Psychopharmacology (1996) 126: 140-146

© Springer-Verlag t996

Chris-Ellyn Johanson • Suzette Evans Jack Henningfield

The discriminative stimulus effects of tripelennamine in humans

Received: 6 December 1995/Final version: 6 March 1996

Abstract Twenty volunteers were trained to discriminate between 75 mg tripelennamine (TP) and placebo. During the first four sessions, the drugs were identified prior to ingestion by letter code. During the next six sessions, the procedure was the same except the capsules were not identified. At the end of the 3-h session, participants indicated which capsule they believed they received using the letter codes. When correct, they received a monetary bonus. If they were correct on five sessions, they entered the third phase which had ten additional training and 12 test sessions. During tests, participants received capsules that contained other drugs, inciuding diphenhydramine (50 and 75 rag), chlorpheniramine (4 and 6 rag), diazepam (5 and 10 nag), d-amphetamine (5 and t0 nag), as well as tripelennamine (25, 50 and 75 nag) and placebo. Thirteen participants learned the discrimination and nine entered the third phase. Except for placebo, most participants identified the test compounds as TP and labeled them as sedatives. TP produced significant

The opinions expressed by the authors are not necessarily those of the United States Government. Portions of the data were presented as a poster at the 1993 annual meeting of the College on Problems of Drug Dependence, which was published as an abstract (Evans S, Henningfield J, Johanson CE (1994) Discriminative stimulus effects of tripelennamine in humans. In Problems of Drug Dependence 1993: Proceedings of the 55th Annual Scientific Meeting. Harris LS (ed) National Institute on Drug Abuse Research Monograph Series t4t : 396) C.-E. Johanson ([~) Department of Psychiatry and Behavioral Neurosciences, Wayne State University, 2761 E. Jefferson, Detroit, MI 48207, USA S. Evans Columbia University School of Medicine, 722 West 168th Street, Box 66, New York, NY 10032, USA J. Henningfield Division of Intramural Research, National Institute on Drug Abuse, P.O. Box 5180, Baltimore, MD 21224, USA

changes on several subjective and physiological measures. The test compounds produced varied effects which were neither clearly dose-related nor related to the identification as TP or placebo. These results indicate that tripelennamine can function as a discriminative stimulus, but with little evidence of pharmacological specificity. Key words Antihistamines • Tripelennamine Drug discrimination • Subjective effects • Humans

Introduction Drug discrimination methods have been used extensively in animals to classify drugs (Stolerman and Shine 1985; Colpaert and Balster t988; Stolerman et al. 1989). Animals are trained to emit one type of response in the presence of a drug stimulus and an alternative response in its absence. Thus, the drug becomes a diseriminative stimulus (DS) that signals the availability of a reinforcer contingent upon a specified response. This methodology has been useful for assessing abuse liability and differentiating drugs with different receptor, neurochemical, or therapeutic actions. Unlike other assays used to classify drugs, the DS effects are believed to be related to the subjective effects produced by these drugs in humans (Schuster and Johanson t988). Drug discrimination studies have also been done with humans and have provided a means of comparing DS and mood-altering effects. These studies indicate a high correlation between these two pharmacological actions with stimulants, anxiolytics, and opiates (Chair et al. 1986a,b; Preston et al. 1987; Bickel et al. 1989; Johanson 1991a). Furthermore, the DS effects of these drugs in humans show a similar profile to those shown in animals (Kamien et al. 1993). Although antihistamines are used therapeutically for treating allergies, cold symptoms and motion sickness,

t41

they also have CNS side effects. The most common side effect reported is sedation; several studies using subjective self-report questionnaires have reported sedation, sleepiness, inability to concentrate or decreased alertness for diphenhydramine (Carruthers et al. 1978), chlorpheniramine (Kulshrestha et al. 1978) and tripelennamine (Stem et al. 1989). However, in studies of antihistamines in animals, the results indicate that many antihistamines have stimulant-like effects (Melville 1973; Barnett et al. 1984; Bergman and Spealman 1986). In pigeons, diphenhydramine, chlorpheniramine and tripelennamine substituted for amphetamine as a DS and in monkeys, this was true for tripelennamine (Evans and Johanson 1989). A subsequent study with pigeons trained to discriminate tripelennamine from saline showed that amphetamine, as well as diphenhydramine and chlorpheniramine substituted as DS (Evans et al. 1991). In neither species did any antihistamine substitute for pentobarbital and vice versa (Evans and Johanson 1989; Evans et al. 1991). These findings were extended in the present study by evaluating the DS effects of tripelennamine in humans. Pharmacological sensitivity was assessed by varying dose and specificity by varying type of drug including other antihistamines, a prototypic stimulant drug, damphetamine, and a prototypic anxiolytic, diazepam.

Materials and methods Participants Seventeen male and three female (seven Caucasian/13 African American) volunteers were enrolled through local area newspaper ads. The participants ranged in age fi'om 21 to 40 years (mean = 30.2). All but three had a high school diploma with an average of 13.2 years of education. Half of the participants had used illicit drugs and with two exceptions this was limited to marijuana only (n = 3) or marijuana and cocaine (n = 5). Potential candidates underwent a complete physical and psychiatric examination and were excluded if they had any medical problem that would interfere with their participation or piace them at an unacceptable level of risk. Only candidates free of any form of substance dependence (except tobacco) or other current psychiatric disorder were included. The protocol was reviewed and approved by a local institutional human use committee. Informed consent was obtained and participants were paid for their time and inconvenience.

General procedure Participants were instructed that their job was to learn to discriminate between two different drugs, "drug A" and "drug B." They were told that they could receive antihistamines, stimulants, tranquilizers, sedatives, or placebo, and that drug A and B would differ. Participants reported to the laboratory on weekday mornings for a total of 32 sessions. Upon arrival, subjects filled out subjective effects questionnaires as described below and physiological signs were monitored. Next, subjects received a capsule which they ingested under observation. Over the next 3 h they were free to engage in various recreational activities available in the laboratory. Subjective effects questionnaires were filled out and physiological signs were monitored 30, 60, 120 and 180 min after capsule ingestion.

Experimental phases

Phase 1: sampling~training (sessions 1-4) The purpose of phase 1 was to familiarize participants with the effects of drug A and drug B and to begin discrimination training. On the first session., everyone received drug A and on the second session, drug B. Italf of the participants received drug A on session 3 and drug B on session 4. The order was reversed for the other half. For half of the participants, drug A was TP and drug B was placebo. The assignments were reversed for the other participants. On each of these four sessions, the letter code of the capsule was revealed to the participant prior to ingestion.

Phase 2: training~selection (sessions 5-10) The purpose of phase 2 was to provide additional training and then select participants who reliably learned the discrimination. On these six sessions, participants received drug A and B three times each. They were administered in a mixed order with the restriction that the same drug was not scheduled more than two sessions in succession. The order was different across participants. On these sessions, participants were not told which drug they received when they ingested the capsule. At the end of the session, they guessed which drug they thought they had received using a letter code. If their response was correct, they received $20. The discrimination was considered reliable if five of the six identifications were correct. Participants were not informed of this criterion at the beginning of the experiment. Those that failed to reach this level of performance were asked to terminate participation. However, the number of sessions in phase 2 was increased for five of the participants who failed to learn the discrimination after six sessions. Two of these participants still failed to learn the discrimination after five and eight additional sessions, respectively; three learned the discrimination after one, four and six additional sessions, respectively. For analyses, only data from the last six sessions of phase 2 were used for these five participants.

Phase 3." testing (sessions 1132) Participants who reached the criterion of five of six correct entered phase 3 but they were not told that a new phase had started. The purpose of phase 3 was to determine whether participants would identify lower doses of tripelennamine and other drugs as placebo or TP. The test phase consisted of 12 test sessions intermixed with ten additional training sessions. On test sessions participants received one of the following drugs with order varied randomly across participants except that the lower dose of a drug (except tripelennamine) was always administered first: 25, 50 and 75 mg tripelennamine; 50 and 75 mg diphenhydramine; 4 and 6 mg chlorpheniramine; 5 and 10 mg diazepam, 5 and 10 mg d-amphetamine; and placebo. Test sessions were identical to training sessions except that participants were not informed whether or not their response was correct. Instead they were told that it was a test session and that they would receive $20 anyway. Participants were not told the purpose of test sessions, nor did they know when test sessions were scheduled until after they had reported their drug identification. The ten additional training sessions were interspersed among the test sessions in an unsystematic fashion with the restriction that no more than two test or two training sessions occurred in succession. These training sessions were exactly like the training sessions during phase 2. Participants received TP and placebo five times each in mixed order.

142 Subjective effects questionnaires

Profile Of Mood States (POMS) An experimental version of the 65-item POMS (McNair et al. 1971) consisting of 72 adjectives commonly used to describe momentary mood states was used. Participants indicated how they felt at the moment in relation to each of the 72 adjectives on a 5-point scale from "not at all" (0) to "extremely" (4). There are eight clusters (scales) of items (Anxiety, Depression, Anger, Vigor, Fatigue, Confusion, Friendliness, Elation) that have names that describe the adjectives in the cluster. Two additional (unvalidated) scales (Arousal, Positive Mood) were derived from the other scales.

for placebo and TP averaged across all training sessions as the basic unit of analysis. These means were analyzed using a three-way mixed model ANOVA (Treatment and Time as within subject factors and Discrimination [those who reached criterion versus those who did not] as a between groups factor). If the Treatment x Time, Treatment x Group or Treatment x Group x Time interaction was significant (P < 0.05), post-hoc tests (Tukey HSD) were used to compare TP and placebo scores at each time or to compare across groups. During phase 3, a similar repeated measures ANOVA was performed comparing TP and placebo (Treatment and Time as withinsubject factors). If the Treatment × Time interaction was significant (P < 0.05), a separate ANOVA was performed with three levels of treatment (TP, placebo, and the test drug). Separate analyses were done for each test drug. Post-hoc tests (Tukey HSD) were used to compare TP, test drug, and placebo scores at each time point.

Addiction Research Center Inventory (ARC[) The ARCI is a true-false questionnaire sensitive to the effects of a variety of classes of abused drugs (Haertzen 1966). A short form of the inventory was used, consisting of five scales with a total of 49 items (Martin et al, 1971). The five scales were the MorphineBenzedrine Group (MBG), a general measure of drug-induced euphoria; the Amphetamine (A) and Benzedrine Group (BG), which measure amphetamine-like effects; the Pentobarbital-Chlorpromazine-Alcohol Group (PCAG), a measure of sedation; and the lysergic acid diethylamine (LSD), a measure of dysphoria and somatic symptoms.

Visual Analog Scales (VAS) This form has six horizontal 100-mm lines, each labeled with an adjective. These adjectives were "stimulated," "high," "anxious," "sedated," "down," and "hungry." The left ends of the lines were labeled "not at all" and the right ends "extremely." Participants were instructed to place a mark on each line indicating how they felt at the moment.

Labeling At the end of the session, participants were asked to label the capsule that they received as a sedative, placebo, or stimulant.

Drugs All drugs were administered in 00-sized opaque gelatin capsules. The color of the capsules varied across participants, but each person always received the same color capsule. Drug capsules contained the drug tablets or capsules plus lactose or dextrose powder; placebo capsules contained lactose or dextrose only.

Data analyses Discrimination results are expressed in terms of the average percent correct on training sessions during phase 2 and 3, separately for TP and placebo. For phase 2, these results are presented separately for discriminators (those who reached criterion) and non-discriminators (those who did not). Discrimination results during test sessions are expressed in terms of the percentage of participants who identified the test capsule as TP. Analysis of variance (ANOVA) for repeated measures (SuperANOVA, Abacus Concepts) was used to analyze the subjective effects questionnaire scores and physiological measures. Results from phases t and 2 were analyzed using individual means

Results

Subject characteristics All twenty participants completed phases 1 and 2. Thirteen participants (three females and ten males) met the criterion of five out of six correct during phase 2 although three required additional training. Another individual learned the discrimination but as soon as he entered phase 3, the discrimination became inaccurate; for purposes of analysis, this individual was designated a non-discriminator. Three discriminators were terminated from the experiment during phase 3 due to illicit drug use (all males) and one (a female) dropped out for reasons unrelated to the experiment. Thus, data analyses :during training were based upon 20 participants (13 discriminators and seven non-discriminators) and during testing on the nine participants (two females, seven males) that completed phase 3. Phases 1 and 2: training During phase 2, overall accuracy was 83 % for TP and 87% for placebo tbr discriminators and 62% and 52%, respectively, for non-discriminators. There were significant Treatment x Time interactions on only two scales of the POMS, two scales of the ARCI and one VAS. TP increased scores on the Fatigue [F(4,72) = 3.36 P < 0.02], PCAG scale [F(4,72) = 4.20 P < 0.01] and Sedated VAS [F(4,72) = 2.51 P < 0.05] and decreased scores on the Elation [F(4,72) = 2.65 P < 0.05] and BG scale [F(4,72) = 2.81 P < 0.04] relative to placebo. Posthoc analyses indicated that the effects were generally significantly different at 60 and 120 min post-ingestion. Two scales of the POMS also showed significant threeway interactions that were not interpretable. There were no other significant interaction effects involving the group factor or any main group effects. There were significant Treatment x Time interactions on diastolic blood pressure [F(4,72)= 8.38 P < 0.000t] and heart rate [F(4,72) = 22.98 P < 0.0001], with TP increasing both relative to placebo. These

143

effects were significant at all times post ingestion for blood pressure and at 120 and 180 min post-ingestion for heart rate. There was a main group effect for heart rate [/7(1,18)= 5.37 P<0.04], with discriminators showing a slightly greater effect. Phase 3: training and testing For training sessions occurring during phase 3, accuracy was 79% for TP and 91% for placebo. Table 1 shows the percent of participants who identified the test capsules as TR Most test compounds, except placebo, were identified as TP and there was Table 1 Percent of participants who discriminated the test drug as 75 mg tripelennamine (TP) and labeled it as a sedative during test sessions Test drug

TP%

Label%

25 mg Tripelennamine 50 mg Tripelennamine 75 mg Tripelennamine 50 mg Diphenhydramine 75 mg Diphenhydramine 4 mg Chlorpheniramine 6 mg Chlorpheniramine 5 mg Diazepam 10 mg Diazepam 5 mg d-Amphetamine 10 nag d-Amphetamine Placebo

78 78 100 78 89 67 78 78 89 67 78 11

78 89 89 89 100 67 67 78 100 67 67 22

Table 2 Significant subjective and physiological effectsa. First column indicates direction of effects for TP relative to placebo. In the remaining columns, empty boxes indicate that the drug x hour interaction was not significant for that scale for the analyses involving three levels of treatment (TP, placebo, drug listed in the column). Where there were significant interactions, TP indicates that the effect of the test drug (TPL tripelennamine; DP diphenhydramine; CP chlorpheniramine; D Z diazepam; A M P d-amphetamine) was 75 mg TPL

25 mg TPL

POMS Arousal Fatigue Vigor

,[, 1" $

TP

ARCJ Bg Pcag Mbg

,{. "J" $

VAS Down Sedated

$ $

PHYSIOL. Systot bp Diastol bp Heartrate

"{" "]" 1"

TP TP

50 mg TPL

50 mg DP

75MG DP

TP TP

TP TP TP

like TP (significantly different from placebo but not TP) at least post-ingestion hour and PL indicates the effect of the test drug was like placebo (significantly different from TP but not placebo). In the case of 10 mg diazepam, the .$ indicates that blood pressure was significantly decreased relative to placebo.U/ Interaction not Interpretable, erratic IB Effects of test drug in between TP and placebo 4 mg CP

6 mg CP

5 mg DZ

t0 mg DZ

PL

UI TP PL

TP PL

TP

TP TP

TP

TP

TP

TP

PL PL

TP TP

modest evidence of dose-response relationships with all drugs. During sessions when participants received TP or placebo, there were several significant drug by hour interactions, with TP decreasing Arousal [F(4,32)= 4.44 P < 0.01], Vigor [F(4,32) -- 2.83 P < 0.05], BG [F(4,32) = 5.12 P < 0.011, MBG [F(4,32) = 3.00 P < 0.04] and increasing Fatigue [F(4,32) = 4.98 P < 0.01], PCAG [F(4,32) = 8.36 P < 0.0001], Down [F(4,32) = 4.30 P < 0.01], Sedated [F(4,32) = 6.47 P < 0.001], systolic [F(4,32) = 3.64 P < 0.02] and diastolic [F(4,32) = 6.57 P < 0.001] blood pressure, and heart rate [F(4,32)= 13.95 P < 0.0001] relative to placebo (Table 2). There were no differences in these effects between TP and placebo prior to drug ingestion and at 30 min. The differences were maximal at 60 min, decreased at 120 min and were gone by 180 min. Heart rate initially decreased under both conditions, but then returned to baseline levels only after TP, with significant differences from placebo at 120 and 180 min. Table 2 shows the profile of subjective and physiological effects for the test drugs relative to the training drugs for those scales and physiological measures where there was a significant Treatment by Hour interaction in the TP vs placebo analyses. In general, diphenhydramine and lower doses of tripetennamine had effects that were like TP relative to placebo with little evidence of any dose-response relationship. The effects of chlorpheniramine were more like placebo relative to TP and again there were no discernible dose-related differences. While the subjective effects of diazepam were minimal,

PL

TP

PL

TP

PL PL UI

UI

UI

10 mg AMP

PL UI

PL PL

TP TP

5 mg AMP

PL PL PL

PL

TP

PL IB

PL PL

$

TP

TP

TP

TP

TP

~Table shows scales where there was a significant drug by hour interaction (P < 0.05) in the analyses of 75 mg tripelennamine (TP) vs. placebo

144 ARCI PCAG

B

lit

75 rag Diphenhydrarnine

,~

5 mg Diazeparn 6 rngChlorpheniramine 10 rr~j d-Amphet~ne Placebo

=

-15

|

J

|

+30

i

i

+60

i

=

i

=

+120

i

=

i

|

+180

SESSION TIME

Fig. 1 The effectsof 75 mg tripelennamine,placebo and severaltest drugs on the Pentobarbital-chlorpromazine-alcoholgroup (PCAG) scale score across session time during phase 3. Asterisks (*) indicate a significant difference(P < 0.05) between active drug and placebo at the indicated hour as determinedt]'ompost-hoc analyses (Tukey HSD) they were more like TR The lower dose did not affect blood pressure and the higher dose decreased blood pressure while still increasing heart rate. Amphetamine showed the opposite profile, with subjective effects like placebo relative to TP and physiological effects like TR Figure 1 shows some representative effects for PCAG (ARCI) for each of the types of test drugs. During all training sessions across phases 2 and 3, TP was labeled as a sedative on 75% of the opportunities, as placebo 15%, and as a stimulant 10%. For placebo, these percentages were 23, 75, and 3%, respectively. For the test drugs, the percent labeled as a sedative corresponded almost exactly to the percentage of identification as TP (Table 1).

Discussion

The results of the present study demonstrate that norreal human volunteers can be trained to discriminate between 75 mg tripelennamine (TP) and placebo with a paradigm similar to that used to train a discrimination between amphetamine or anxiolytics and placebo (Chait et al. 1984; Johanson 1991a). Of those trained, 65% learned the discrimination according to the five of six criteria, although three of these discriminators received additional training during phase 2. This level of discrimination acquisition (50-65%) is similar to that seen with 10 mg d-amphetamine (Chait et al. 1989), t5 mg buspirone (Johanson 1993), 0.32 mg/70 kg triazolam (Kamien et al. 1995) but lower than seen with 10 mg diazepam (Johanson 1991a,b). Studies with opioid experienced individuals have indicated highly accn-

rate levels of opioid drug discrimination performance even with minimal training (Preston et al. 1987, 1989; Bickel et al. 1989). If human drug discrimination methods are to be used to screen drugs for abuse liability, therapeutic utility, or to increase our understanding of pharmacological actions of specific drug classes, it is important to demonstrate that participants who acquire the discrimination are not just learning a discrimination between the presence or absence of any drug effect. Pharmacological specificity can be evaluated by contrasting test results of compounds that have pharmacological effects similar to the training drug with compounds that have little overlap in their actions. Previous human discrimination studies using an almost identical procedure with stimulants and anxiolytics have provided evidence of pharmacological specificit?: For instance, individuals trained to discriminate amphetamine identify other psychomotor stimulants as amphetamine but identify non stimulant-like drugs as placebo (Chair et al. 1985, 1986a,b). Likewise, individuals trained to discriminate anxiolytics from placebo identify other anxiolytics as drug-like but not stimulants (Johanson 1991a,b). On the other hand, there have been human drug discrimination studies where specificity was not as good. For instance, in a study by Bickel et al. (1989) that trained a discrimination among hydromorphone, pentazocine and placebo in humans with a history of opiate abuse, there was partial substitution for pentazocine when amphetamine, secobarbital and lorazepam were tested (Bicket et al. 1989) but the authors failed to speculate about these findings. In the present study, pharmacological specificity was evaluated by testing other antihistamines, a prototypic stimulant and sedative, as well as placebo. Although placebo was identified correctly, all the other drugs were identified as TP by most participants. Furthermore, there was little evidence of a dose-response relationship with the test drugs, or with tripelennamine itself. That is, although TP identifications decreased as the dose of tripelennamine decreased, the decrease was minimal (100% to 78%). Thus, in striking contrast to previous human drug discrimination studies, there was little evidence of pharmacological specificity or sensitivity. In animal drug discrimination studies, specificity has been shown to be directly related to the dose of the training drug (Young 1991). The lack of specificity in the present study, therefore, may have been due to the use of too low a dose of tripelennamine during training. However, 75 mg tripelennamine did produce significant changes in subjective effects that were only slightly tess than those reported for 10 mg diazepam in previous studies using an almost identical experimental design (Johanson, 1991a,b). Furthermore, pharmacological specificity has been observed in discrimination studies with stimulant drugs, even at doses that are discriminated by only 50% of the participants (Chait et al. 1985, 1986a,b).

145 In addition to drug identification, participants filled out several m o o d questionnaires before and several times after capsule administration. Because drug discrimination is considered to be an analog of h u m a n subjective drug effects (Schuster and Johanson 1988), it is important to describe the correspondence between these measures of subjective effects and drug identifications. In previous studies with stimulants, anxiolytics, and opiates, discriminative stimulus and subjective effects were highly correlated. In the present study, TP produced significant effects on mood, suggesting that m o o d changes might have been used as cues. Further, some of the test drugs that were identified as TP produced similar changes in mood, usually sedative-like. However, unlike previous studies, the correspondence between subjective effects and drug identification was not: consistent. For instance, chlorpheniramine and amphetamine were largely identified as TR but both produced placebo-like subjective effects. There were also differences between TP and placebo in terms ofphysiologicaI effects. However, there were only minor physiological changes following the administration of diphenhydramine, chlorpheniramine, diazepam, and other doses of tripelennamine even when the subjective effects for these test compounds were similar to those of TR In contrast, although the subjective effects of amphetamine were placebo-like, its physiological effects were similar to those of TR Thus, there were divergences between subjective effects and discriminative stimulus effects as well as physiological effects. However, when participants were asked to label the test drugs as a sedative, stimulant, or placebo, the percentage of "sedative" labels corresponded almost exactly with the percentage of TP identifications. Despite discrepancies across domains, TP clearly had sedative-like effects. Sedation has also been reported as a side effect of m a n y antihistamines clinically and previous h u m a n studies have also reported that tripelennamine produces sedative-like effects (Stern et al. 1989). In contrast, drug discrimination studies with several other Species, including rhesus monkeys, have demonstrated that tripelennamine has stimulant-like discriminative stimulus effects (Evans and Johanson 1989; Evans et al. 199t). Although the discriminative stimulus effects of psychoactive drugs in humans and other species have been reported to be remarkably similar (Kamien et al. 1993), tripelennamine and other antihistamines appear to be exceptions. The implications of the findings of the present study are that the general assumption underlying drug discrimination studies in humans of pharmacological specificy needs to be accepted with caution. Without adequate pharmacological specificity, the use of this approach to evaluate abuse liability, to increase our understanding of pharmacological actions of specific drug classes, and to model subjective effects m a y be compromised. While the use of a low oral dose of tripelennamine may have been a major determinant of the

lack of specifity, other factors cannot be ruled out. As in animal studies, there has been a paucity of experiments designed to evaluate non-pharmacological factors relevant to the acquisition and maintenance of drug discriminations which may contribute to pharmacological sensitivity and specificity. Clearly, the findings of the present study indicate a need for research in this area. Acknowledgements This study was carried out at the Division of Intramural Research of the National Institute on Drug Abuse located in Baltimore, MD. The authors would like to thank Anne Gupman, Diana Lafko, William Rea and Jill Kuennen (Wayne State University) for their assistance in conducting the study and the statistical analyses.

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