ournal of
`
`lull V
`
`TUP 1-8111.1110V1
`
`February 1996
`
`re;
`
`HEALTH SCIENUES LIBRARI
`
`inical FEB U7 1996
`chopharmacology
`
`Editors-in-Chief
`Richard I. Shader, M.D.
`David J. Greenblatt, M.D.
`Assistant Editors
`
`Lawrence G. Miller, M.D.
`Domenic A. Ciraulo, M.D.
`Tufts University School of Medicine
`Boston, Massachusetts
`
`Barbara Kern, Managing Editor
`
`Editorial Board
`David J. Kupfer, M.D., Pittsburgh, Pennsylvania
`Louis Lasagna, M.D., Boston, Massachusetts
`V. Markku I. Linnoila, M.D., Ph.D.,
`Bethesda, Maryland
`Herbert Y. Meltzer, M.D., Cleveland, Ohio
`Jack H. Mendelson, M.D., Belmont, Massachusetts
`Roger E. Meyer, M.D., Washington, D.C.
`Robert E. Rakel, M.D., Houston, Texas
`Donald S. Robinson, M.D., Melbourne, Florida
`Alan F. Schatzberg, M.D., Stanford, California
`Joseph J. Schildkraut, M.D., Boston, Massachusetts
`Edward M. Sellers, M.D., Ph.D., Toronto, Ontario
`Joe P. Tupin, M.D., Sacramento, California
`Richard J. Wyatt, M.D., Washington, D.C.
`
`Cole, M.D., Belmont, Massachusetts
`'is, M.D., Chicago, Illinois
`▪ T, M.D., Pittsburgh, Pennsylvania
`▪ ledel, M.D., Birmingham, Alabama
`-7- hon, M.D., Pittsburgh, Pennsylvania
`-
`. Glassman, M.D., New York, New York
`4- ' M.D., Stanford, California
`
`E , Goodwin, M.D., Bethesda, Maryland
`towsky, M.D., Chapel Hill, North Carolina
`Tik, M.D., Ph.D., Los Angeles, California
`r.- :-. lein, M.D., New York, New York
`
`0
`
`re,
`
`L
`•
`* • C.
`* • o
`* 0 OW
`
`*
`*
`*
`* CIN
`*
`$,-
`*
`r —
`*
`
`9
`
`.c
`U) G)
`
`OLI-N3
`U)'
`r.-1. .1
`
`›—
`* •
`f—
`•— c0 X<
`*
`OW
`*
`* a.. ==.0v)
`
`Ross J. Baldessarini, M.D., Belmont, Massachusetts
`
`Magda Campbell, M.D., New York, New York
`
`Bernard Carroll, M.D., Ph.D., Durham, North Carolina
`
`Page 1
`
`SHIRE EX. 2059
`KVK v. SHIRE
`IPR2018-00293
`
`

`

`JOURNAL OF
`CLINICAL PSYCHOPHARMACOLOGY
`
`VOLUME 16
`
`FEBRUARY
`
`NUMBER 1
`
`CONTENTS
`1 Editorial. Twice May Be Too Many: Redundant Publications. Richard I. Shadpr, David,J. Green-
`blatt
`
`2 Mitchell B. Baiter Award: Call for Papers
`
`2 Editors' Note
`
`3 Paroxetine as a- Treatment for Premenstrual Dysphoric Disorder. Kimberly A. Yonkers,
`Christina Gullion, Anita Williams, Kimberly Novak, A. John Rush
`
`9 Fluvoxamine in Prevention of Relapse in Bulimia Nervosa: Effects on Eating-Specific Psy-
`chopathology. Manfred M. Ficther, Ralf Kruger, Winfried Rief, Robert Holland, Jutta Dohne
`
`19 A Study of the Effect of Age and Gender on the Pharmacokinetics of Nefazodone After Sin-
`gle and Multiple Doses. Rashmi H. Barbhaiya, Akshay B. Buch, Douglas S. Greene
`
`26 Investigation of Pharmacokinetic and Pharmacodynamic Interactions After Coadministra-
`tion of Nefazodone and Haloperidol. Rashmi H. Barbhaiya, Umesh A. Shukla, Douglas S. Greene,
`Hans-Peter Breuel, Kamal K. Midha
`
`35 Relatively Low Doses of Cisapride in the Treatment of Nausea in Patients Treated With
`Venlafaxine for Treatment-Refractory Depression. Johnna L. Russell
`
`38 Antipsychotic and Anxiolytic Properties of Rispgridone, Haloperidol, and Methotrimeprazine
`in Schizophrenic Patients. Olivier Blin, Jean Miche Azorin, Philippe Bouhours
`
`45 Prediction of Haloperidol Steady-State Levels in Plasma After a Single Test Dose. Javaid I.
`Javaid, Philip G. Janicak, Rajiv P. Sharma, Anne M. Le ch, John M. Davis, Zhengyu Wang
`
`51 Multiple Drug Use and Psychiatric Comorbidity in Patients Admitted to the Hospital With
`Severe Benzodiazepine Dependence. Usoa E. Busto, Myroslava K. Romach, Edward M. Sellers
`
`58 Buprenorphine Versus Methadone in the Treatment of Opioid Dependence: 'Self-Reports,
`Urinalysis, and Addiction Severity Index. Eric C. Strain, Maxine L. Stitzer, Ira A. Liebson, George
`E. Bigelow
`
`Brief Reports
`68 Lithium and Angiotensin-Converting Enzyme Inhibitors: Evaluation of a Potential Inter-
`action. Patrick R. Finley, John G. O'Brien, Robert W. Coleman
`
`72 Acute Tolerance to Subjective but not Cardiovascular Effects of d-Amphetamine in Nor-
`mal, Healthy Men. Lisa H. Brauer, John Ambre, Harriet de Wit
`
`JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY (ISSN 0271,0749) is published bimonthly, in Feb., Apr., June, Aug., Oct., and Dec., by
`Williams & Wilkins, 351 West Camden Street, Baltimore, MD 21201-2436. Subscription rates $114.00 ($149.00 foreign); institutions $174.00
`($209.00 foreign); in-training $57.00 ($92.00 foreign); single copy $24.00 ($26.00 foreign). (Prices subject to change). The GST number for Cana-
`dian subscribers is 123394371. Second class postage paid at Baltimore, MD, and at additional mailing offices. POSTMASTER: Send address
`changes to JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY, 351 West Camden Street, Baltimore, MD 21201-2436. Indexed by Current
`Contents (Clinical Medicine, Life Sciences, Science Citation Index, Research Alert, ISI/BioMed), Index Medicus, Excerpta Medica, BIOSIS,
`Psychlnfo and Toxicology Abstracts. Printed in U.S.A. Copyright © 1996 by Williams & Wilkins.
`
`Page 2
`
`

`

`0271-0749/96/1601-0072603.00/0
`Journal of Clinical Psychopharmacology
`Copyright © 1996 by Williams & Wilkins
`
`Vol. 16, No. 1
`Printed in U.S.A.
`
`Acute Tolerance to Subjective but not Cardiovascular
`Effects of d-Amphetamine in Normal, Healthy Men
`
`LISA H. BRAUER, PilD,1.4 JOHN AMBRE, MD, PHD,2 AND HARRIET DE WIT, PHD3
`'Postdoctoral Fellow, Department of Psychiatry, University of Chicago, Chicago, Illinois;
`2Director, Department of Toxicology and Drug Abuse, American Medical Association,
`Chicago, Illinois; 3Associate Professor, Department of Psychiatry, University of Chicago,
`Chicago, Illinois; and 4Research Associate, Department of Psychiatry, Duke University
`Medical Center, Durham, NC •
`
`This is a descriptive report on the relationship
`between the pharmacokinetics and plarmacody-
`namics of d-amphetamine in healthy, normal vol-
`unteers. Six men, aged 22 to 31, attended two ex-
`perimental sessions during which they received
`single oral doses of 20 mg- of d-amphetamine.
`Plasma levels Qf drug and measures of drug effect
`were collected predrug and at regular intervals
`Is
`for 24 hours after drug administration. P1 ma
`drug levels peaked at 4 hours and remained a de-
`tectable levels for 24 hours after drug admini tra-
`tion. Subjective ratings, including "feel drug" 1.nd
`"feel high" peaked at 1% to 2 hours and returned
`to baseline levels by 3 to 4 hours. Evaluation of
`phase plots (i.e., drug effect vs. drug concentra-
`tion) indicated, that acute tolerance developed to
`the subjective but not to the cardiopressor effects
`of d-amphetamine. This finding, implies that indi-
`viduals who repeatedly administer the drug to
`maintain certain levels of subjective effects may
`increase plasma drug levels and physiologic ef-
`fects to toxic levels. (J Clin Psychopharmacol
`1996;16:72-76)
`
`THE RELATIONSHIP BETWEEN drug concentration
`
`in plasma and drug response is important to inves-
`tigate because understanding pharmacokinetic-pharma-
`codynamic relationships may improve our knowledge of
`the basic mechanisms by which drugs produce their ef-
`fects. For example, these relationships may reveal the
`extent to which observed drug effects are directly re-
`lated to receptor occupancy or to the effects of metabo-
`lites.1 The relationship between drug concentration and
`drug effect is particularly important in the study of drugs
`that are abused, because it may influence repeated drug
`
`Received January 10, 1995, and accepted June 22, 1995.
`Address requests for reprints to: Harriet de Wit, PhD, Department
`of Psychiatry, University of Chicago, MC3077, 5841 South Maryland
`Ave., Chicago, IL 60637.
`
`administration within an episode of drug-taking. A ma-
`jor factor believed to maintain repeated ingestion of a
`drug is its mood-altering, or subjective effects.2 The drug
`effects that appear to be most desirable to drug abusers
`are those experienced during the onset of the drug effect
`(e.g., the "rush") 3' 4 After this initial effect, acute tolerance
`may develop to the mood-altering effects of the drug. That
`is, after the drug produces its initial effects on mood,
`these effects may rapidly dissipate, even though plasma
`levels of the drug are still increasing. However, tolerance
`to other effects of the drug, such as the cardiovascular ef-
`fects, may not develop at the same rate. Consequently, as
`individualS repeatedly self-administer a drug to maintain
`.desired mood effects, they may inadvertently escalate
`plasma concentrations and cardiovascular effects to
`toxic levels.
`Several-investigators have examined the pharmacoki-
`netic and pharmacodynamic profiles of cocaine in co-
`caine abusers,5-9 and the observed relationship betweeri
`drug concentrations in plasma and drug effects has been
`inconsistent across studies. For example, Javaid and
`colleagues' found that the times to peak for subjective
`and physiologic effects of single doses of cocaine corre-
`sponded well with plasma levels, but that subjective and
`physiologic effects had returned to baseline values be-
`fore plasma levels declined. These findings suggest that
`acute tolerance developed to both subjective and phys-
`iologic effects of cocaine. Fischman and colleagues'
`also demonstrated acute tolerance to both subjective
`and physiologic effects of single doses of cocaine using
`different procedures and different measures of drug ef-
`fect. Other studies have shown that acute tolerance to
`the subjective and certain physiologic effects of co-
`caine may develop at different rates.8, s For example,
`Foltin and associatess examined subjective and physio-
`logic responses to repeated doses of 96 mg of intranasal
`cocaine. They found that blood pressure increases cor-
`responded closely with increases in plasma levels of co-
`caine but that heart rate and subjective responses
`
`Page 3
`
`

`

`Acute Tolerance to d-Amphetamine
`
`J CLIN PSYCHOPHARMACOL, VOL 16/No 1, FEBRUARY 1996
`
`73
`
`Procedures
`
`view. Subjects were screened by a clinical psychologist
`reached their peak before plasma levels and declined
`much more rapidly. This pattern of results suggested 1.--ancl-a.earfliologist to rule out any psychosocial or med-
`that acute tolerance developed to the subjective, but
`ical condition that might contraindicate participation in
`not to the pressor, effects of cocaine. However, a sub-
`the study. Candidates with past or current serious med-
`sequent reanalysis of their data using more quantitative
`ical conditions, including cardiac or liver disease, high
`methods showed that tolerance, in fact, developed to
`blood pressure, or abnormal electrocardiograms, or
`the pressor effects of cocaine as well.'°
`who met criteria for past or current major axis I disor-
`Few studies have investigated the relationship be-
`ders (excluding nicotine dependence; DSM-III-R) were
`tween plasma levels of d-amphetamine and drug effects
`excluded.
`in normal, healthy volunteers.11-13 In general, studies
`with normal volunteers have found dissociation be-
`tween plasma levels and drug effects. For example, An-
`grist and coworkers13 administered 0.25 mg/kg oral d-
`amphetamine to normal subjects and measured
`subjective and cardiovascular effects and plasma levels
`over a 5-hour period. They found that, while plasma lev-
`els peaked at 2 to 3 hours after drug administration, car-
`diovascular and subjective responses peaked at 1 and 2
`hours, respectively. Both cardiovascular and subjective
`effects of d-amphetamine had declinedby 4 hours after
`drug administration, while blood levels remained sig-
`nificantly elevated.
`Studies with normal volunteers are important to ex-
`amine tolerance without the possible influence of vari-
`ables related to repeated drug use, such as conditioned
`responses and neuroadaptation, which may alter the
`pharmacodynamic profiles of drugs in drug abusers.
`Thus, the purpose of this descriptive report is to extend
`previous findings by examining the relationship be-
`tween plasma d-amphetamine levels and drug effects
`over a longer period of time (i.e., 24 hours) and on a
`broader range of dependent measures in normal volun-
`teers. By examining this relationship over a 24-hour pe-
`riod, both ascending and descending limbs of the plasma
`drug level- and drug effect-time curves can be charac-
`terized. Six male subjects attended two sessions during
`which they received 20 mg of oral d-amphetamine.
`Plasma levels and subjective and physiologic responses
`were measured predrug and for 24 hours thereafter.
`
`Data were collected as part of another study designed
`to investigate interactions between d-amphetamine and
`the dopamine antagonist pimozide. Because pimozide
`had no detectable effect on any measure of response to
`d-amphetamine (unpublished .data; see below), the re-
`sults are presented as the mean of the two sessions with
`d-amphetamine. Each subject attended two sessions
`separated by 1 week. Sessions were conducted in the
`University of Chicago Clinical Research Center •(CRC)
`and lasted from 6:30 a.m. until 9:45 a.m. the following
`day. During each session, subjects received a:capsule
`containing 20 mg of d-amphetamine. There was no
`placebo control condition in this study because the
`variable of interest was plasma d-amphetamine levels
`over time. Subjects were told that the capsules might
`contain a stimulant/appetite suppressant, sedative/mi-
`nor tranquilizer, major tranquilizer, or placebo. Sub-
`jects gave written informed consent before participa-
`tion, This study was approved by the University of
`Chic go Institutional Review Board.
`P s of subjects were admitted to the CRC at 6:30
`a.m.
`er an overnight fast. Subjects were provided with
`one glass of clear fruit juice upon arrival, but no other
`food or drink was available until 1.p.m., when they ate a
`light lunch. At 7 am., a baseline blood sample was ob-
`tained from an intravenous catheter placed in the sub-
`jects! riondominant arms. Subjects were then allowed to
`relax and acclimate to the catheter and the surround-
`ings. At 7:20 a.m. they completed baseline mood ques-
`tionnaires, and physiologic and behavioral measures
`were obtained (see below). These measures were col-
`lected again at 8:30 and at 9:20 a.m. At 9:30 am., subjects
`ingested a capsule containing 20 mg ofd-amphetamine
`(Dexedrine; Smith, Kline and French, Philadelphia,
`PA). This dose of d-amphetamine has been shown in
`previous studies in our laboratory to produce reliable
`effects on mood without producing adverse physiologic
`effects.15 Blood samples (10 ml) were collected before
`d-amphetamine administration (9:25 a.m.) and at 10,
`10:30, 11, -11:30, 12 p.m., 12:30, 1, 1:30; 2:30, 3:30, 9:30
`p.m. and 9:,30 a.m. Subjective and behavioral measures
`were obtained at the same times as blood samples,
`whereas physiologic measures were only collected at
`
`Methods
`
`Subjects
`
`.
`
`Six healthy men aged 22 to 31 (mean = 27 years) were
`recruited from the university community with adver-
`tisements and posters. To minimize possible pharma-
`cokinetic variability related to gender differences, only
`men were tested.'4 Interested participants were initially
`screened over the telephone. Individuals who were
`within 10% of normal body weight (mean = 74.2 .kg,
`range = 65.4-84.1), reported drinking at least one alco-
`holic beverage per week (mean = 4.0, range = 1-8), were
`high school graduates, and were native English speak-
`ers were asked to come to the laboratory for an inter-
`
`Page 4
`
`

`

`74
`
`J CLIN PSYCHOPHARMACOL, VOL 16/NO 1, FEBRUARY 1996
`
`hourly intervals until 3:30 p.m. and then at 9:30 p.m. and
`9:30 the next morning. When subjects were not com-
`pleting questionnaires, they relaxed in the testing room.
`They were allowed to read, watch television, play
`games, talk; or engage in other leisure activities. After
`completing the study, subjects attended a debriefing in-
`terview and were paid $160.
`
`Plasma d-Amphetamine
`
`•
`
`I
`
`50
`40
`30
`20
`10
`
`o 1 2
`
`3 4 5 6 12 24
`Hour
`
`50
`40
`30
`20
`10
`0
`0
`
`Brauer and Associates
`
`"Feel Drug"
`
`I 2
`
`.4 5
`'3
`Hour
`
`X A,
`6 12 24
`
`Dependent measures
`
`Subjective effects were assessed with the Profile of
`Mood States,16,17 the 49-item Addiction Research Center
`Inventory (ARCI18,19), a locally developed Drug Effects
`Questionnaire (DEQ; unpublished), and several Visual
`Analog Scales. Each of these questionnaires has been
`shown to be sensitive to the mood effects of a variety of
`psychoactive drugs, including stimulants.2° Only data
`from the MBG (euphoria) and A (stimulant-like effects)
`scales of the ARCI, and the "feel drug," "like drug," and
`"feel high" scales of the DEQ will be presented here.
`Physiologic measures included blood pressure and
`heart rate and were obtained using a Dynamap Vital
`Signs Monitor (Critikon, Inc., Palatine, IL). Plasma sam-
`ples were analyzed for d-amphetamine using positive
`, ,chemical ionization gas chromatography mass \ pec-
`
`
`trometry (Center for Human Toxicology, Salt Lake City;
`UT) using procedures described elsewhere.21,22
`
`Data analyses
`
`Measures obtained immediately before d-ampheta-
`mine administration (9:25 a.m.) were used -as baseline
`in all analyses. Because analyses of variance revealed
`that there were no significant differences between the
`two sessions on any measure, 'either between the first
`and second sessions or between sessions when sub-
`jects did or did not receive pimozide, the two determi-
`nations for each subject were averaged. Data for each
`variable were plotted, both across time and as phase
`plots, and inspected to determine whether the pharma-
`cokinetic and pharmacodynamic profiles of d-ampheta-
`mine covaried (see Figs. 1 and 2).
`
`Results
`
`The time course of plasma levels arid several subjec-
`tive and physiologic effects of d-amphetamine are
`shown in Figure 1. Plasma levels were detectable 1 hour
`after drug administration and reached a peak level of 40
`ng/ml at 4 hours. Plasma levels plateaued and then be-
`gan to decline 5 hours after drug administration but re-
`mained detectable even at 24 hours.
`Subjective effects produced a different profile. In
`general, subjective effects of d-amphetamine reached
`peak levels at 1% to 2 hours and declined significantly
`within the first 6 hours of the session. Ratings of "feel
`
`Systolic Blood Pressure
`
`"Like Drug"
`
`140
`130
`120
`110
`100
`
`f
`
`•
`•
`•
`•
`0 1 2 3 4 5 672 24
`Hour
`
`Heart Rate
`
`90
`80
`70
`60
`50
`0 1 2 3 4 5 67224
`Hour
`
`5.5
`4.5
`3.5
`2.5
`1.5
`0
`
`co
`
`i
`
`2 3 4 5
`Hour
`
`6 12 24
`
`FIG. 1. Mean (SE) plasma levels and drug effects of 20 mg d-amphet7
`amine as a function of time. The 0 time point shows values obtained
`immediately before drug administration (9:25 a.m.), and each subsel
`quent point shows values obtained at various intervals thereafter:
`"Feel drug" and "like drug" scores range from 0 to 100, and Addiction
`Research Center Inventory A scale scores range from 0 to 11.
`
`drug," "like drug," "feel high," and "euphoria" (ARCI
`MBG) reached peak levels at 114 hours, while stimulant
`like effects (ARCI A) peaked at 2 hours. Ratings of "feel
`drug," "like drug," and "feel high" had returned to base-
`line levels by hour 5, and scores on the> A and MBG
`scales of the ARCI reached baseline levels at 12 hours
`postdrug (Fig. 1).
`Figure 1 also shows the time course of cardiovascu-
`lar responses to d-amphetamine. In general, changes in
`systolic blood pressure paralleled changes in plasma
`drug concentration over time, but blood pressure was
`still slightly elevated when plasma levels were begin-
`ning to decline. In contrast, heart rate remained low
`while plasma levels were increasing and began to rise 4
`hours after drug administration. Heart rate continued to
`increase for the duration of the session.
`Phase plots of plasma drug concentration versus
`drug effect are shown in Figure 2. This figure illustrates
`that the subjective effects of d-amphetamine show con-
`siderable clockwise hysteresis: the relationship be-
`tween plasma concentration and subjective response
`changes over the rising and falling phases of the drug
`concentration curve. This pattern of results suggests
`the development of acute tolerance. In contrast, the car-
`
`• ••• -.4••••••••
`
`•••••••••••••••..-.
`
`Page 5
`
`

`

`Acute Tolerance to d-Amphetamine
`
`J OLIN PSYCHOPIIARMACOL, VOL 16/NO 1, FEBRUARY 1996
`
`75
`
`40
`
`30
`
`20
`
`10
`
`0
`0
`
`E
`
`40 .
`30
`20
`10
`- Plasma 4-Amphetamine
`(ng/ml)
`
`0
`
`20
`10
`40
`30
`Plasma 4-Amphetamine
`(ng/ml)
`
`a.
`2
`02
`
`90
`
`80
`
`70
`
`60
`
`50
`0
`
`155
`145
`a '135
`125
`U vs 115
`105
`0
`
`1
`
`40
`30
`20
`10
`Plasma 4-Amphetamine
`(ng/m1)
`
`40
`30
`20
`10
`Plasma 4-Amphetamine
`(ng/ml)
`
`Plasma 4-Amphetamine
`(ng/ml)
`
`FIG. 2. Phase plots of drug concentration versus drug effect for sys-
`tolic blood pressure and for representative subjective responses to c/-
`amphetamine. Subjective responses to d-amphetamine (left panel)
`show marked clockwise hysteresis, suggestive of acute tolerance to
`these effects. In contrast, the panel on the right shows no evidence of
`hysteresis, and thus of acute tolerance, to the cardiopressor effects
`of d-amphetamine. (ARCI, Addiction Research Center Inventory).
`
`diopressor effects of d-amphetamine show little or no
`hysteresis: the maximal effect on blood pressure is pro-
`duced by plasma d-amphetamine concentration of
`aboUt 15 to 20 ng/ml and is sustained throughout the ex-
`perimental session. Thus, there is no evidence of acute
`tolerance development to these effects.
`
`Discussion
`
`The purpose of this report was to describe the rela-
`tionship between plasma concentrations and subjective
`and physiologic effects of d-amphetamine in six
`healthy, normal men. The results of the study indicate
`that the time course of plasma levels and drug effects of
`d-amphetamine are dissociable. For example, although
`plasma levels peaked 4 hours after drug administration
`and were still detectable at 24 hours, subjective effects
`peaked at approximately 2 hours and declined within 6
`hours (Fig. 1). Systolic blood pressure rose quickly, and
`the increase was sustained. The heart rate response
`
`was apparently dampened initially and then exhibited a
`delayed nse. These results suggest tolerance to the sub-
`jective effects of d-amphetamine but not to the pressor
`effects. At similar plasma drug concentrations, subjec-
`tive responses were greater on the ascending compared
`with the descending limb of the concentration-effect
`curve. This is evident in the phase plots as marked
`clockwise hysteresis (Fig. 2). In the absence of evi-
`dence for the production of active antagonist metabo-
`lites' of d-amphetamine, the most likely explanation of
`this finding is the development of acute tolerance. Co-
`caine exhibits a similar phenomenon (e.g., see ref. 7).
`An interesting finding in this study was the time course
`of the heart rate effects of d-amphetamine. Heart rate re-
`mained at baseline levels until 5 hours into the session
`and began to rise steadily thereafter, at a time when
`plasma levels were beginning to decline (see Fig. 1). A
`similar pattern of physiologic response to d-ampheta-
`mine has been reported in a study by Martin and col-
`leagues.19 They found that although blood pressure rose
`steadily within the 5 hours after drug administration,
`heart rate remained low during this time and did not be-
`gin to increase until blood pressure was declining. Mar-
`tin and colleagues19 attributed this relationship to reflex-
`ive slowing of the heart rate in response to increased
`blood pressure. Our findings also suggest an early physi-
`ologic reflex response and a later adjustment to the pres-
`sor rise. These cardiovascular responses are consistent
`with the mechanism of action of d-amphetamine (i.e., re-
`lease of norepinephrine at sympathetic nerve synapses).
`Norpinephrine infusion causes a pressor response with
`reflec cardiac slowing. The actual heart rate depends on
`a balAnce of chronotropic modifying factors.23
`Although the results of this study are suggestive of the
`development of acute tolerance to some of the effects of
`d-amphetamine, the absence of a placebo control con-
`dition makes it difficult to rule out other possible inter-
`pretations of the data. For example, the time course of
`the cardiovascular effects of d-amphetamine could be
`related to nonpharmacologic factors such as uncon-
`trolled variations related to circadian rhythms or to en-
`vironmental events. The time course of the subjective ef-
`fects could be the result of adaptation to repeated
`administration of the questionnaires. These issues can
`only be addressed by subsequent studies including a
`placebo control condition. Nevertheless, the results are
`consistent with the development of acute tolerance and
`are in agreement with the findings of studies with an-
`other psychomotor stimulant, cocaine (see above).
`The findings of this study have implications for un-
`derstanding the toxicity sometimes associated with
`stimulant abuse. It is commonly assumed that individu-
`als self-administer doses based on the subjective effects
`experienced.2 Thus, as subjective effects begin to wane,
`
`Page 6
`
`

`

`76
`
`J CLIN PSYCHOPHARMACOL, VOL 16/NO 1, FEBRUARY 1996
`
`Brauer and Associates
`
`individuals may take additional doses of the drug. The
`consequences of such a pattern may be dangerous be-
`cause subjective effects appear to dissipate at times
`when plasma levels and physiologic responses are still
`maximal or rising. Thus, individuals who repeatedly
`self-administer the drug in an attempt to maintain a cer-
`tain level of euphoria may be at increased risk for car-
`diovascular toxicity. These results also suggest that
`acute tolerance to the subjective effects of d-ampheta-
`mine may develop in drug-naive, normal volunteers in
`much the same manner as acute tolerance to cocaine's
`effects develops in cocaine abusers. Additional studies
`with d-amphetamine should be conducted to character-
`ize more fully the relationship between plasma levels
`and drug effects.
`
`Acknowledgment
`
`This research was supported by a grant from the National Institute
`on Drug Abuse (DA02812) and a Grant-in-aid of Research from Sigma
`Xi, The Scientific Research Society. The authors acknowledge the sup-
`port and expert assistance of the Clinical Research Center (USPHS
`grant MO1 RR00055). The authors are also extremely grateful to Dr.
`Daniel Luchins for his suggestions and support.
`
`References
`1. Dingemanse J, Danhof M, Breimer DD. Pharmacokinetic-phar-
`macodynamic modeling of CNS drug effects: an overview. Phar-
`macol Ther 1988;38:1-52.
`2. Foltin RW, Fischman MW. Assessment of abuse liability of stim-
`ulant drugs in humans: a methodological survey. Drug Alcohol
`Depend 1991;28:3-48.
`3. Farre M, Cami J. Pharmacokinetic considerations in abuse liabil-
`ity evaluation. Br J Addict 1991;86:1601-6.
`4. de Wit H, Bodker B, Ambre J. Rate of increase of plasma drug
`level influences subjective response in humans. Psychopharma-
`cology 1992;107:352-8.
`5. Javaid JI, Fischman MW, Schuster CR, Dekirmenjian H, Davis JM.
`Cocaine plasma concentration: relation to physiological and sub-
`jective effects in humans. Science 1978;292:227-8.
`6. Fischman MW, Schuster CR, Javaid JI, Hatano Y, Davis JM. Acute
`tolerance development to the cardiovascular and subjective ef-
`fects of cocaine. J Pharmacol Exp Ther 1985;235:667-82.
`7. Ambre JJ, Belknap SM, Nelson J, Ruo TI, Shin S, Atkinson Al.
`Acute tolerance to cocaine in humans. Clin Pharmacol Ther
`1988;44:1-8.
`
`8. Foltin RW, Fischman MW, Pedroso JJ, Pearlson GD. Repeated in-
`tranasal cocaine administration: lack of tolerance to pressor efr
`fects. Drug Alcohol Depend 1988;22:169-77.
`9. Foltin RW, Fischman MW. The relationship between cocaine ve-
`nous blood levels and the cardiovascular and subjective effects of
`smoked and intravenous cocaine. In Harris LS, ed. Problems of
`drug dependence 1990: proceedings of the 52nd Annual Scientific
`Meeting, Committee on Problems of Drug • Dependence, Inc.
`Washington, DC: US Government Printing Office, 1990:440-1.
`10. Ambre JJ. Acute tolerance to pressor effects of cocaine in hu-
`mans. Ther Drug Monit 1993;15:537-40.
`11. Brown WA, Corriveau DP, Ebert MH. Acute psychologic and neu-
`roendocrine effects of dextroamphetamine and methylphenidate:
`Psychopharmacology 1978;58:189-95.
`12. Dommisse CS, Schulz SC, Narasimhachari N, Blackard WG, Hamer
`RM. The neuroendocrine and behavioral response to dextroam-
`phetamine in normal individuals. Biol Psychiatry 1984;19:1305-15.
`13. Angrist B, Corwin J, Bartlik B, Cooper T. Early pharmacokinetics
`and clinical effects of oral d-amphetamine in normal subjects.
`Biol Psychiatry 1987;22:1357-68.
`14. Yonkers KA, Kando JC, Cole JO, Blumenthal SB. Gender differ-
`ences in pharmacokinetics and pharmacodynamics of psy-
`chotropic medication. Am J Psychiatry 1992;149:587-95.
`15. Brauer LH, de Wit H. Subjective responses to d-amphetamine
`alone and after pimozide pretreatment in normal, healthy volun-
`teers. Biol Psychiatry (in press).
`16. McNair DM, Lorr M, Droppleman LF. Profile of mood states (man-
`ual). San Francisco: Educational and Industrial Testing Service,
`1971.
`17. Johanson CE, Uhlenhuth E. Drug preference and mood in hu-
`mans: d-amphetamine. Psychopharmacology 1980;71:275-9.
`18. Haertzen CA, Hill HE, Belleville RE. Development of the Addic-
`tion Research Center Inventory (ARC1): selection of items that
`are sensitive to the effects of various drugs. Psychopharmacology
`1963;4:155-6.
`19. Martin WR, Sloan JW, Sapira JD, Jasinski DR. Physiologic, sub-
`jective, and behavioral effects of amphetamine; methampheta-
`mine, ephedrine, phenmetrazine, and methylphenidate in man.
`Clin Pharmacol Ther 1971;12:245-57.
`20. Fischman MW, Foltin RW. Utility of subjective-effects measure-
`ments in assessing abuse liability of drugs in humans. Br J Addict
`1991;86:1563-70.
`21. Wilkins D, Crouch D, Rollins D. Analysis of phenylpropanolamine
`by positive chemical ionization mass spectrometry [abstract
`K17]. Presented at the Annual Meeting of the American Academy
`of Forensic Science. Las Vegas, NV, 1989.
`22. Elkins K, Gibb J, Hanson G, Wilkins D, Johnson M. Effects of ni-
`modipine on the amphetamine- and methamphetamine-induced
`decrease in tryptophan hydroxylase activity. Eur J Pharmacol
`1993;250:395-402.
`23. Hoffman BB, Lefkowitz RJ. Catecholamines and sympath-
`omimetic drugs. In Gilman AG, Rall TW, Nies AS, Taylor P, eds.
`The pharmacological basis of therapeutics. New York: Pergamon
`Press, 1990:187-220.
`
`Page 7
`
`