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Experimental and Clinical Psychopharmacology 1999, Vol. 7, No. 2, 145-150

Sleepiness and the Reinforcing and Subjective Effects of Methylphenidate Timothy Roehrs, Kate Papineau, Leon Rosenthal, and Thomas Roth Henry Ford Hospital On 4 days, 6 volunteers received 10 mg methylphenidate or placebo at 0900 after 4 or 8 hr time in bed (TIB) and then on 4 days after 4 or 8 hr TIB chose their preferred capsule. On sampling days, 4 hr TIB increased multiple sleep latency test (MSLT) scores and Fatigue scale scores on the Profile of Mood States (POMS). In both TIBs, the drug increased the MSLT and POMS Vigor and Tension scale scores. It reduced POMS Fatigue scores and improved divided attention performance to a greater extent after 4 versus 8 hr. Drug was chosen on 88% of days after 4 hr, but only 29% of days after 8 hr. Preference for the drug depends on sleepiness and is mediated by performance-enhancing and fatigue-altering effects.

Methylphenidate, a psychomotor stimulant with pharmacokinetics and pharmacological mechanisms similar to amphetamine, is used to treat the sleep disorder narcolepsy and the behavior disorder attention deficit hyperactivity disorder. The abuse liability of amphetamine has been well documented, whereas that of methlyphenidate has not been established (Fischman, 1987). Case reports of methlyphenidate abuse have appeared in the literature since the 1970s (Haglund & Howerton, 1982; Jaffe, 1991; Lundquest, Young, & Edland, 1987; Parran & Jasinski, 1991). Also, recent data from the Drug Abuse Warning Network (1991) and the Drug Enforcement Administration (1995) indicate that abuse of methylphenidate is a problem. Laboratory assessment of a drug's subjective, discriminative, and reinforcing effects is useful in estimating its abuse liability. However, such studies of methlyphenidate are few and inconclusive. The subjective effects of high methylphenidate doses have been found to be similar to those reported for amphetamine and cocaine, although studies of low doses have not shown consistent effects (Clark, Geffen & Geffen, 1986; Foltin & Fischman, 1991; Huey et al., 1980). Methylphenidate is similar to amphetamine in its discriminativestimulus effects in people with drug abuse histories, but in people without drug abuse histories, it does not consistently substitute for amphetamine (Heishman & Henningfield, 1991; Martin, Sloan, Sapira, & Jasinski, 1971; Rush, Kollins, & Pazzaglia, 1998). One study of the reinforcing effects of methylphenidate has been performed, and it showed that 20^40 mg was chosen versus placebo on 28% of opportunities (Chait, 1994). Variations in the reinforcing and subjective effects of

stimulants, both within and among individuals, have been reported. Studies have identified differences among healthy volunteers in the subjective effects, which relate to differences in self-administration behavior (deWit, Uhlenhuth, & Johanson, 1985, 1986; Lasagna, Von Felsinger, & Beecher, 1955; Uhlenhuth, Johanson, Kilgore, & Kobasa, 1981). Amphetamine preference was related to "positive" mood effects, including increases in vigor and arousal, and amphetamine avoidance was related to what the authors described as "negative" mood effects (Johanson & deWit, 1989). In another study, "dysphoric" mood predicted amphetamine preferences (Uhlenhuth et al., 1981). Studies of low methylphenidate doses (10 or 20 mg) also suggest individual differences in mood effects. Some low-dose studies have reported positive mood effects, but other studies have failed to find drug-placebo differences in mood effects (Foltin & Fischman, 1991). Whether these conflicting results may be due to systematic individual differences in sleepiness should be explored. The enhanced vigor and arousal reported by those who prefer amphetamine is consistent with such a hypothesis, and wide variations in sleepiness among noncomplaining volunteers have been found (Levine, Roehrs, Zorick, & Roth, 1988). Within-subject differences in the subjective and reinforcing effects of stimulants as a function of time of day have also been reported. Amphetamine (5 mg) has been shown to have stimulantlike effects during midday, but not evening, hours (deWit et al., 1985; Johanson & deWit, 1989). This temporal pattern of effects is consistent with the known circadian rhythm of sleepiness-alertness, which is characterized by increases of sleepiness over the midday (i.e., when subjective effects are detected) and increases of alertness in the early evening (i.e., when subjective effects are absent; Roth, Roehrs, Carskadon, & Dement, 1994). Although this was a low-dose study with a single assessment, the time-ofday differences also suggest the hypothesis that sleepiness levels may modulate the subjective and reinforcing effects of stimulants. In a recent study, level of sleepiness was directly manipulated, and 10 mg methylphenidate (t.i.d.) produced subjec-

Timothy Roehrs, Kate Papineau, Leon Rosenthal, and Thomas Roth, Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Michigan. This study was supported by National Institute on Drug Abuse Grant RO1-DA05086. Correspondence concerning this article should be addressed to Timothy Roehrs, Sleep Disorders and Research Center, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, Michigan 48202. Electronic mail may be sent to [email protected].

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tive and performance-enhancing effects after sleep deprivation but not after 8 hr of sleep (Bishop, Roehrs, Rosenthal, & Roth, 1997). This finding replicated that of an earlier study in which amphetamine's performance-enhancing effects were dependent on prior sleep deprivation (Newhouse et al., 1989). The present study was conducted to further investigate the effect of sleepiness on the subjective and performance-enhancing effects of methylphenidate. Rather than total sleep deprivation, as in these previous two studies, a partial deprivation more akin to people's everyday experiences was used in the present study. The primary purpose of this study was to explore the impact of sleepiness on the reinforcing effects of methlyphenidate. The only previous study found that methylphenidate was chosen on only 28% of opportunities (Chait, 1994). However, level of sleepiness was not directly manipulated in that study. The present study sought to determine whether reduced sleep times would enhance the reinforcing effects of methylphenidate. Method Participants Participants were 6 healthy volunteers (4 women and 2 men), 21-30 years of age, with no sleep complaints, normal sleep patterns, and no primary sleep disorders (e.g., sleep apnea or leg movements). They showed no daytime sleepiness on questionnaires, a screening polysomnogram (PSG), and a multiple sleep latency test (MSLT). The study protocol was approved by the Henry Ford Hospital Institutional Review Board. All participants signed written informed-consent forms and were paid for taking part.

Screening Procedure Medical and psychological screening. Each participant underwent a physical examination, completed the Cornell Medical Index (Cornell University Medical College, 1974) and the Minnesota Multiphasic Personality Inventory (MMPI; Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989) and underwent standard clinical laboratory analyses of blood and urine samples for hematologic, hepatic, renal, and other major system functions. Participants with clinically significant positive laboratory findings were excluded. Those with MMPI elevations (i.e., T scores > 2 SD) on the clinical scales were also excluded. Alcohol and drug use history. Participants were interviewed to quantify their drug and alcohol use. No participants reporting greater than 300 mg of caffeine use per day were admitted. None of the participants reported smoking, although this was not an exclusion criterion. Participants reporting use of over-the-counter medications containing ephedrine or pseudoephedrine and those reporting a current or past history of illicit drug use or alcoholism were not included (a urine drug screen was used to verify the absence of current drug use). Participants were light to moderate social ethanol drinkers (i.e., 1-14 drinks per week and 6 drinks or less per occasion). Sleep evaluation. After the initial screening described earlier, each participant underwent additional evaluation to validate his or her normal sleep. A sleep disorders evaluation, including a sleep history and a nocturnal PSG, was done. For the sleep history, each participant completed a 2-week sleep diary of his or her usual sleep habits and a detailed questionnaire regarding any sleep-wake

complaints. Participants with insufficient (less than 6.5 hr sleeping times) and irregular sleep-wake schedules (i.e., bedtimes and arise times varying more than 2 hr) on 2-week sleep logs or other evidence suggestive of a circadian rhythm disorder were excluded. The PSG obtained from each participant included the standard central (C3-A2) and occipital (Oz—A2) electroencephalograms (EEGs), bilateral horizontal electrooculograms (EOGs), a submental electromyogram (EMG), and an electrocardiogram (ECG) recorded with a V5 lead (Rechtschaffen & Kales, 1968). Also, airflow was monitored with oral and nasal thermistors, and leg movements were monitored with electrodes placed over the left tibialis muscles (Bornstein, 1982; Coleman, 1982). The recordings, made at a 10 mm/s paper speed with polygraphs located in a separate monitoring room, began at 2300 hr and continued for 8 hr. The respiration and tibialis EMG recordings were evaluated by a clinical polysomnographer, and participants having any evidence of apneas or of leg movements (e.g., more than five per hour of sleep for either) were excluded. All recordings were scored in 30-s epochs according to the standards of Rechtschaffen and Kales (1968). The nocturnal PSG was followed by an MSLT the next day (according to the procedures described subsequently). MSLT assessment. For the screening MSLT, participants were tested at 1000, 1200, 1400, and 1600 hr for sleepiness via standard MSLT methods (Carskadon et al., 1986). Participants were monitored by means of standard polysomnography (EOG, chin EMG, ECG, and C3, C4, and Oz EEGs referenced to the ears). They were asked to lie down on a bed in a darkened room free of auditory and visual distraction and to try to take a nap. Each test lasted 20 min if sleep did not occur; if sleep did occur, the test was terminated 15 min after sleep onset. On these screening MSLTs, participants remained in bed after sleep onset for 15 min to test for the appearance of REM sleep. Sleep latency was defined as minutes from lights out to the first 30-s epoch of any sleep stage. Only participants with average daily sleep latencies of 8-16 min and no REM sleep on any latency test were included. Performance assessment. Participants also underwent divided attention and auditory vigilance performance testing beginning at 1100 and 1500 hr during screening (Bishop et al., 1997). A 15-min divided attention task was administered on an Epson Equity le computer. For this task, participants were to track a moving target across the video screen using a joystick and simultaneously press a button in response to the appearance of a white circle in the periphery of the screen or in the middle of the moving target. After a brief break, a 40-min auditory vigilance task was conducted. In this task, participants were required to detect a long (500-ms) 900 Hz tone against the background of short (250-ms) 900 Hz tones. At the screening, each participant was trained on the tasks to ensure the absence of practice effects during the study sessions.

Experimental Procedure Experimental time in bed (TIB) and drug schedule. Qualifying participants then served in three phases each consisting of 4 consecutive nights and days. They entered and remained at the laboratory for each phase; between phases, they returned home for a recovery period of 3 or 10 days. Each phase began at 2200 hr (when participants reported to the laboratory) to ensure that the appropriate bedtime was maintained. Phase 1 was a sampling week in which each participant underwent four TIB and drug combinations on 1 night and day each: placebo-8 hr TIB, placebo^- hr TIB, methylphenidate-8 hr TIB, and methylphenidate^t hr TIB, presented in a random order. TIB was manipulated by requiring that participants go to bed at 2300 hr or 0300 hr and arise at 0700 hr. Phases 2 and 3 were choice weeks, and each consisted of 4


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EFFECTS OF METHYLPHENIDATE consecutive nights and days with either a 4-hr or 8-hr TIB each night. TIB order was counterbalanced among participants. In the sampling phase, after the appropriate TIB the previous night, participants were administered methylphenidate (10 mg) or placebo (as a color-coded capsule) double blind at 0900 hr. Study capsules, prepared by the Institutional Research Pharmacy, consisted of crushed methylphenidate tablets (10 mg) with lactose added or capsules filled with lactose alone. During the sampling phase, participants were instructed to attend to capsule color because they would be required to make choices during the subsequent weeks. In Phases 2 and 3, participants chose 10 mg methylphenidate or placebo based on capsule color (forced choice) at 0900 hr. Capsule choices were made by completing a form on which the participants indicated the desired capsule color for that day. The technician then oversaw the administration of the proper capsule color. Daily schedule. During the three experimental phases of the study, MSLTs were administered at 0930, 1130, 1330, and 1530 hr (the experimental version of the MSLT, in which a test is terminated 1.5 min after sleep onset, was used). Mood and subjective drug effect testing was done at 1000 hr (1 hr postdrug) and 1200 hr (3 hr postdrug). The performance testing, including the divided attention and vigilance tests described earlier, was conducted beginning at 1005, 1205, 1405, and 1605 hr. The 1005 and 1205 assessments were used to evaluate drug effects, and the 1405 and 1605 assessments were scheduled to require a behavioral load and the continued alertness of the participants. Mood and drug effect assessment. For the mood assessment, participants completed the 72-item version of the Profile of Mood States (POMS). The POMS is an adjective checklist assessing momentary mood states; it has been used in a variety of drug effect studies and yields six mood scales, two of which are Vigor and Fatigue (McNair, Lorr, & Droppleman, 1971). Drug effects were assessed with the 49-item Addiction Research Center Inventory (ARCI), which yields five empirically derived scales representing drug effects associated with certain drug classes: Amphetamine (stimulation, high), Morphine-Benzedrine (euphoria), Lysergic Acid Diethylamide (somatic complaints or dysphoria), Benzedrine (mental efficiency and cognitive effects), and PentobarbiitalChlorpromazine-Alcohol (sedation; Haertzen, 1974). Study restrictions. Throughout the nights and days participants spent at the laboratory, use of caffeinated beverages and foods was not allowed. Napping other than that involved with the latency tests was not allowed. Participants were monitored to ensure compliance with these restrictions. Each laboratory day, a breakfast consisting of a roll and orange juice was provided at 0800 hr; lunch, provided at 1300 hr, consisted of sandwiches and a noncaffeinated beverage of choice. The participants were allowed their choice of dinner fare. During the 3 or 10 recovery days at home, participants were

cautioned to maintain their regular exercise habits and sleep-wake schedule. They were told to refrain from use of alcohol during the day before entering the laboratory and that breath testing would be used to assess their compliance.

Analyses The number of methylphenidate choices was compared between the two TIBs via a paired t test. Sleep latency was averaged over the four MSLTs conducted each day. Average daily sleep latency on the sampling days was compared via one-factor (four conditions) repeated measures multivariate analyses of variance (MANOVAs); tests for interactions involved two-variable MANOVAs with TIB (8 vs. 4 hr) as one variable and methylphenidate versus placebo as the other. Greenhouse-Geiser corrected probability levels were used in all MANOVAs. The POMS (six scales) and ARCI (five scales) data were averaged over the assessments conducted at 1000 and 1200 hr. These averaged scores on the sampling days were analyzed in the same manner as the sleep latency data. Finally, the divided attention and vigilance performance data were analyzed in a similar manner. The parameters on the divided attention task were central and peripheral reaction times (seconds) and tracking deviations (CRT pixels); on the vigilance task, parameters were mean reaction time (milliseconds) and total number of errors. Vigilance data did not show effects and are not further reported. To generate a summary divided attention measure, we converted each of the three divided attention measures to z scores and averaged the three z scores to create a divided attention score for each participant in each condition.

Results Total numbers of methylphenidate and placebo capsule choices after 4 hr or 8 hr TIB the previous night are presented in Table 1. The total number of methylphenidate choices after 4 hr TIB was significantly greater than that after 8 hr TIB, t(5) = 4.72, p < .005, and every participant showed the same pattern of choice. In the 4 hr TIB, methylphenidate was chosen on 88% of opportunities, whereas it was chosen on only 29% of opportunities in the 8 hrTIB. The effect of TIB and methylphenidate on MSLT score during the sampling week of the study is illustrated in Figure 1. Reduced TIB to 4 hr versus 8 hr decreased sleep latency, F(3, 15) = 4.46, p < .02. Methlyphenidate (10 mg) produced an overall increase in sleep latency, F(l, 5) = 9.63, p < .027, and there was no interaction of TIB with the

Table 1 Number of Methylphenidate and Placebo Choices 4 hrTIB

8 hr TIB

Participant

Methylphenidate

Placebo

Methylphenidate

Placebo

Participant 1 Participant 2 Participant 3 Participant 4 Participant 5 Participant 6 Total

4 4 4 3 3 3 21

0 0 0

0 2 1 2 0 2 7

4 2 3 2 4 2 17

Note.

TIB = time in bed.

1 1

1

3


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Fatigue scale score was greatest in the 4 hr TIB, F(l, 5) = 97.43, p