Neurological Aspects of Substance Abuse, Second Edition

475 Pages·2004·3.19 MB·English

by  John Brust

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NEUROLOGICAL ASPECTS OF SUBSTANCE ABUSE ISBN 0-7506-7313-2
©2004, 1993 Elsevier Inc. (USA) All rights reserved
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NOTICE
Medicine is an ever-changing field. Standard safety precautions must be followed but as new research
and clinical experience broaden our knowledge, changes in treatment and drug therapy may become
necessary or appropriate. Readers are advised to check the most current product information provided
by the manufacturer of each drug to be administered to verify the recommended dose, the method and
duration of administration, and contraindications. It is the responsibility of the treating physician,
relying on experience and knowledge of the patient, to determine dosages and the best treatment for
each individual patient. Neither the Publisher nor the author assumes any liability for any injury
and/or damage to persons or property arising from this publication.
The Publisher
Library of Congress Cataloging-in-Publication Data
Brust, John C. M. (John Calvin M.), 1936-
Neurological aspects of substance abuse/John C. M. Brust–2nd ed.
p. ; cm.
Includes bibliographical references and index.
ISBN 0-7506-7313-2
1. Psychopharmacology. 2. Substance abuse–Complications. I. Title.
[DNLM: 1. Neurologic Manifestations. 2. Substance-Related
Disorders–physiopathology. 3. Nervous System–drug effects. WM 270 B912n 2004]
RM316.B78 2004
616.86–dc22
2003065533
Editor:Susan F. Pioli
Editorial Assistant:Joan Ryan
Publishing Services Manager: Joan Sinclair
Project Manager: Mary Stermel
Printed in the United States of America
Last digit is the print number: 9 8 7 6 5 4 3 2 1
As before, for Meridee, Mary, Frederick, and James
Preface for First Edition
Reminiscent of “The Sorcerer’s Apprentice,” we are awash in a deluge of redundant
medical texts. Nevertheless, my colleague Dr. Lewis P. Rowland persuaded me that
neurologists would welcome a book on drug abuse. If you disagree, blame him.
If you agree with the premise but don’t like the product, blame me.
The title has been carefully considered, for it is my view that most biomedical
aspects of drug abuse are in fact neurological. Accordingly, the text addresses
pharmacology and animal studies, overdose and withdrawal, medical and neurolog-
ical complications, fetal effects, and pharmacotherapy. Historical background and
epidemiology are also considered, partly because the subject is often quite enter-
taining, and partly because contradictory and bizarre societal attitudes toward
particular substances are better understood in an historical context.
Some of this material has appeared in a chapter on drug dependence I wrote for
Joynt’s Clinical Neurology, and I thank the publishers at Harper & Row for letting
me occasionally plagiarize my own sentences without fear of copyright infringe-
ment. I also thank Dr. Robert Joynt for inviting me to write that chapter, without
which I doubt I would have had the fortitude to proceed with the present text.
Other thanks are due to Nancy Megley, formerly at Butterworth, for early encour-
agement; Christopher Davis, also formerly at Butterworth, whose cheerful patience
remained unflagging as one promised delivery date after another receded into
the future; Susan Pioli, currently at Butterworth, who brought the final product to
the finish line; Sandra Sands, Janet Rivera, and Jeffrey Green for indispensable
assistance with the manuscript; Dr. Edward B. Healton and Ellen Giesow of the
Columbia P&S Dean’s office at Harlem Hospital Center, for support tangible and
intangible; and—even though his suggestion effectively demolished 52 consecutive
weekends—Dr. Lewis P. Rowland.
John C.M. Brust, M.D.
New York, New York
ix
Preface
The observation in Ecclesiastes that there is nothing new under the sun might apply
to public attitudes toward substance abuse and addiction; as the decades roll by, the
March of Folly otherwise known as America’s War on Drugs continues apace. Amidst
political posturing, media distortions, and corporate turpitude, however, enough is
new on the neurobiological and clinical fronts to justify a second edition of this text.
In no particular order, questions addressed in the present volume include: Is there a
pharmacological common denominator for all addictive drugs? What is the extended
amygdala? Is sensitization the switch that turns on addiction? Does ethanol bind to neu-
rotransmitter receptors? How many Americans currently use illicit drugs? How many
American 21-year-olds are binge drinkers? What are blunts? What are bidis? What do
nitrites have to do with AIDS? What ever happened to the “crack babies”? What per-
cent of United States federal antidrug expenditures is for education and treatment? What
is bad about Stadol? What is bad about Oxy-Contin? How do endocannabinoids act?
Why was it so difficult for the FDA to ban ephedra products? What drugs turn up at
“raves”? What is “whack”? How many people worldwide will the tobacco industry kill
over the next three decades? Does angel dust cause schizophrenia? What is “doing a
shotgun”? What effect on U.S. illicit drug consumption has defoliation of the South
American continent had? What effect on international drug trafficking has the War in
Afghanistan had? Does marijuana cause lasting cognitive impairment? Does cocaine?
Does “Ecstasy”? Does tobacco? What is a grimmie? What is “candyflipping”? What is
post-hallucinogen perceptual disorder? Why would someone drink toner cartridge
cleaner? Does ethanol cause strokes or prevent them? Does ethanol cause dementia or
prevent it? What is “U4Euh”? Does heroin maintenance therapy make sense? How does
kava affect eye movements? What is DARPP-32? Does therapeutic ibogaine have a
future? What are the “date-rape” drugs? Who didn’t inhale?
A number of people deserve thanks for advice, encouragement, or simply for-
bearance, but some merit special mention. My secretary, Shirley E. Myers-Jones,
working as she does with a word processor illiterate, was a good deal more involved
with the text than secretaries these days expect to be. Susan Pioli of Elsevier once
again cheerfully nudged the book to completion as one missed deadline succeeded
another. Finally, Columbia University’s former Chairman of Neurology, Dr. Lewis P.
Rowland, continues to visit us regularly at Harlem Hospital Center, as does his
successor, Dr. Timothy A. Pedley. Without their support, out-of-job-title projects like
“Neurological Aspects of Substance Abuse” would not be possible.
John C.M. Brust, M.D.
New York, New York
xi
Chapter 1
Questions and Definitions
Giving up smoking is easy. I’ve done it hundreds of times.
—Mark Twain
Just say no.
—Nancy Reagan
I didn’t inhale.
—William Jefferson Clinton
What Do We Mean byDependence, compulsive drug-seeking behavior. Physical depend-
Addiction, andAbuse? ence induces “physical” symptoms and objective
signs. Psychic and physical dependence can occur
In 1964, the World Health Organization (WHO) independently or together, and only mind–brain
Expert Committee on Addiction-Producing Drugs dualists need concern themselves over the volun-
recommended that the terms drug addiction and tary or nonorganic aspects of the former and the
drug habituationbe replaced bydrug dependence, involuntaryororganicaspects of the latter.
defined as: These definitions were subsequently subjected
to a fair amount of tinkering. For example, in 1982,
a state of psychic or physical dependence, or both, on a
a WHO memorandum suggested replacingphysical
drug, arising in a person following administration of that
drug on a periodic or continuous basis. The characteristics dependencewithneuroadaptive stateand explicitly
of such a state will vary with the agent involved …for distinguished dependence from drug-related dis-
example, dependence of morphine type, of barbiturate ability.2 The American Psychiatric Association’s
type, of amphetamine type, etc.1 Diagnostic and Statistical Manual (DSM-IV), more-
Psychic dependence is “…a feeling of satisfaction over,has its own set of criteria for dependence and
and a psychic drive that requires periodic or con- abuse (Tables 1–1, 1–2).3Nevertheless, the original
tinuous administration of the drug to produce pleas- definitions of physical and psychic dependence
ure or avoid discomfort.” Physical dependence is have remained in general usage.
“…an adaptive state that manifests itself by intense Addiction is psychic dependence. An addict is
physical disturbances when the administration of someone whose psychic dependence—with or with-
the drug is suspended or when its action is affected outphysical dependence—has made drug procure-
by administration of a specific antagonist.” Psychic ment a daily preoccupation. Addiction used to be
dependence thus induces “psychic” symptoms and equated with physical dependence; it was believed
1
2 NEUROLOGICAL ASPECTS OF SUBSTANCE ABUSE
Table 1–1.DSM-IV Criteria for Substance Dependence
A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three
(or more) of the following, occurring at any time in the same 12-month period:
1. Tolerance, as defined by either of the following:
(a) need for markedly increased amounts of the substance to achieve intoxication or desired effect
(b) markedly diminished effect with continued use of the same amount of the substance
2. Withdrawal, as manifested by either of the following:
(a) the characteristic withdrawal syndrome for the substance
(b) the same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms
3. The substance is often taken in larger amounts or over a longer period than was intended
4. There is a persistent desire or unsuccessful efforts to cut down or control substance use
5. A great deal of time is spent in activities necessary to obtain the substance (e.g., visiting multiple doctors or driving
long distances), use the substance (e.g., chain-smoking), or recover from its effects
6. Important social, occupational, or recreational activities are given up or reduced because of substance use
7. The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological
problem that is likely to have been caused or exacerbated by the substance (e.g., current cocaine use despite recognition
of cocaine-induced depression, or continued drinking despite recognition that an ulcer was made worse by alcohol
consumption)
Specify if:
With Physiological Dependence:evidence of tolerance or withdrawal (i.e., either Item 1 or 2 is present)
Without Physiological Dependence:no evidence of tolerance or withdrawal (i.e., neither Item 1 nor 2 is present)
Source: Modified from Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Washington, DC: American
Psychiatric Association, 1994, with permission of the publisher.
that prolonged exposure of neurons to a drug led to addiction4—as emphasized by the U.S. Surgeon
adaptive responses, which in turn led to craving, General, when in 1988 he pronounced tobacco an
which in turn led to drug-seeking. Such a sequence addictive drug.5
of events would occur whether the drug was self- The term drug abuse is a social judgment. One
administered (by an animal or human) or passively might be considered a drug abuser for using an
administered (by an investigator or nurse). In fact, illegal substance (e.g., heroin or cocaine), for using
many patients who receive morphine passively a legal substance in amounts that others consider
for pain have prominent withdrawal symptoms yet excessive (e.g., ethanol), or for using a legal sub-
little or no craving for the drug. Conversely, absti- stance in any amount (e.g., tobacco). Pharmacolo-
nent tobacco smokers often have intense craving gists often use the term abuse liability to signify a
without observable physical signs. Conditioning drug’s potential for inducing addictive behavior;
and learning are crucial to the development of indeed, that concept is the basis of Drug Enforcement
Table 1–2. DSM-IV Criteria for Substance Abuse
A. A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one
(or more) of the following, occurring within a 12-month period
1. Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home
(e.g., repeated absences or poor work performance related to substance use; substance-related absences,
suspensions, or expulsions from school; neglect of children or household)
2. Recurrent substance use in situations in which it is physically hazardous (e.g., driving an automobile or operating a
machine when impaired by substance use)
3. Recurrent substance-related legal problems (e.g., arrests for substance-related disorderly conduct)
4. Continued substance use despite having persistent or recurrent social or interpersonal problems caused or
exacerbated by the effects of the substance (e.g., arguments with spouse about consequences of intoxication,
physical fights)
B. The symptoms have never met the criteria for Substance Dependence for this class of substance
Source: Modified from Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Washington, DC: American
Psychiatric Association, 1994, with permission of the publisher.
Questions and Definitions 3
Administration (DEA) drug scheduling under the although by the above-mentioned definition caffeine
1970 Controlled Substances Act (Table 1–3). In is an addicting drug, its legality and lack of perceived
clinical practice, however, abuse is not the same as harmfulness allow coffee drinkers to pass their
addiction. Even one-time use of a drug is abuse if days free of social stigma. As we shall see, in the
it causes harm to oneself—for example, cocaine—or United States neither addiction liability nor physi-
to others—for example, ethanol. Conversely, cal harm has much bearing on a drug’s legal status.
Table 1–3. Federal Schedules of Controlled Drugs, 2003
Opioids Stimulants Sedatives/Hypnotics Other
Schedule I Benzylmorphine Cathinone Methaqualone Bufotenine
Dihydromorphinone N-methylamphetamine Quaalude Ibogaine
Heroin 3,4-Methylenedioxy- Lysergic acid
Ketobemidone methamphetamine diethylamide
Levormoamide MDMA LSD
Morphine- Ecstasy Marijuana
methylsufanate Phenylpropanolamine Mescaline
Nicocodeine 4-methylaminorex Peyote
Nicomorphine 4-bromo-3, 4-dimethoxy- Phencyclidine
Racemoramide phenylethylamine PCP
Psilocybin
Schedule II Alfentanil Amphetamines Amobarbital
Alfenta Cocaine Amytal
Codeine Dextroamphetamine Glutehimide
Fentanyl Dexedrine Doriden
Sublimaze Methamphetamine Pentobarbital
Hydromorphine Desoxyn Nembutal
Dilaudid Methylphenidate Secobarbital
Levorphanol Ritalin Seconal
Levo-Dromeram Phenmetrazine
Methadylacetate Fastin
(LAAM) Preludin
Meperidine
Demerol
Methadone
Morphine
Oxycodone
OxyContin
Perocet
Percodan
Oxymorphone
Numorphan
Pantopon
Sufentanil
Sufenta
Schedule III Buprenorphine Benzphetamine Butabarbital Dronabinol
Buprenex Ditrex Butisol Marinol
Subutex Phendimetrazine Butalbital Testosterone
Buprenorphine + Plegine Fiorecet
Naloxone Fiorinal
Suboxone Methyprylon
Codeine compounds Noludar
Tylenol #3 Gamma-
Tussionex hydroxybutyrate
Xyrem
Continued
4 NEUROLOGICAL ASPECTS OF SUBSTANCE ABUSE
Table 1–3. Continued
Opioids Stimulants Sedatives/Hypnotics Other
Schedule IV Propoxyphene Diethylpropion Alprazolam
Darvon Tenuate Xanax
Darvocet Phentermine Chloral betaine
Pentazocine Fastin Chloral hydrate
Talwin Modafinil Noctec
Provigil Chlordiazepoxide
Librium
Clonazepam
Klonopin
Clorazepate
Tranxene
Diazepam
Valium
Estazolam
Prosom
Ethchlorvynol
Placidyl
Ethinamate
Flurazepam
Dalmane
Halazepam
Paxipam
Lorazepam
Ativan
Mazindol
Sanorex
Mephobarbital
Mebaral
Meprobamate
Equanil
Methohexital
Brevital Sodium
Methylphenobarbital
Midazolam
Versed
Oxazepam
Serax
Paraldehyde
Paral
Phenobarbital
Luminal
Prazepam
Centrax
Temazepam
Restoril
Triazolam
Halcion
Zaleplon
Sonata
Zolpidem
Ambien
Continued
Questions and Definitions 5
Table 1–3. Continued
Opioids Stimulants Sedatives/Hypnotics Other
Schedule V Opium preparations 1-Deoxyephedrine Chlordiazepoxide
Donnagel PG Vicks Inhaler Librax
Kaopectalin PG
Schedule I: High potential for abuse, no accepted medical use
Schedule II: High potential for abuse, currently accepted medical use
Schedule III: Accepted medical use, lower potential for abuse than Schedule I and II drugs
Schedule IV: Lower potential for abuse than Schedule III drugs
Schedule V: Lowest abuse potential of the controlled substances; includes over-the-counter antitussives and antidiarrheals
What IsToleranceand What Does It anticipatory compensation, which attenuates the
Have to Do with Physical Dependence drug’s effect, perhaps by causing environmentally
and Addiction? cued changes in drug disposition.11
The interrelationships between tolerance,
Tolerance is “... an adaptive state characterized by physical dependence, and drug-seeking behavior
diminished response to the same quantity of drug or are complex.12 In animals, tolerance and physical
by the fact that a larger dose is required to produce dependence for psychoactive addicting agents tend
the same degree of pharmacodynamic effect.”1There to develop and persist together, and inhibitors of
are several kinds of tolerance. Metabolic, dispo- protein synthesis block both.13 On the other hand,
sitional, or pharmacokinetic tolerance results from in humans, marijuana and lysergic acid diethyl-
increased metabolism and decreased availability of amide (LSD)-like drugs produce striking tolerance,
the drug at its locus of action. Cellular or pharma- yet marijuana causes few symptoms of physical
codynamic tolerance, on the other hand, is a reduced dependence, and with hallucinogens withdrawal
response despite unchanging drug concentrations symptoms do not occur. With opioids, which pro-
and availability; it signifies an adaptive change in duce predictable, severe withdrawal symptoms and
the brain.6 signs, tolerance is much more marked for psychic
Different from pharmacokinetic and pharma- and analgesic effects than for smooth muscle actions.
codynamic tolerance are behavioral and environ- Withdrawal from amphetamine and cocaine causes
mental tolerance. Behavioral tolerance is a reduced depression, hunger, and intense craving but few
response consequent to a drug’s negative effect on objective signs, and although tolerance develops
reward-seeking or punishment-avoiding behavior.7 to the euphoric effects of these psychostimulants,
For example, rats intoxicated with ethanol and per- there seems to be reverse tolerance (sensitization)
forming equilibratory tasks develop tolerance to the to psychosis, abnormal movements, and seizures.
drug’s ataxic effects faster than rats not being tested.6 Whether tolerance is required for physical depend-
Environmental tolerance is the result of a drug being ence is unclear, and it is possible that an explanation
administered in a setting of familiar cues.8It could of either phenomenon—in terms of, say, enzyme
be considered an atypical pavlovian response. Pavlov regulation, receptor change, or functional hyper-
observed classical conditioning in dogs receiving trophy of alternate pathways—will shed little light
morphine injections (the unconditioned stimulus); on addiction per se.
after enough trials, the appearanceof the technician
(the conditioned stimulus) was sufficient to produce
morphine-like effects of salivation, vomiting, and What Is the Significance of Sensitization?
sleep.9By contrast, animals receiving morphine “in
the context of pre-drug cues” may belesssensitive to As noted, with repeated drug administration
its analgesic, thermic, locomotor, sedating, and even some effects decrease (tolerance) yet others
lethal effects than animals tested in an unfamiliar increase (“sensitization,” “reverse tolerance”). This
setting.8,10 This particular conditioned response— phenomenon, perhaps comparable to electro-
environmental tolerance—seems to result from an physiological kindling, is particularly evident