behavioral activity 531
Health risks have been associated with inhalant abuse 532
Gamma-Hydroxybutyrate 534
Background 534
Behavioral and Neural Effects 535
GHB produces behavioral sedation, intoxication,
and learning deficits 535
GHB and its precursors have reinforcing properties 535
Effects of GHB are mediated by multiple mechanisms 536
PCP and ketamine have significant abuse potential 517
Use of PCP, ketamine, or related drugs can cause a
variety of adverse consequences 519
Box 15.2 Pharmacology In Action Getting High on
Cough Syrup 520
Novel therapeutic applications have been proposed for
ketamine 522
Medical and Recreational Uses of GHB 538
GHB is used therapeutically for the treatment of
narcolepsy and alcoholism 538
GHB has significant abuse potential when used
recreationally 539
Anabolic–Androgenic Steroids 540
Background and History 541
Anabolic–androgenic steroids are structurally related to
testosterone 541
Anabolic–androgenic steroids were developed to help build
muscle mass and enhance athletic performance 542
Anabolic–androgenic steroids are currently taken by many
adolescent and adult men 543
Anabolic–androgenic steroids are taken in specific patterns
and combinations 543
Pharmacology of Anabolic–Androgenic
Steroids 545
Research is beginning to unravel the mechanism of action
of anabolic–androgenic steroids on muscle 545
Many adverse side effects are associated with anabolic–
androgenic steroid use 546
Regular anabolic–androgenic steroid use causes
dependence in some individuals 548
Box 16.1 Of Special Interest Anabolic–Androgenic
Steroids and “Roid Rage” 549
Testosterone has an important role in treating
hypogonadism 552

17 Disorders of Anxiety and Impulsivity and the Drugs Used to
Treat These Disorders 559
Neurobiology of Anxiety 560
What is anxiety? 560
The amygdala is important to emotion-processing
circuits 561
Multiple neurotransmitters mediate anxiety 564
Box 17.1 The Cutting Edge Neural Mechanism
Responsible for High Tonic Cell Firing Mediating
Anxiety 566
Genes and environment interact to determine the tendency
to express anxiety 574
The effects of early stress are dependent on timing 576
The effects of early stress vary with gender 577
Characteristics of Anxiety Disorders 579
18 Affective Disorders: Antidepressants and Mood Stabilizers 601
Characteristics of Affective Disorders 602
Major depression damages the quality of life 602
In bipolar disorder moods alternate from mania to
depression 602
Risk factors for mood disorders are biological and
environmental 604
Animal Models of Affective Disorders 608
Models of bipolar disorder 608
Neurochemical Basis of Mood Disorders 610
Serotonin dysfunction contributes to mood disorders 611
Norepinephrine activity is altered by antidepressants 614
Norepinephrine and serotonin modulate one another 615
19 Schizophrenia: Antipsychotic Drugs 633
Characteristics of Schizophrenia 634
There is no defining cluster of schizophrenic
symptoms 634
Etiology of Schizophrenia 636
Abnormalities of brain structure and function occur in
individuals with schizophrenia 636
Genetic, environmental, and developmental factors
interact 639
Contents xv
Drugs for Treating Anxiety, OCD, and PTSD 587
Barbiturates are the oldest sedative–hypnotics 588
Benzodiazepines are highly effective for anxiety
reduction 590
Second-generation anxiolytics produce distinctive
clinical effects 595
Antidepressants relieve anxiety and depression 596
Many novel approaches to treating anxiety are being
developed 597
Neurobiological Models of Depression 615
Box 18.1 The Cutting Edge Epigenetic
Modifications in Psychopathology and Treatment 618
Therapies for Affective Disorders 621
Monoamine oxidase inhibitors are the oldest
antidepressant drugs 621
Tricyclic antidepressants block the reuptake of
norepinephrine and serotonin 623
Second-generation antidepressants have different
side effects 624
Third-generation antidepressants have distinctive
mechanisms of action 625
Drugs for treating bipolar disorder stabilize the highs
and the lows 628
Box 19.1 The Cutting Edge Epigenetic Modifications
and Risk for Schizophrenia 642
Preclinical Models of Schizophrenia 646
Box 19.2 Pharmacology In Action
The Prenatal Inflammation Model of Schizophrenia 648
Neurochemical Models of Schizophrenia 650
Abnormal dopamine function contributes to
schizophrenic symptoms 650
xvi Contents

The neurodevelopmental model integrates anatomical and Dopamine receptor antagonism is responsible for
neurochemical evidence 651 antipsychotic action 655
Glutamate and other neurotransmitters contribute to Side effects are directly related to neurochemical
symptoms 652 action 657
Classic Neuroleptics and Atypical Atypical antipsychotics are distinctive in several ways 660
Antipsychotics 650 Practical clinical trials help clinicians make decisions
about drugs 663
Phenothiazines and butyrophenones are classic
neuroleptics 654 There are renewed efforts to treat the cognitive
symptoms 664

20 Neurodegenerative Diseases 671

Parkinson’s Disease and Alzheimer’s Box 20.1 The Cutting Edge Alzheimer’s Disease:
Disease 672 It’s all in your gut??? 684

Parkinson’s Disease 672 Other Major Neurodegenerative

Diseases 685
The clinical features of PD are primarily motor
related 672 Huntington’s Disease 685
Patients with Parkinson’s may also develop dementia 673 Symptoms 686
The primary pathology of PD is a loss of dopaminergic Only symptomatic treatments are available for HD;
neurons in the substantia nigra 673 none alter disease progression 686
Animal models of PD have strengths and limitations 676
Amyotrophic Lateral Sclerosis 687
Pharmacological treatments for PD are primarily
symptomatic, not disease altering 676 The symptoms and disease progression in ALS
are devastating 687
There are several unmet needs in PD diagnosis
and treatment 677 The loss of motor neurons in ALS is complicated
and poorly understood 687
Alzheimer’s Disease 678 Two medications exist that are approved for ALS
AD is defined by several pathological cellular treatment 688
disturbances 679
Multiple Sclerosis 688
There are several behavioral, health, and genetic
risk factors for AD 681 The symptoms of MS are variable and unpredictable 689
Alzheimer’s disease cannot be definitively diagnosed Diagnosis 689
until postmortem analysis 682 Causes of MS 690
Several different animal models contribute to our Treatments fall into several categories for MS
understanding of AD 683 and can be very effective 691
Symptomatic treatments are available, and several others Box 20.2 Pharmacology in Action Can We Repair
are under study for slowing disease progression 683 or Replace Myelin? 693

Glossary G-1
References R-1
Author Index AI-1
Subject Index SI-1
Preface
When we wrote the preface to the Second Edition of
Psychopharmacology: Drugs, the Brain, and Behavior, we
were struck by the many exciting developments in the
field and the remarkable rate of progress elucidating
the underlying neurobiological mechanisms of psycho-
active drug action. This has not changed over the 5
years since the publication of that edition. The entire
field of neuroscience, including neuropsychopharma-
cology, continues to be driven by technical advances.
Using optogenetics, neurobiologists can activate or
suppress anatomically and molecularly defined popu-
lations of nerve cells with amazing temporal precision.
Neuropharmacologists can visualize the 3-dimensional
structure of neurotransmitter receptors, enabling syn-
thetic chemists to design novel agonist or antagonist
drugs with much greater selectivity than could have
been possible before. And huge projects like the Human
Connectome Project (www.humanconnectomeproject.
org) are using the most advanced neuroimaging tech-
niques to map the detailed circuitry of the living human
brain. Because of these technical innovations, we con-
tinue to add new information to Chapter 4, on Methods
of Research in Psychopharmacology. Readers may choose
to go through the chapter in its entirety to familiarize
themselves with all of the neuropharmacological and
behavioral methods reviewed, or they may choose to
use the chapter as a reference source when they en-
counter an unfamiliar method in one of the book’s later
chapters.
Development and introduction of new pharma-
ceutical compounds continues as well, although the
emphasis has somewhat shifted away from the large
pharmaceutical companies to a greater reliance on
drug discovery efforts by researchers at universities
and medical centers. Statistics show that development
of new drugs for CNS disorders (e.g., schizophrenia,
depression, and Alzheimer’s disease) costs more than
for other kinds of disorders, and the failure rate is sig-
nificantly higher. These data have caused many of the
large companies to downsize their CNS drug discovery
programs. As you read the chapters on drug addiction,
mental disorders, and neurodegenerative disorders, it
will become apparent that new medications for these
disorders are being introduced at a slower rate than
expected, despite ongoing research that continues to
identify potential new molecular targets for pharma-
cotherapy. For this reason, we must admit that excit-
ing advances in understanding the basic structure and
function of the nervous system have not yet led to sim-
ilar progress in treating, much less “curing,” disorders
of this system. We came to the same conclusion when
writing the preface to the Second Edition, so it’s disap-
pointing that the hoped-for surge in medication devel-
opment failed to occur during the intervening period.
As before, this new edition of the text is complete-
ly updated to incorporate the latest research findings,
methodological advances, and novel drugs of abuse.
Regarding the latter, illicit drug labs in the United
States and abroad are working hard to turn out mas-
sive amounts of recreational drugs, whether already
known compounds such as cocaine or fentanyl, or
novel synthetic compounds that can only be identi-
fied by submitting drug seizures to advanced forensic
laboratories for chemical analysis. The national drug
epidemic involving fentanyl, heroin, and other opioid
compounds is discussed in Chapter 11. New and, in
some cases, highly dangerous stimulant and cannabi-
noid drugs are introduced in Chapters 12, 14, and 15
respectively. Most chapters have new opening vignettes
and breakout boxes, and new photographs, drawings,
and graphs have been added to bring attention both
to updated material and to completely new topic areas
for discussion.
Importantly, in preparing this next edition of the
book we have maintained our conviction that a deep
understanding of the relationship between drugs and
behavior requires basic knowledge of how the nervous
system works and how different types of drugs interact
with nervous system function (i.e., mechanisms of drug
action). We have also continued to present the methods
and findings from behavioral pharmacological studies
using animal models alongside key studies from the
human clinical research literature. Pharmacologists
must depend on in vitro preparations and laboratory
xviii Preface
animal studies for determining mechanisms of drug
action, for screening new compounds for potential ther-
apeutic activity, and, of course, for basic toxicology and
safety testing. In cases in which clinical trials have al-
ready been performed based on promising preclinical
results, both sets of findings are presented. In other
instances in which clinical trials had not yet been un-
dertaken at the time of our writing, we have striven to
point you toward new directions of drug development
so that you can seek out the latest information using
your own research efforts.
A new point of emphasis in the text concerns neural
circuits as mediators of behavior and as targets of drug
action. As implied above in referring to the Human
Connectome Project, focusing on circuits instead of
cells as the nervous system’s functional units is the con-
temporary way to think about how our brains control
our actions, and how drugs, whether recreational or
medicinal, alter our subjective awareness and behavior.
The Third Edition of Psychopharmacology: Drugs, the
Brain, and Behavior retains the same four-section orga-
nization as the previous editions. Chapters 1 through 4
provide extensive foundation materials, including the
basic principles of pharmacology, neurophysiology
and neuroanatomy, cell signaling (primarily synaptic
transmission), and current methods in behavioral as-
sessment and neuropharmacology. An increased use
of clinical examples demonstrates the relevance of the
material to real-life issues. Chapters 5 through 8 de-
scribe key features of major neurotransmitter systems,
including the catecholamines, serotonin, acetylcholine,
glutamate, and GABA. These are the neurotransmitter
systems most often associated with psychoactive drug
effects, and presentation of their neurochemistry, anat-
omy, and function lays the groundwork for the chap-
ters that follow. Chapters 9 through 16 cover theories
and mechanisms of drug addiction and all the major
substances of abuse. Finally, Chapters 17 through 20
consider the neurobiology of neuropsychiatric and neu-
rodegenerative disorders and the drugs used to treat
these disorders. Among the neuropsychiatric disor-
ders, special emphasis is placed on affective disorders
such as major depression and bipolar disorder, various
anxiety disorders, and schizophrenia. Bulleted interim
summaries highlight the key points made in each part
of the chapter. New to this edition, study questions are
provided at the end of each chapter to assist students
in reviewing the most important material. Finally, a
dedicated website for the book (oup-arc.com/access/
meyer-3e) is available that offers Web Boxes (advanced
topics for interested readers), study resources such as
flashcards, web links, and animations that visually
illustrate key neurophysiological and neurochemical
processes important for psychopharmacology.
It has been our privilege in the first two editions
of Psychopharmacology: Drugs, the Brain, and Behavior to
introduce so many students to the study of drugs and
behavior. With this new and updated edition, we hope
to continue this tradition and perhaps inspire some of
you to continue your studies in graduate school and
join the thousands of researchers worldwide who are
working to better understand and ultimately defeat ill-
nesses like addiction, depression, schizophrenia, and
Alzheimer’s disease.

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 acknowl-
edge the outstanding editorial team at Sinauer Asso-
ciates: Sydney Carroll, Martha Lorantos, and Danna
Lockwood, thank you all for your suggestions for
improving the Third Edition, your help and guidance
throughout the process of writing and revising, and not
least for your patience (textbook writing is a slow pro-
cess when one is simultaneously teaching, conducting
research, and meeting administrative responsibilities).
You were unwavering in your vision to produce the
best possible psychopharmacology textbook. Mark Sid-
dall did a superb job of seeking out just the right photo-
graphs for the book. We are indebted to other key staff
members of Sinauer Associates who worked on this
project, including Chris Small, Ann Chiara, and Joan
Gemme. And we must acknowledge Dragonfly Media
Group for the beautiful job rendering the illustrations.
The following reviewers contributed many excel-
lent suggestions for improving the book:
Joel Alexander, Western Oregon University
Sage Andrew, University of Missouri
Susan Barron, University of Kentucky
Ethan Block, University of Pittsburgh
Kirstein Cheryl, University of South Florida
Matt Clasen, American University
Patricia DiCiano, The Centre for Addiction and
Mental Health and Seneca College
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
Michael Kane, University of Pennsylvania
Thomas Lanthorn, Sam Houston State University
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
Evan Zucker Loyola University
Most of all, we are indebted to our spouses, Melinda
Novak and Ray Rosati, who supported and encouraged
us and who willingly sacrificed so much of our time
together during this lengthy project. Linda gives special
thanks to her husband Ray for providing extensive ed-
itorial advice during the final production period.
Media and Supplements to accompany
Psychopharmacology, Third Edition
FOR THE STUDENT
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The Psychopharmacology, Third Edition companion
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•• Web Links list suggested websites and other
online resources related to each chapter.
•• Suggested Readings provide additional references
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Psychopharmacology
Drugs, the Brain, and Behavior
THIRD EDITION
 CHAPTER 1

Maggot therapy can be used to clean wounds and prevent infection.

(PA Images/Alamy Stock Photo.)
Principles of Pharmacology
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 maggots to clean
wounds, it was Baer who once again recognized their importance, espe-
cially 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 infec-
tions 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 sug-
gested that in modern times, maggot therapy will be reintroduced to treat
those wounds infected with antibiotic-resistant bacteria. Presently 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. n
4 Chapter 1
Pharmacology:
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 stud-
ied 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 prepa-
ration and use of more than 700 remedies for ailments
as varied as crocodile bites, baldness, constipation,
headache, and heart disease. Of course, many of these
treatments included elements of magic and incantation,
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 Organi-
zation 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 medicines
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
associated 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 development of
several specialized areas of pharmacology. Two of these
areas are of particular interest to us. Neuropharma-
cology is concerned with drug-induced changes in the
functioning of cells in the nervous system, and psycho-
pharmacology emphasizes drug-induced changes 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 molecular changes lead to more widespread al-
terations in physiological or psychological functions,
which we consider drug effects. The site of drug ac-
tion may be very different from the site of drug effect.
For example, atropine is a drug used in ophthalmology
to dilate the 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, morphine 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 vari-
ety of target sites, they always have multiple effects.
Some may be therapeutic effects, meaning that the
drug–receptor interaction produces desired physical
or behavioral 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 alert-
ness and insomnia, increased heart rate, and decreased
appetite. Drugs in this class reduce the occurrence of
spontaneous sleep episodes characteristic of the disor-
der called narcolepsy, but they produce anorexia (loss
of appetite) as the primary 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, depend-
ing 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,
nonspecific drug effects are those that are based not
on the chemical activity of a drug–receptor interaction,
Another random document with
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aside; and what was a greater Misfortune, the Prince and his
Retinue beheld with winking Eyes, all their Hovels on fire ashore:
The Occasion this; we happening to have all our Colours flying, and
some Guns let off in honour of the 28th of May, another Leader on
shore misinterpreting it as a particular Respect to Jacobus, grew
jealous, seized his House during the Revel, his Wives, and his
Dashees, drank up all his Brandy, eat all his Victuals, cudgelled his
People, and set both his Houses on fire.
Next Morning, on unravelling the Mystery, the Surprize was over,
and all became good Friends again. They have very little Knowledge
or Use of Fire-Arms, because no Trade scarce; their Weapons being
Spears, Arrows, and Clubs, and it is a bloody Battle among them,
when half a dozen of a side are knocked down.
 A
V O YA G E
TO
Brasil, and the West-Indies.
From Cape Lopez (parting with the Coast) we came in sight of the
Island Annabona, the Breezes small at South, and Calms
alternatively; hereabout we cruised three or four days, for our
Consort the Swallow, that some how or other was separated; and
missing her, bore away for Brasil.
In the Passage it may be first observed, that when we had sailed
ninety Leagues to the Westward, and got into 3°° S. the Winds that
were at South veered, so as to become a true S E. Trade, that
carried us four or five Knots.——And still as we advanced farther
Westward, it blew fresher at E S E. 7, 8, and 9 Knots constantly, with
neither Thunder nor Lightning. Quære, whether this distance is not a
proper Medium to allow for the Attraction of all Exhalations by the
Land; at least that they considerably abate after that length from all
Shores, allowing for Latitude, and as they are Montainous or Plain.
We see within this Dimension, (plainly) that it takes off the Influence
of the Sun, and varys the Trade Wind towards itself: Nor is it so
astonishing, since Animals themselves obey; several sorts of Fish
and Fowl have a periodical return to such and such places, and not
so of those inhabiting the more stable Element of Land: Wherefore it
is highly rational to think, that as the fluid Elements they live in yield
to the attractive Power of the Earth and Planets, so also their
Inhabitants have their Instinct more sensibly fated by them.
 Secondly, in this Trade-Wind sailing, we are every day diverted
with flying Fish, Bonetos, and Sea-Fowl; the Sails require little labour
in trimming, the Ship goes steady, and the Bowl unslung; so that at
leaving such a Country we might cheerfully sing,

How happy were we, when the Wind blew abaft!

One of these cheerful Evenings, eleven at night, the full Moon
became totally eclipsed, a Darkness surprizing, as it was
unexpected; when she had recovered her Light, we repeated our
Sacrifice in Bowls, and fell into Reflections and Admiration of that
Power which supports the Regularity of the planetary Motions, and
the Sublimity of that Art which can so exactly calculate them: They
demonstrate the Sphericity of the Earth, because Countries, as they
are farther East or West, observe them hours sooner or later,
according to their Longitude, which could not be on a Plain, but
visible to all at once.
This Longitude therefore in a general View, is the same thing as
Time, the difference of it being the distance East and West of any
two places, allowing 15 Degrees, or 300 Leagues to an Hour; the
whole 24 being lost or gained in a Circum-navigation of the Globe,
West or Eastward.
A natural, tho’ hitherto incorrect way of estimating the Parts of
Longitude in those Runs, till Instruments and Rules are discovered,
is, I think, First, to make exact Tables of the Sun’s Risings and
Settings, at Places commonly departed from, and those we go to for
every day in the year: and then, Secondly, to carry two proved
Watches of equal Goodness, kept in equal Warmth, and freest from
Motion and Weather, to measure the difference of time where you
are, by the same edge of the Sun the Tables were made from; the
Minutes sooner or later, according as you go East or West, is so
many Leagues of Longitude for that day. I would insinuate by this
only my Opinion, that those literal Improvers of Time, the Watch
Makers, bid as fair for the Discovery of Longitude as the Astronomer;
for if Watches can be made not to err above two or three Minutes in
the time a Ship is running 1000 Leagues, or if they do err more, a
Rule could be found how much, (like as an Azimuth corrects the
common Compass;) or if any Movement could be depended on only
from Observation to Observation, then the Error would be no greater
than what is met in different Quadrants, observing Latitude. As it is, it
seems a proper Method to correct or assist the present Rules of
calculating meridional Distance.
We made this Passage of 8 or 900 Leagues to Brasil in three
Weeks; but having elsewhere given my Observations on the Country,
I shall only take notice that the Trade blowing very fresh, and
bringing in a great Swell, we hastened from the Coast to our
intended Ports in the West-Indies.
In our Progress thither, a Remark or two: First, that in the
Navigation from Brasil, we crossed the Æquinoctial, two or three
Degrees W. of Cape Roque, keeping on with a pleasant S E. Trade
that gradually lessened, and in 4°° North Latitude, left us in Calms,
Rains, and uncertain Squalls, (varying round the Compass;) That
this continued for several days, till we drew in or near the Parallel of
Barbados, and then we as gradually had obtained the Trade to
Northward of the East, running 150 Leagues with it, that is, to
Barbados.
Secondly, The reason of Calms, and Rains met in Latitudes
between 4°° and 11°° N. (with a little Variation, as the Sun is of this
or that side the Equinoctial) is probably from a Contest between the
N E. and S E. Trade; but whether the passing them be more
favourable far to the Eastward or Westward, I am uncertain.
 BARBADOS.
Barbados was discovered by Sir William Carter, in King James I’s
time, planted to little purpose until 1627; since which, the Crops have
been so advantageous, as to have raised the Price of Ground thirty
fold.
We anchored here in Carlisle-Bay the beginning of August, the
resort of most Shipping who load at this Island. The Bay is made by
Needham and Pelican Points; the Anchorage 20 Fathom, so clear
Water that you may see to the bottom; but so foul and rocky, that the
Cables are always buoy’d up with Cask. In the bottom of the Bay
stands Bridgetown, the principal of the Island, and is the Residence
of the Governor, Factors, and Merchants, who transact their
Business here and at their Plantations alternately. There is only one
large Church, with an Organ, and about twenty Chappels at different
parts of the Island, all Episcopal, there having been no Dissenters
these many years. The People are for the most part polite and well-
bred, promoting Trade by a magnificent way of living; the chief of
them are Colonels, or Captains of Militia, and in the Assembly are
divided into a Party-Interest, on the civil Affairs of the Island, their
chief Distinction; murmuring, or elate, just as they are in or out of the
Governor’s Favour, who can abate in the Customs, or imploy in the
Application: (tho’ by the way the fewer Officers, and those Menials,
the better advantage to him.)
The whole is a sweet Spot of Earth, not a Span hardly uncultivated
with Sugar-Canes; all sides bend with an easy Declivity to the Sea,
and is ever green: This delight to the Planter has its Inconveniencies,
that there is no Recreation out of Business, but in Drinking or
Gaming.
 The Propriety was given by King James I. to the Earl of Carlisle;
and Anno 1661, King Charles II. purchased it back of Lord Kinoul,
that Earl’s Heir, allowing him 1000l. per Ann. Acknowledgment.
Anno 1663, an Act passed by the President (who acts as
Governor in their absence) the Council and Assembly, for 4½ in
Specie Duty of all Commodities, the Produce of the Island, which it’s
computed will amount to 10000l. per Annum.—Madeira Wines
imported, at 4l. 10s. per Pipe, raises 7000l. and this, with one Pound
of Gunpowder per Tun on each Ship, is appropriated for Stores, and
Repairs to Forts.
The Governor is appointed by the King, his Salary formerly used to
arise at an uncertain Sum of 4 or 5000l. per Ann. from Presents and
Perquisites, since fixed at 1200l., 2000l. and now is 6000l. And as
the Council, a part of their Constitution, is in a manner of his own
Nomination, being appointed by Letters of Mandamus, as they have
Power to make Demands on ancient Perquisites, and sway in the
Application of the publick Money; there are various ways of obliging,
and his Party will always be uppermost in the Legislature, which
consists of him, the Council of twelve, and an Assembly of twenty
two, chose at the several Parishes by a Majority of Votes.
One Law is, That no Inhabitant shall be carried off the Island
without Leave; whoever engages in the Project, is liable to the
Debts; so that when a Family sees Ruin approaching, (a frequent
Case of late years) their Remedy is stealing away in Boats to some
other Place of Subsistence; and if they cannot this way escape a
hard Creditor, they comfort themselves in dying, that it may be their
Lot next. Those who depart fairly, are obliged to give publick notice
at the Secretary’s Office; and no body objecting in twenty one days,
are at liberty.
Another Act in 1676, passed against the Industry of the Quakers,
whose Conversion of the Negroes, it was pretended, hazarded the
Safety of the Island. They are computed at 80 or 90000, and are
countenanced in Polygamy; yet not dangerous, because no
Mountains to fly to, Detections and Executions would soon follow
their Rebellions. The English are reckoned 20000, the Women
among them most Scotch and Irish, very homely, and great
Swearers. The Men, contrarily, are very gay, clean, and handsome,
from mean Originals, often succeeding with rich Widows; it being but
Justice to link a fat Plantation to the truely nauseous Draught of
Matrimony.
The way of feeding such a Multitude, and providing Necessaries in
an Island yielding little besides Sugar, is principally by their Fisheries
and Importations.
The Sea gives them great plenty of flying Fish, Dolphins,
Barricuda and King Fish, particularly the first; they bait with their own
Specie, which thrown about, the Fish fly in such numbers to the
Boats, that they take them up with Dip-nets, and sometimes the
Dolphins with them; the Season goes off at the Autumnal Equinox.
Their Importations by Ships from England, Ireland, New-England,
Pensylvania, Carolina, or New-York, constantly supplying any Defect
of Food or Necessaries, every Vessel bringing them something or
other of this kind, which the Merchants keep in store and sell the
Planters occasionally, who give their Sugars, Rum, and Molosses in
return. The Price in what I was acquainted is, viz.
Bought,
Rum at 1s. 2d. per Gallon.
Citron Water 40 0
Pickled Pepper 10 0
Preserved Ginger 5 0 per lb.
Sugar, twenty Shillings a hundred; and before
our Improvements (says Gee) the
Portuguese sold for 7 and 8l. a hundred.
Cocoa, 3 or 4l.
Aloes 4d. per lb.

Sold,
Salt Beef and Pork, 40 Shillings for a
Cask of 2 Cwt.
Bisket, 17s. per hundred
 Candles, 6½ per lb. &c.
Exchange 30 per Cent. or more.

I have heard that the Custom-house Books had one year 35000
Hogsheads of Sugar entred, which at 10l. per Hogshead, amounts to
350000l. Every Acre was supposed 10s. a year Profit to the national
Stock of England, besides what the Planter got, and Mouths fed by
it; but I must observe, the Crops of late years have very much failed,
and put many of them under great Necessities. The Soil fertile in the
Age past, seems now growing old, and past its teeming-time; they
endeavour to mend this by a few Cattle kept for the sake of Manure;
few, I say, because Land imploy’d this way, gives not 1/10 its Value.
Wherefore when a thoughtless Man has joined to unlucky Events
and Seasons an inadvertent way of living, he falls a Prey to the more
astronomical Heads of Factors, who supply him with Food and
Necessaries. The Hardships of many Planters at this time, through
such Inclemencies, cannot be better laid open to the Reader, than in
transcribing part of a Sermon, that I am informed was preached by
Command of his Excellency the Governor, May 1734.

A Charity S e r m o n at Bridgetown,
for the two Parishes, St. Philip, and Christ-Church.

“Here I should have left off, but I am commanded by his Excellency

the Governor, to exhort you to that Charity, the Necessity of which
has been laid before ye.
“Remember therefore, that one of the ways observed of seeking
God is, by obeying the Dictates of his Holy Spirit, that Humanity and
Charity undepraved Nature feels towards all that are poor and
distressed.
“What an excellent Grace of Christianity this is, St. Paul from the
Spirit of God teacheth, (1 Cor. xiii.) saying, that when the Gift of
Tongues, of Prophecies, of Miracles shall cease, a greater, even that
of Charity, shall never cease in the Church militant, never in the
Church triumphant; nor can there be any greater Inducements to
provoke us to Charity, than first, it covers a Multitude of Sins, and
next, bringeth God himself (as he is pleased to esteem it) in debt to
us; for he who giveth to the Poor lendeth to the Lord, and look, what
he layeth out shall be paid him again; paid in Blessings here, and
hereafter eternal Life, if no mortal Sin continue in the Giver, to hinder
these blessed Effects.—I need say no more to ye who read the
Bible, how dear to God those Christians are, who according to their
Ability are liberal to poor Persons and Families; so that what remains
for me to say, is to expatiate a little upon the miserable State of the
Poor of these two Parishes, and leave the whole to your pious
Consideration.
“In one of these, St. Philip’s, mine Eyes beheld all the Signs of an
approaching Famine; the Face of the Earth appeared as it were a
dry Crust, burnt up and gaping for its watry Nutriment; hardly any
thing green appeared, and I am told, the Face of the Country is
much the same in Christ-Church Parish. Now how miserable must it
be with the single Poor, and with Families! I assure you, several are
come into ours, and others are gone farther Leeward to seek for
Work and Food. You who are tender Parents, consider how terrible it
must be for Families with nothing in their House, nothing growing on
their Land, not a grain of any thing to support themselves and dear
helpless Children: No Money, and no Credit, no Relief from without,
and no Bread, nor Water either, hardly within or without. I have heard
of poor Men going about for Work, to sustain their own Bodies,
forced to leave Wife and Children at home to starve; sure your
Hearts must relent, and every one of you give according as you are
able, with a free Mind, and willing Heart. But here some may object,
Why should I give to those two Parishes, when our own Poor may be
in as great Want? I answer, some may be so; but the Calamity
(blessed be God) is not so general here; it is not so bad with us in
that one necessary Article of Water. Thirst is terrible, let us then pity
our poor Brethren, their Wives and Children, who go so far for Water
that they have not due time to get their Bread, were there Work for
them to earn it by.
“I believe, you know we have here poor Families in great want,
and I could wish our Vestry would meet, particularly to consider it;
but in the mean time, let us not forget the poorer People of these two
Parishes, as now perishing for want of Food; yea, his L——p and the
Council’s Belief is, (you hear) that some have already died for want
of Bread.
“What Christian Man or Woman then in Affluence and Plenty, can
have an Heart so hard as not to bestow liberally on so great, so sad,
so calamitous a Necessity and Misery? and what poorer Christian,
who has somewhat, tho’ little above his daily Wants, but will fling his
Mite to stop so dread an Evil?
“What Christian Woman, who has young and helpless Children of
her own, and Bread to give them, but whose Bowels must yearn and
Heart ake to hear, that in these two Parishes are many Infants crying
at the empty Breasts of their Mothers, and their Mothers weeping
and languishing at the same time for Bread to sustain themselves.
“What compassionate Fathers or Brothers but must grieve to
understand, that grown Children too young to work, are now starving
in these Parishes, and their Parents and Brothers nothing to relieve
them.
“What good Children but must bleed at heart to see their Parents
starving? yet such is the Fate of some in these Parishes.
“Christians consider, that one way of keeping Famine from us of
this Parish, is to bestow our Charity in a Proportion to their Wants,
and our Ability: That is the likeliest Method to move God to give us
fruitful Seasons, to renew our Springs, and bring a cheerful Green
over the Face of our Plants and Seeds.
“May the blessed Spirit, &c.”

The Consequence of this Distress now among the Barbadians, is

shifting their old Habitations; several impelled by Necessity, and
Wants, (stronger Motives than Religion;) are stealing away to mend it
where they can.
The Sufferings of these Islanders, I think, will carry some
Similitude to larger Countries; where the remarkable Decay, or Loss
of one single Branch of Trade, it’s observed, will sensibly affect
Multitudes, not only those immediately concerned in the retailing,
who must change Trades, infringing on others, or seek other
Countries, but also those not concerned; because as an
extraordinary Trade stamps an extraordinary Value on Land, and that
on Provisions, when the one fails, or changes hands, as it has and
will do, (Venice, the Hans Towns, Antwerp, Holland, and which by
the way, shews all Countries bordering on the Sea, within 50°° of
Latitude, equally advantageous for Trade) the other ought to give
way for the lowering of Provisions, and Charge of Subsistence to the
Poor, (some ways of it being supposed now to be cut off or
curtailed:) and if Landlords do it slowly, the Law should oblige;
because, as publick Virtue is no private Man’s Profession, he will
take his Lands into his own hands, tho’ with Loss, rather than submit
to the Reduction of his Rents; and because he can afford it, will
hoard, and suffer Grain to decay and spoil, before he will fall the
Price.
In our Plantations, the inferior sort of Merchants are not unlike
Sharpers in Gaming; they by a better Skill, know how to prey on the
Wants, the Weakness, and Passions of their Customers (the
Planters and Artificers) chaining them down by degrees to their
Service; many of the Inconsiderate being ruined without knowing it,
till the very Day they want Victuals.
 SUGAR-CANES.
In the Wars between Holland and Portugal in Brasil, a Dutch-Man
arrived here from thence, who taught them the way of Planting and
making Sugars. They are set out between August and December, six
Inches deep, and do not come to Maturity until one year and a
quarter: when ripe, which is known by their Colour, they cut them up
with a Bill, and send them to the Wind-mills, which presses out the
Juice so clean, the Canes by being an hour or two in the Sun,
become fit for Fuel.
The Liquor must not remain in the Cistern above a day, for fear of
souring; it is therefore by a Gutter conveyed to the Copper or Boyler,
and in the boiling, the Filth scummed off; thence it’s conveyed into
the second and third, and in the last, called the Tack, is boiled to a
Consistency, and turned into a Grain by throwing in of Temper, which
is only the Infusion of Lime and Water made strong according to the
Goodness of the Cane. Nine Pounds of Juice makes one of
Muscovado, and one of Molossus.
From hence it is carried to the cooling Cistern, till fit to put in Pots,
which have Holes at Bottom to drain off the Molossus.
Of these Molossus again, they sometimes make another worse
Sugar, called Paneels. Of the Scum, coarse Molossus, Washings of
the Boilers and Pots, fermented together, is made Rum.
To refine Sugar, is to boil it over again, and clarify with the same
Lime-Water and Eggs, reckoned better than the clayed Sugars of
this Region, made by putting a clayey Earth mixed with Water to the
thickness of a Batter upon them, and repeated three or four times
according to the degree of Whiteness design’d; both ways carry the
Treacle and Molossus downwards, but the former most esteemed,
as mixing less, and purging to better purpose. Lime refines from
Impurities, and imparts a softer Taste, experienced in throwing it into
Wells of hard Water; the best refin’d in Loaves comes back to the
Sugar-Colonies from England, sell at 50 or 100 per Cent. Advance,
and are of common Use; they must be kept dry, a hot and moist Air
dissolving them.
From Molossus, Distillers make a clean Brandy, and it gives a
pretty tasted Spirit to Malt Liquors, boiled and worked in the Tun.
Besides Rum and Sugars, they have Quantities of Ginger, Aloes,
Tamarinds, Citron, Cassia, Coloquintida, Cassava, Limes, Oranges,
Guavas, Pine-Apples, Mastick, Cedar, Cotton and Palmeto Trees,
prickled Pear; but our Apples and Pears, nor any of our Shrub-Fruits,
Goose-berry or Currant, will thrive. Of the Potato they make a brisk
Small-beer, called Mobby.
About two or three years ago, the low Price of Sugars, that had
reduced and beggar’d the Planters, brought on a Complaint, and Bill
in Parliament in their favour. They urged, according to the best of my
Remembrance, that the northern Colonies, especially New-England,
being suffered to trade with the French Islands, was in a great part
the Occasion of this, and a Loss to the Nation; for they took off all
the French Molossus, which before they had no use for, but sold it
our Islands at very low Prices.
The French therefore were helped by this Sale, to afford their
Sugars cheaper, and still more enabled by a nearer Way of Living;
by the Customs being taken off, allowing them to go thence to any
Market, and other Encouragements to undersell, and take the foreign
Markets from us, who were clogged with all those Inconveniencies.
The New-England People alledged, their Trade seemed the least
essential Article in the Injury complained of; for unless our Islands
found means to take off the other Impediments, and bring their
Sugars to as cheap, or cheaper Price than the French and Dutch,
they would be the same in respect to foreign Markets; and if new
Grounds are better, or more wanted in Plantations, there are enough
at Jamaica, St. Christopher’s, &c. to redress the Evil. But this is not
in their View, say they; the more Lands are employed, the less will
be the Value of the present Estates, an impolitick Reduction of all
prodigal Expences; for every Island singly, reckon their Happiness in
part, not from the flourishing Condition of another, but from
Casualties, and bad Seasons; the less quantity there is to answer
the Demand, the higher the Price.
Barbados formerly used to buy the French and Dutch Sugars,
making all that Trade go through their own hands, till in 1715, laying
a Duty turned the Channel, and they would now make up that
oversight by imposing their own Price on us.
The Northern Colonies deserve Favour, they think, as vastly
superior in Number and Trade, take off more of the Manufactures of
England for themselves, and their Trade with the Indians, who
exchange Furrs and Pelfry to make Hats; for the same Reason, they
want more Molossus to manufacture among themselves, than our
Islands can sell, or if they could, cannot take off one quarter of the
Lumber, Horses, and refuse Fish, with which we trade with the
French, not only for Rum and Molossus (which may as well come to
us this way, as through their hands) but sometimes also Money; and
without which we have no means of purchasing, nor could get rid of
our Produce and Industry, which is very unreasonable.
To lay a Tax of six-pence a Gallon on French Molossus, is the
same as a Prohibition, which their Country cannot so easily bear.
They take 20000 Hogsheads a year (each 100 Gallons) from the
Dutch and French, which is 50000l. whereas they have no Specie to
pay it, their Currency being all Paper, and that but 30000l. Besides, it
would be the first Tax on a charter’d Colony from England, where
they have no Representatives.
Lastly, it was said, the French buy their Negroes, and Sugar-
Materials (Mills, Coppers, &c.) 40 per Cent. dearer than us; therefore
for our Islands to say they cannot afford as cheap, is to say, they will
not abate of their Pride and Luxury, but help to maintain it by a Tax
on our more humble Industry.
 T h e W E S T- I N D I E S .
For a general Idea of the West-Indies, we may understand by that
Term, all the Continent, Sea, and Islands, from Terra Firma to
Florida, or from near the Equinoctial to 28°° of N. Latitude; and if you
include Bermudas, to 32°°. The main Land in this Circuit divided into
Spanish Provinces, is more peculiarly called the Spanish West-
Indies, they possessing all, unless to the Southward in Guiana and
Paria, where there are a few English, Dutch, and French,
interspersed on the Rivers and Coast of Oronoko, Surinam, and
Amazons.
They import hence to Europe, besides Rum and Sugars, great
quantities of Cocoa, Indigo, Cotton, Logwood, Ginger, Lignum-vitæ,
Cochineel, Snuff, Cassia, Aloes, Pimento, Tortoise-shell, Dyers, and
other Wood, a Variety of Drugs, and above all, prodigious Quantities
of Plate, and some Gold.
The Islands in this Sea are the Charibbees, Sotovento, Antilles,
and Bahama.
Charibbees were the lesser Antilles, about 30 in number, whereof
the French have Martinico, St. Lucia, Bartholomew, Deseada,
Granada, Marigalant, Guadalupe, and Santa Cruz. To the Dutch
belong in whole or part, Saba, Eustatia, St. Vincent, and Tobago, or
Tobacco Island; so called, from the Plenty of that Weed there, or the
Weed so called, as first transplanted thence. The rest are English,
and of them Barbados is chief. Others next of Note are Antegoa,
Nevis, St. Christopher’s, and Montserrat; which have a separate
Governor, stiled General of the Leeward Islands, their principal
Produce with us, is Rum and Sugars; but the French, besides these,
cultivate Cocoa, and Indigo: and as the managing of more Lands
naturally gives Plenty, and makes room for an Increase of People,
the French Policy of late years has considerably increased their
Colonies at Martinico and Hispaniola; some say 40000 settled there
at the French King’s Expence, with the Addition of a year’s
Maintenance, to countenance their Mississipi Settlements, and these
further Views of drawing over Men’s Affections, by affording
Europeans the West-India Commodities, at the cheapest rate, and
strengthning themselves against the Resentment of any who dislike
it.
In some are found large Caves that run half a Mile under ground,
supposed the Dwelling-places of the old Natives, who quickly
forsook them to the new Inmates; tho’ Dampier says, he met some of
these Charibbees at St. Lucia, and St. Vincent, and others say the
like of Curasao: The Name imports Cannibals, an Inhumanity
charged on them at the Discovery, as a proper Accusation for
Dispossessors.
Sotovento Isles lie E S E. and W N W. along the Terra Firma,
called so because the Spaniards in their Voyages to Mexico, make
them one after another sub vento (to Leeward.) Of these, the Dutch
have Curasao, Oruba, and Berraire. The Spaniard the others, (La
Trinidad, and Margarita, chief;) from whence, and the Antilles, they
have of late years very much infested this Navigation, with their
Guard le Costas, confiscating the English Effects in Reprisal, it is
supposed, for the Loss of their Fleet near Messina, 1718.
The greater Antilles are, Cuba, Hispaniola, Portorico, and
Jamaica; the three former, Spanish.
Cuba is principal; a very pleasant and flourishing Island, the
Spaniard building and improving for Posterity, without dreaming, as
the English Planters do, of any other Home. They make the best
Sugars in the West-Indies. It was from this Island, (Velasquez
Governor,) that Cortez in 1518, made his Expedition and Conquest
of Mexico.
The Havana, its chief Port and Town, is esteemed the richest in
America; for besides its own valuable Produce, the Spanish Fleets
from all parts on the Main, make up here in their return to Europe.
 The Islands on the South Side of it, and the Camaines, are
resorted to for the largest and best Turtle.
Porto-Rico, and Hispaniola (the diminutive of Hispania) are Islands
we make, in our Passage to Jamaica, famous of late for their Guard
le Costas. These Privateering Fellows, when they are not acting by
lawful Commission, they know the Governor’s Mind, and bring in
Ships on a pretence they are trading with the King of Spain’s
Subjects in a clandestine and prohibited manner; if they find any
Pieces of Eight, it is a Condemnation; an Encouragement in
searching a Ship, to deposite some there themselves: Or if this Trick
fails, they are yet detained, and on various Pretences lengthned out
with Law-suits, till ruined. We called, after weighing from Barbados,
at Sancto Domingo, the chief Town of Hispaniola, where we found
three English Masters of Ships under these Hardships. They had got
the better in Law, but with such Charge and Delay, that it had spoiled
their Ships and Voyages; and lest that should not do it effectually,
their Damages are against the Captains of the Privateers, who are
perhaps the Governor’s servile Dependants, and not worth a Groat.
Sancto Domingo Harbour has 15 Fathom Water at the Bar, and
the Entrance defended by several Batteries. The Town is the
Residence of an Arch-Bishop, and a President from Spain, who lives
in a House that is said to have been built and occupied by
Christopher Columbus himself. To this Officer (on account of its prior
Settlement) Appeals come from all the Spanish West-India Islands,
whose Sentence is definitive, unless called by a particular
Commission to Old Spain. They buy their Places, it seems, and
consequently execute them oppressively.
The Island is diminished of its Inhabitants, for this, or a securer
and better Settlement on the Continent; so that the French now,
about Petit Guavas, equal, if not outnumber them, tho’ both together
are vastly short of what its Extent and Fertility deserves. A Soil that
produces any thing; their Sea and Rivers full of Fish, and the
Country spread with Forests of Cabbage and Palm-Trees, in which
are prodigious Numbers of wild Hog and Beef, which the Hunters of
different Nations at certain Seasons shoot, the latter for their Hides;
and the Pork, they jerk (as they call it) that is, strip it from the Bones,
and then salting the Flesh a little, dry it in the Sun.
Bahamas, so called from the Principal, or Lucayes from Lucayone
(new Providence, the largest of them) where the English have a
Governor: They are noted for a dangerous and rapid Chanel,
commonly called the Gulph of Florida, through which the Spanish
Fleets always take their Passage to Europe, and are frequently
shipwrecked.
The Pyrates often take their rise here, or if not, seldom fail in the
Course of their Adventures to visit these Seas. There are Multitudes
of little Islands and Kays, besides this Division above, that afford
Refreshments of wild Hog, Cow, Goat, Sheep, Parrots, Guanas,
Turtle, and Fish; many of them uninhabited, and seldom visited but
on that account, whereby they are a natural and good Security. The
Sailor, when he would express the Intricacy of any Path-way, stiling it
the Caribbees.
They commonly make their Beginning here after this manner;
when any Spanish Ship is wrecked in Florida, the Jamaicans fit out
Vessels to fish upon her, (the best I believe, being always pleas’d
with going shares in such Voyages, which may be judged of by their
Treatment of the Galleon cast away on Jamaica, a very few Years
ago) and dispute a Right of Plunder with the Spaniard himself, who
is also fitted from the Havana on these Accidents, to recover what
they can; the Contest therefore is with various Fortune, and
sometimes turns to a bad account.
Our Logwood-Cutters from Campechy and Honduras, who have
been unfortunate by the frequent Visits of the Spaniards to destroy
that Trade, remove hither, or those to them, to consult of Reparations
to their broken Fortunes. Saunterers also, who are turtling from
different Parts, do all together make a considerable Resort
sometimes, and being prompted to Revenge for the Injuries
sustained, they combine and furnish out a little Sloop perhaps
against them at first, who finding little come by confining their Ways
and Means to the Spaniards only, who sail in Fleets, they fall at last
on any Nation; the Transition being easy from a Buccanier to a
Pyrate; from plundering for others, to do it for themselves.
These Logwood-Cutters, (since mentioned) I must observe, were
originally settled at the Bay of Campechy, but with a contested Right
that made it hazardous, the Spaniard opposing the Legality, and
when uppermost, treating them as Pyrates, which our People have
frequently returned again with Interest. It was taken 1659, by Sir
Christopher Mins. In 1678 again, by the English and French
Privateers; and what Licence the Peace of Utrecht gave, I am
uncertain, but they are since drove out, and now support themselves
with their Arms at the Bay of Honduras.
They are about 500 (Merchants and Slaves,) and have taken up
their Residence at a Place called Barcaderas, about 40 Miles up a
narrow River full of Alligators; and what is a greater Inconvenience
against transporting their Effects, is a strong Current in it from the
Freshes up Land, and the Banks being covered with Shrubs, that
makes it difficult to walk and tow the Boats; covered also with infinite
Numbers of Sand-Flies, and Muskitos. They live in Pavilions; a
Servant at their time of lying down to rest, shaking them till cleared of
these Vermin, that are an unsufferable Plague and Impediment to
Sleep.
At the Season (once a year) they move their Pavilions from the
pleasurable Spots, the better to attend the Logwood cutting, which
carries them sometimes many Miles from this principal Residence, to
follow the Wood, which runs in a Line or Vein (like Minerals in the
Earth) of some Miles perhaps, and then as many, without a Stick of
it. They cut it into large Pieces, and leave it on the Ground till the
Land-Flood favours their bringing it into the River, and then Canoos
are laden away with it, to lay in store at Barcaderas, where the Chief
are still left residing.
They have all good Arms, and knowing the Spanish Clemency,
defend themselves desperately, if attacked; which has happened
seldomer than at Campechy, and always by Sea.
A Servant, which is the first Step with Seamen into the Trade, is
hired at a Tun of Logwood per Month, and has one Day in seven for
himself, making together about 10l. a Month to him; hence, if
thoughtful and sober, they in time become Masters, join Stock, and
trade independently. They have a King, chose from among their
Body, and his Consort is stiled Queen, agreeing to some Laws by
common Consent, as a Guide to them.
The Ships that come into the Bay, are on their Guard also, fetch it
down in flat-bottomed Boats, each Crew being allowed on the
Voyage, a Bottle of Rum and some Sugar, and row generally in the
Night, as freest from those stinging Flies, and rest in the Day.
The Exchange with Ships is for Money, Beer, Flower, or any sort of
Provisions and Necessaries; these, the cunningest reserve in Store
against the Wants and Demands of the Inconsiderate, and so make
extraordinary Returns.
It may not be improper to conclude this Head with an Observation
or two on the Channel and Current of Florida, which I submit to the
more Skilful.
This Gulph is as dangerous a Navigation as any known; the
Spaniards often experience it, because it’s an Addition to the
Danger, that they have unwieldy Ships, and lubberly Seamen. We
commit Errors, I imagine, by our common Charts, which lay down the
Channel double the Breadth it is; the most intelligent in the Passage
having assured me, it is not above 16 or 18 Leagues over; and
therefore when a Storm happens, build on a false Supposition.
The Spaniard is likewise over-careful to be safe; the nicer
Observations made on Shoals, Currents, or Winds, either here or in
the Bay, when and how to make them advantageous, are from an
imagined Security against any maritime Power, committed only to
their Admiral (according to common Report) whose Light the Fleet
are to follow; and for their better Recovery of any shipwrecked Cargo
in the Gulph, (frequent in losing the Admiral,) they have a Garrison at
St. Augustine, on the Florida Shore, a barren Spot where they are
almost starved, and which would not be worth keeping but for this.
Ships and Vessels may, and often have sailed through this Channel
from the N End to Cuba, or the Bay of Mexico, notwithstanding the
common Opinion, on account of the Current, that is against it. They