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Sleep and Some Psychoactive Drugs
Sleep and Some Psychoactive Drugs DAVID C. KAv, M.D. At least four major groups of psychoactive drugs have been described which are associated with significant abuse: opiates, sedative-hypnotics (including alcohol), stimulants, and hallucinogens (with some pharmacologists including marijuana in the latter group). This paper will primarily review the opiates, sedativehypnotics and stimulants, with no discussion of hallucinogens and only short discussion of some other psychoactive drugs. Because of the rapid increase in data. no claim is made that this review is exhaustive for drugs or species, or that it extends much beyond the pertinent English literature.
creased early in the night and delta sleep was not affected by this dose. Morphine thus has an arousal effect on the sleep of several species. The only investigation which has studied the mechanism of this arousal effect3 ,4 has supported neither the antiserotonergic nor the noradrenergic hypotheses which were tested. Chronic opiate administration leads to a somewhat different pattern of effects on sleep. Khazan et al. 2 found that after 3 days of increasing intravenous dosage, rats showed tolerance to the decreases in SWS and PS. Self-in-
OPIATES
After Khazan and Sawyer! found that morphine reduces paradoxical sleep (PS) in rabbits, Khazan et al.~ demonstrated that morphine has an arousal effect in rats: continuous intravenous infusion of morphine initially increased wakefulness and decreased both slow wave sleep (SWS) and PS. Echols and Jewetfl,4 have also found that morphine decreases PS and SWS in cats. These effects of morphine in the rabbit. rat and cat parallel those effects found in the human postaddict by Kay et aP Single doses of morphine (7.5. 15 and 30mg/70 kg) increase wakefulness (Fig. I) and drowsiness, and decrease both delta sleep (Fig. 2) and rapid eye movement sleep (REMS: Fig. 3). Estimates from this study as to the acute dose of morphine required to abolish REMS measures range over 20-25 mg/70 kg. Morphine differentially affects various REMS measures: it decreases the number and mean duration of REMS episodes while increasing REMS latency and having indeterminate effect on the REMS ~ycle. Lewis et al. G found that 7.5 mg of heroin had comparable effects on nonaddicts: it decreased REMS and increased drowsiness. Sleep onset was delayed, but spindle sleep was inDr. Kay is from the National Institute of Mental Health, Addiction Research Center, Lexington, Kentucky, U.S.A. 108
MORPHINE EFFECT ON WAKING STATE DURING STANDARD NIGHT (WS/450minl 50
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Figure I. Morphine significantly (p < 0.01) increased waking state in the 7Y2 hours after lights out. Morphine dose is expressed on the abscissa in milligrams/70 kg. Waking state is expressed on the ordinate as percentage of the 450 minute standard night. Each X represents the total response of one subject, and each • represents the mean of 8 subjects. The arithmetic regression equation was calculated from the 4 dosage means.
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SLEEP AND SOME PSYCHOACTIVE DRUGS-KAY
jection then produces a characteristic pattern: wakefulness, with bursts of high voltage slow waves in the EEG,7 followed each injection, and sleep (especially PS) preceded each injection of morphine. After repeated doses of 7.5 mg of heroin for 3-7 nights, nonaddict humans also showed tolerance to the decrease of REMS. 6 Six men who chronically received 140-240 mg of morphine daily showed several significant phenomena: 8 ,9 wakefulness was no longer increased, even during the induction phase after the dose had been increasing for three weeks. Delta sleep tended to increase, and shifted toward later in the night. Delta bursts (4-20 sec in duration) increased significantly during drug administration, both in number and total time. REMS was still significantly decreased during both the induction phase and the stable phase. REMS measures varied in their response to chronic morphine: the number of REMS episodes remained low and the REMS cycle remained longer in period
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MORPHINE EFFECT ON DELTA SLEEP (STAGE 4) DURING A SUNDARD NIGHT (05/450)
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Fi!:lIre 2. Morphine significantly (p < 0.001) decreased delta sleep in the 71;2 hours after lights out.
Morphine dose is expressed on the abscissa in milligrams/70 kg. Delta (stage 4) sleep is expressed on the ordinate as percentage of the 450 minute standard night. Each X represents the total response of one subject, and each • represents the mean of 8 subjects. The arithmetic regression equation was calculated from the 4 dosage means. March-April, 1973
during both induction and stabilization phases, while mean REMS episode duration was diminished only during the induction phase. REMS latency and REM density were not significantly different from control during either phase of drug administration. Chronic administration of methadone shows a comparable pattern. Henderson et al. tO found that tolerance developed to the initial decrease in REMS and delta sleep after stabilization on methadone, but some signs appeared of persistent arousal. Kay and Martin ll and Martin et al.l~ found that little difference could be seen in the sleep of 6 men between the control and drug phases, except that vocalization during REMS and nocturnal delta bursts were increased during drug administration. However, waking EEG showed a marked increase in slow wave activity during drug administration. The effects of chronic opiate administration appear to be a combination of varying degrees of tolerance to the arousal effects and the emergence or exaggeration of slowwave activity. It is not certain whether this slow wave activity is evidence of sleep and/or subconvulsive phenomena. Withdrawal of opiates produces sleep and EEG changes which have not been completely d~fined. There is inconclusive evidence for an increase in REMS in humans after the initial decrease by single doses,fl,G or soon after withdrawal of morphine in rats. 2 There are many reports from clinical studies that insomnia is a major symptom of early abstinence from opiates, and the only appropriate sleep study2 supports this impression in the rat. Integrated EEG voltage is decreased after drug withdrawal in both the sleep and wakefulness of rats experiencing early abstinence. 13 ,14 A more specific effect was seen in human waking EEG by Martin et al. 12 at 6 weeks after withdrawal of methadone (early abstinence): slow wave activity was decreased even with alpha activity present. The protracted abstinence syndrome after withdrawal of methadone from 5 humans showed two effects on sleep:ll an increase in REMS which peaked at t 3 weeks after withdrawal, and a later increase in delta sleep. 109
PSYCHOSOMATICS
barbiturates16,19,25,27,29 in a dose-related fashion. 25 REMS latency is increased by barbiturate;16,18,19.21,28,30 this effect is significant (p
Khazan and Colasantp5 have also found a change in the response of rats to single doses of morphine depending on the phase of the addiction cycle. Naive rats show a pattern of behavioral stupor with bursts of high voltage slow waves in the EEG for 60-90 min, followed by behavioral and EEG arousel for 60-90 min. This pattern was not distinct during chronic morphine administration or during early abstinence. During protracted abstinence, the rats showed a prolonged arousal to single doses of mcrphine, with the gradual return of the stupor plus EEG slowwave response as time increased after withdrawal. Henderson et al. 10 have described more nocturnal awakenings in 4 human ex-addicts when compared to control. Thus, growing evidence from quantified sleep studies supports the importance of persistent physiologic changes after drug withdrawal; these facts could support the concept of a pharmacologic factor in opiate drug abuse.
30
MORPHINE EFFECT ON REM STATE DURING STANDARD NIGHT
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Volume XIV
SLEEP AND SOME PSYCHOACTIVE DRUGS-KAY
et aI. 22.2f interpreted the increase of spindle sleep as compensatory for the decrease in REMS, and most of the other studies did not see this effect as a primary drug effect. During the study by Kay et a1. 25 spindle burst incidence during spindle sleep was increased by pentobarbital (75, 150 and 300 mg/70 kg), especially in the middle and late thirds of the night when peak drug effect was probably occurring (Fig. 5). This increase in incidence of spindle bursts, as well as an increase in duration and amplitude of spindles, with a slowing of sigma frequency, would support the hypothesis that the increase of spindle sleep is a primary effect of barbiturate. However, Lester et al. 27 found an opposite effect: 200 mg of secobarbital decreased the incidence of spindle bursts from 6.0 bursts per minute (bpm) to 2.0 bpm. They used their finding to support the hypothesis that barbiturates selectively inhibit phasic events in sleep (e.g.: sigma waves in spindle sleep, eye movements in REMS, and spontaneous electrodermal responses in delta sleep). Feinberg et aJ.33 have reported data on total spindles which can be used to estimate an average of 4.6 bpm in normal young adults; this compares with placebo values of 3.5 bpm in the Kay et a1. 25 subjects and 6.0 bpm in the Lester et al. 27 subjects. Delta sleep has shown the most reported variability after barbiturate. Lester and Guer-
SPINDLE
SLEEP
AND
rero-Figueroa28 found that both thiopental and phenobarbital increased delta sleep; however, EEG slow waves after barbiturate have been reported as evidence for anesthesia,34 so this effect would require differentiation from delta sleep. Most studies I6,20,25,27,29 report no significant change in delta sleep after barbiturate. Feinberg et al.,19 and Kales et a1.2 2.24 found a decrease in delta sleep after barbiturate. This decrease becomes significant during the first week of continued drug use,24 with a gradual return toward normal after withdrawal. This pattern of effect is more typical of tolerance phenomena or chronic toxicity rather than of acute effects of a drug. Probably some of the variability in delta sleep response to barbiturate is due to the subject population: Bohlin et al. 35 found differences between normal and anxious subjects in their delta sleep response to sedatives. Sleep latency has been quantified in few studies; it is decreased by barbiturate,16,18,20,21,25 but is not dose-related. 25 Waking state. number of awakenings, body movement and/or muscle tension are decreased by barbiturate. 16,18.20,25,27,29 Difficulty in quantifying a decrease in total waking state or an increase in total sleep can be related in several studies to the use of normal subjects and to the necessity for a fixed bedtime and a limit to spontaneous AM arousal. Few studies have been done of the effects
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March·April, 1973
(p < 0.001) decreased REMS and significantly (p < 0.001) increased spindle (stage 2) sleep. The mean of 8 subjects is expressed on the abscissa for each dose of pentobarbital in milligrams170 kg. Each measure is expressed on the ordinate as total minutes during the 450 minutes after lights out, and is paired with its arithmetic regression equation. III
PSYCHOSOMATICS
of chronic barbiturate administration on quantified sleep. Oswald and Priest36 were the first to quantify barbiturate withdrawal effects on sleep with continuous EEG monitoring. In their study, 2 subjects received 400 mg of oral amylobarbitone for 9 nights and then 600 mg for 9 nights. After an initial decrease in REMS and increase in REMS latency with each dosage increase, tolerance tended to develop over the 9 night sequence. Insomnia, poor sleep and nightmares dominated the first 2 weeks after drug withdrawal, with an increase in REMS up to 5-6 weeks after drug withdrawal (especially in the first 2 hours of sleep). Evans et al. IH found total sleep was reduced but REMS was increased after withdrawal from amylobarbitone. Evans and Lewis 37 claim that chlorpromazine will block these signs of abstinence. One subject dependent on 1.0 G of pentobarbital had a reduced level of REMS SPINDLE
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(p < 0.05) increased by pentobarbital. Each X rep· resents the value for one subject, and each • represents the mean of 8 subjects. The dose of pentobarbital is expressed on the abscissa in milligrams/ 70 kg. Spindle burst incidence is expressed on the ordinate as bursts per minute of spindle sleep during the 450 minutes after lights out. 112
while on drug, with an increase in REMS, vivid dreams and nightmares while the drug was reduced over two months. 22 ,::!3,38 REM density increases after withdrawal of barbiturate,23,39 which has been correlated with the vivid dreaming and nightmares. 22 ,4o,41 Delta sleep also shows change with chronic barbiturate use and withdrawal. It is decreased or absent with chronic use,19,22,24,38 and gradually returns to normal in a few months after withdrawal. 38 OTHER SEDATIVE-HYPNOTICS
Non-barbiturate sedative-hypnotics have also been studied for their effects on sleep. REMS decreases after single doses of alcohoJ,42.48 chloral hydrate,::!::!,49 glutethimide,22,24,:;o'52 methyprylon,::!::!,24,a2 methaqualone,2::!,a:l and flurazepam!',::!·a4 Spindle sleep increases after alcohol,H,46,4i chloral hydrate,4H glutethimide,24,:;1 methyprylon,24 methaqualone,',I,r'3 and flurazepam."3.":; Delta sleep is increased and then decrcased H or it is unchanged 4fi ,4i after alcohol; it is unchanged after chloral hydrate 26,49,53,,,,, or methyprylon.::!4 Delta sleep is decreased 24 or unchanged"1 by glutethimide, decreased"l or unchanged l .,49,r,:1 by methaqualone and decreased by flurazepam.":!·"" Waking state is unaffected by single doses of alcohol,4!>,4i decreased!!' or unaffected 5:!,:;" by chloral hydrate, decreased by glutethimide,"1 and methyprylon,24 decreased"I,"!> or unaffected l ',49 by methaqualone. and decreased by flurazepam.::!],;\4,r,a With chronic drug administration, delta sleep is persistently decreased by alcohol,H,,,. glutethimide,::!::! and flurazepam. 22 Chronic use of alcohol has also been associated with increased but fragmented sleep."8,59 Upon withdrawal of drug, an increase in REMS and/or an increase in REM density, as with barbiturates,2::!,:!!>,;;2 is found with alcohol,42,H,4!>'4H/",!>o,fil chloral hydrate,::!::! glutethimide,22,24,,,(1."2 methyprylon,::!::!,::!4,;,::!,fi2 methaqualone, 22,,,1,53,62 and flurazepam!'" An increased incidence of vivid dreaming and nightmares, similar to that seen with barbiturates,22,36,52 is seen upon withdrawal of alcohol,42,44,57,6o,61 glutethimide,22,24,52 methyprylon,22,24,52,62 and methaqualone. 62 The effects of other sedative-hypnotics (such as ethinimate, ethchlorvinyl or oxazepam) have not been quantified as yet. Volume XIV
SLEEP AND SOME PSYCHOACTIVE DRUGS-KAY
Although antihistamines have sedative actions, little is known of their quantified effects on sleep. Diphenhydramine decreases REMS in single doses, with an increase in delta sleep during chronic administration and an increase in REMS upon withdrawal.:!:! Alpha-chloralose is an anesthetic with unusual hypnotic characteristics: it decreases REMS and increases delta sleep,28,63 while not affecting spindle sleep or waking stateli.1 at the dose tried. Scopolamine has some effects on quantified sleep similar to barbiturate: in single doses it decreases REMS,1I4 increases spindle sleep,li4 and does not change delta sl eep1l4,115 or waking state. U4 MINOR TRANQUILIZERS
This group of psychoactive drugs has some actions quite similar to barbiturate. In quantified studies, REMS was decreased by meprobamate lill and nitrazepam,:!11,36,67 but was not affected by the doses tried of diazepam:!2 or chlordiazepoxide.:!l Spindle sleep is increased by single doses of nitrazepam 31i,07 and meprobamate.(Ill Delta sleep is unchanged by meprobamate,';t: and is unaffected:l5 or decreased:l5 ,li7 by nitrazepam. Waking state is decreased by chlordiazepoxide 21 and not affected by meprobamate';l1 or nitrazepam. 67 Delta sleep is decreased during chronic administration of diazepam:!:? or chlordiazepoxide. 22 Withdrawal from nitrazepam is associated with an increase in REMS and/or REM density,36,62 and an increase in vivid dreaming and nightmares. 31i Insufficient evidence is available to differentiate these drugs from barbiturate on the basis of quantified sleep studies. MAJOR TRANQUILIZERS
Chlorpromazine MI• 7:! and reserpine 73 decrease REMS at some doses, but both chlorpromazine 111 ,7U,H and reserpine 71i.8o have also increased REMS. Spindle sleep is decreased by single doses of chlorpromazine64 ,69,74 and resperine. 77 Delta sleep is increased by chlorpromazine,19,:?8, t:4,1I11,71,7:!,H but dec rea sed by reserpine. 75 ,77 Waking state is decreased 68.72,74 or unchangedt:4 by chlorpromazine; and it is unchanged,76 increased 7:!,77 or decreased 73 by
reserpine. Chronic reserpine administration is associated with no change,:!2 or with a persistent decrease in delta sleep.80 ANTIDEPRESSANTS
Single doses of imipramine,68,71,72,74,81.84 desipramine,H,8o amitriptyline,21,72,74,81 and phenelzine 8o,l
Oswald:19,lIlJ, III has reviewed the clinical data, much of which have come from his laboratory. REMS has been the sleep state most studied, and it is decreased by single doses of most stimulants: amphetamine,16,30,32,611,1I2 methamphetamine,7:! methylphenidate,32,113 diethylpropion,:l2,92,!14 chlorphentermine,32,\l2 phenmetrazine,32,!14 aminorex,32 benzphetamine,32 and phentermine.32 Fcnfluramine decreases REMS in cats:12 ,!11i and in humans at higher doses !lll or when added to amphetamine,ll2 but has no significant effect at some dosesll 2,1l4,117 except for an increase in REMS latency.92,1l7 A new amphetamine derivative JP 992 [(meta trifluoromethyl-phenyl)-l-(benzoyl oxy)eth yl amino-2-propane] decreases REMS early in the night at a higher dosell 1 but not at a lower dose.1I 7 Despite the fact of studying stimulants, several investigations do not quantify effects on waking state, or seek to minimize such effects. Amphetamine increases waking state in humans even with barbiturates,16 as well as in
March-April, 1973
113 _._~~.
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PSYCHOSOMATICS
cats.32,69 Diethylpropion also increases waking state in humans,94 and JP 992 increases shifts into drowsiness and waking state. 9l ,97 Several amphetamine derivatives increase waking state in cats,32,72 except for chlorphentermine which has no effect3 2 and fenfluramine which decreases waking state after single doses. 32 ,95 Drowsiness (stage 1) is increased by several stirn ul an ts: fenfluramine,92,94,97 diethylpropion,92,94 JP 992,97 chlorphentermine 92 and amphetamine. 92 Shifts into drowsiness were increased by JP 992. 91 ,97 Spindle (stage 2) sleep is increased by methylphenidate,93 amphetamine,16,92 and diethylpropion,94 but has been reported to be decreased by amphetamine in cats. 69 Delta sleep (stages 3 and/or 4) is decreased by amphetamine,16,69 fenfluramine,94 diethylpropion,94 and JP 992. 97 SWS is decreased by several derivatives in the cat32,72 except for chlorphentermine which has no effect~2 and fenfluramine which increases SWS.32,95
probably are an increase in waking state and/or drowsiness, plus a decrease in delta sleep and REM sleep; spindle sleep effects are not clear. The little evidence available would support the idea that sleep returns toward normal during chronic stimulant use, although no data are available to evaluate the degree of tolerance or persistent effect. Withdrawal appears to be correlated with an increase in REMS and total sleep(possibly including a delta sleep increase), accompanied by excessive dreaming and occasional nightmares. ADDICTION CORRELATES
From the facts reviewed above, one acceptable hypothesis would be that most opiates, stimulants, and sedative-hypnotics decrease REMS after acute administration (with sufficient dose) and show increased REMS after withdrawal. These facts led some investigators99 to postulate that all drugs are addictive which show these effects; however, this concept had to be modified after more drugs were investigated, I know of no sleep studies which have used and some with no obvious abuse problem, chronic stimulant administration to humans such as antidepressants, were discovered to preceded by a nondrug control. Oswald and significantly decrease REMS, with REMS inThacore 98 reported apparently normal sleep in 6 creased for several weeks after withdrawal. humans who had been chronically taking stimuSome investigators19,22,99 have proposed anlants (amphetamine, phenmetrazine) either other relationship of sleep disorder to drug alone, or in combination with barbiturate; abuse: chronic drug use leads to suppression of they found an increase in both REMS and the REMS system, and withdrawal of drug then total sleep upon withdrawal of the drug (s) . releases the eNS, with abnormal amounts of When Rechtschaffen and Maron30 gave 3 subREMS being associated with nightmares and/or jects amphetamine plus barbiturate for 3 nights delirium. This theory evolved from the study they noted a reduction in REMS which did not of withdrawal from alcohol or sedative hypnotreturn to control level in all subjects, followed ics in which the REMS increase and a delirium by an increase in REMS in 2 succeeding placeare correlated in time. Although withdrawal bo nights. from alcohol,100.102 barbiturates l03 ,104 and other Oswald et al. 94 found that 2 subjects had less sedative-hypnotics is known to be associated REMS while receiving phenmetrazine for 7 with seizures and delirium, this pattern is not nights, which was followed by a decreased seen with other psychoactive drugs. An acute REMS latency upon withdrawal. They also toxic psychosis or a paranoid psychosis is assofound a decreased REMS latency upon with- ciated with amphetamine abuse,105.107 but these drawal of diethylpropion from 2 other subjects, subside during withdrawal. Except for meperbut no such effect after a clinical dose of fenflu- idine and dextropropoxyphene (which can proramine in 4 subjects. Johnson et aJ.95 found duce a toxic psychosis during chronic abuse), that REMS returned toward control during toxic psychosis is not a consistent feature either chronic fenfluramine administration in cats, of chronic opiate abuse or of withdrawal from and increased upon drug withdrawal. opiates. These differing patterns of toxic psyThe acute effects of stimulants on sleep chosis must be contrasted with the apparent 114
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SLEEP AND SOME PSYCHOACTIVE DRUGS-KAY
increase in REMS and dreaming after withdrawal from compounds in all three drug classes. There might well be some causal relationship between changes in sleep and the phenomena of drug abuse, but it is not obvious. The finding of increased REMS and delta sleep during protracted abstinence after opiates appears important: sleep studies would thus be established as a sensitive method to quantify protracted abstinence effects" which might be correlated with drug-seeking behavior. Even if REMS effects are comparable, can addicth e or nonaddictive drugs be classified on the basis of the total pattern of their effects on ~Ieep? I have summarized in Table I my best estimate of some acute drug effects on sleep, based on the data reviewed above. This table includes a representative stimulant (amphetamine), opioid analgesic (morphine) and sedative-hypnotic (pentobarbital), as well as an antidepressant (imipramine) and two antipsychotic drugs (reserpine and chlorpromazine). REMS appears to differentiate only the anti-psychotics, which increase REMS at some doses. Delta sleep clearly differentiates only chlorpromazine, which increases delta sleep, although the effects of pentobarbital and imipramine are not well-established. Waking state is increased by amphetamine, morphine and reserpine, but is decreased by pentobarbital, imipram"r:e and chlorpromazine. This would appear lJ be a gross arousal/sedation classification, except that morphine and imipramine might have been expected to be reversed. Spindle sleep apparently is increased by pentobarbital and imipramine, decreased by reserpine and chlorpromazine, and variably affected by amphetamine and morphine. The grouping of pentobarbital with imipramine appears puzzling. Inspection of this table would indicate that the measures which best differentiate these drugs are waking state and spindle sleep; those have been the measures least investigated by sleep researchers. Many drugs cannot be easily classified within these 6 groups, which is to be expected. As our knowledge increases about drug effects on sleep, hopefully a pharmacologic classification will evolve which can differentiate compounds already known to have significantly different eNS effects. March-April, 1973
TABLE I ACUTE EFFECTS OF PSYCHOACTIVE DRUGS Drug Amphetamine Amphetamine Morphine Reserpine Pentobarbital Imipramine Chlorpromazine + Increase, -
=
Waking State
Spindle Sleep
Delta Sleep
+ + + +
+,+,-
0, -
+
0, -
o
REM Sleep
+,-
+?
+
+, -
= Decrease, 0 = No Change SUMMARY
Morphine in single doses increases wakefulness and drowsiness while decreasing REMS and delta sleep. Partial or complete tolerance to these effects develops after continued morphine administration; however, sleep then precedes and wakefulness follows each drug dosage and bursts of slowwave activity appear in sleep and waking EEG. Withdrawal from methadone in man is associated with an initial increase in dreaming and then several weeks of insomnia during early abstinence, with a decrease in slow wave activity in the waking EEG. Protracted abstinence is characterized by an increase in REM sleep, followed by an increase in delta sleep. Tolerance develops to morphine's initial synchronizing effect on the EEG, leaving a persistent arousal effect from morr"'ire for several months during protracted abstinence. Barbiturate in single doses increases total c!cep and EEG spindling while decreasing REM sleep. With continued barbiturate administration, some tolerance probably develops to the effect on REMS, but delta sleep becomes persistently decreased. Withdrawal from barbiturate is associated with insomnia and nightmares, the latter occurring during a marked increase in REM sleep. Delta sleep remains low during chronic barbiturate use and gradually returns to normal levels after withdrawal without known increase above normal. Alcohol and most other sedative-hypnotics appear to have the same general pattern as barbiturate. Both alcohol and barbiturate are associated with a psychosis during withdrawal, which appears to occur during the greatest increase in REMS. liS
PSYCHOSOMATICS
Amphetamine in single doses increases wakefulness and decreases all states of sleep. Tolerance apparently develops to these effects, since chronic amphetamine users are reported to have sleep patterns within normal limits. Withdrawal from chronic amphetamine is associated with increased sleep, especially REMS. Amphetamine is also associated with a psychosis during chronic use, which tends to disappear during withdrawal. Most other CNS stimulants appear to have the same general pattern as amphetamine. REM sleep apparently increases during withdrawal from opiates, sedative-hypnotics or stimulants; psychosis occurs during chronic use of stimulants, but only occurs upon withdrawal from sedative-hypnotics, and does not usually occur either during chronic use or during withdrawal from opiates. Delta sleep is increased late after withdrawal from opiates and possibly early after withdrawal from stimulants; no increase in delta sleep has yet been describ<:d after withdrawal from sedative-hypnotics. However, measures of sleep states apparently are sensitive indicators of CNS homeostasis, and might help to defiine pharmacologic factors in recurrent drug-seeking behavior.
13. 14. 15. 16. 17. 18. 19.
20. 21. 22.
23.
24. 25.
26. 1. 2. 3. 4.
5. 6.
7. 8. 9. 10. 11. 12. 116
REFERENCES Khazan, N .. and Sawyer, C. H.: PsycllOpharmacologia. 5:457-466, 1964. Khazan, N., Weeks, J. R., and Schroeder, L. A.: J. Pharmacol. Exp. Ther., 155:521-531, 1967. Echols, S. D., and Jewett, R. E.: Pharmacologist, II :254, 1969. Echols, S. D., and Jewett, R. E.: Psychopharmacologia, 24:435-448, 1972. Kay, D. C., Eisenstein, R. B., and Jasinski, D. R.: Psychopharmacologia, 14 :404-416, 1969. Lewis, S. A., Oswald, I., Evans, J. I., Akindele, M. 0., and Tompsett, S. L.: Electroellcephalogr. Clill. Nellrophysiol., 28:374-381, 1970. Khazan, N., and Weeks, J. R.: Pharmacologist, 10: 189, 1968. Kay, D. C.: Fed. Proc., 29:384, 1970. Kay, D. C., and Kelly, O. A.: Psychophysiology, 7:346, 1971. Henderson, A., Nemes, G., Gordon, N. B., and Roos, L.: Psychophysiology, 7:346-347, 1970. Kay, D. C., and Martin, W. R.: Psychophysiology, 9:95, 1972. Martin, W. R., Jasinski, D. R., Haertzen, C. A., Kay, D. C., Jones, B. E., Mansky, P. A., and
27.
28. 29.
30. 31. 32. 33. 34. 35. 36. 37.
Carpenter, R. W.: Methadone-a re-evaluation. (in preparation). Khazan, N.: Fed. Proc., 29:780, 1970. Khazan, N., and Colasanti, B.: J. Pharmacol. Exp. Ther., 177:491-499, 1971. Khazan, N., and Colasanti, B.: Psychopharmacologia, 22: 56-63, 1971. Baekeland, F.: Psychopharmacology, II :388-396, 1967. Davison, K., Duffy, J. P., and Osselton, J. W.: Call. Med. Assoc. J., 102:506-508, 1970. Evans, J. I., Lewis, S. A., Gibb, I. A. M., and Cheetham, M.: Br. Med. J., 4:291-293. 1968. Feinberg, I., Wender, P. H., Koresko, R. L., Gottlieb, F., and Piehuta, J. A.: J. Psychiatr. Res., 7:101-109,1969. Haider, I.: Pakistall Med. Forum, 4:21-30, 1969. Hartmann, E.: Psychoplwrmacologia, 12: 346353, 1968. Kales, A., Heuser, G., Kales, J. D., Rickles, W. H., Rubin, R. T., Scharf, M. B., Ungerleider, J. T., and Winters, W. D.: AIIII. Illtern. Med., 70: 591-614, 1969. Kales, A., Malmstrom. E. J., Scharf, M. B., and Rubin, R. T.: Psychophysiological and biochemical changes following use and withdrawal of hypno,ics. In A. Kales (Ed.), Sleep:-Physiology alld Pathology. Philadelphia: J. B. Lippincott Company. 1969, pp. 331-343. Kales, A., Preston. T. A., Tan. T. L., and Allen, C.: Arch. Gell. Psychiatry, 23:211-218, 1970. Kay. D. c., Jasinski, D. R., Eisenstein, R. B., and Kelly, O. A.: Clill. Pharmacol. Ther., 13: 221-231. 1972. Lehmann, H. E., and Ban, T. A.: 1m. Z. Klill. Plwrmakol. Ther. Toxikol., 1:424-427, 1968. Lester, B. K.. Coulter, J. D., Cowden, L. C., and Williams. H. L.: PsycllOpharmacologia, 13:275286, 1968. Lester, B. K., and Guerrero-Figueroa, R.: Psychophysiology, 2:224-236, 1966. Oswald, I., Berger, R. J., Jaramillo, R. A., Keddie, K. M. G., Olley, P. D., and Plunkett, G. B.: Br. J. Psychiatry, 109:66-78, 1963. Rechtschaffen, A., and Maron, L.: Electroellcephalogr. Clill. Nellrophysiol., 16:438-445, 1964. Fisher, C.: Excerpta Med. lilt. COllgr. Ser., No. 150, 1967, pp. 168-177. Johnson. D. N., Funderburk, W. H., and Ward, J. W.: Ellr. J. Pharmacol., 15:176-179, 1971. Feinberg, I., Koresko, R. L., and Heller, N.: J. Psych iatr. Res., 5: 107-144, 1967. Gibbs, F. A., and Maltby, G. L.: J. Pharmacol. Exp. Ther., 78: 1-10, 1943. Bohlin, G., Wikmark. G., and Dureman, I.: Siirtryck IIr Nordisk Medicill, 83: 137-142, 1970. Oswald, I., and Priest, R. B.: Br. Med. J., 2: 1093-1095, 1965. Evans, J. I., and Lewis, S. A.: Arch. Gell. Psychiatry, 19:631·634, 1968. Volume XIV
SLEEP AND SOME PSYCHOACTIVE DRUGS-KAY 38. Kales, A., Malmstrom, E. J., Rickles, W. H., Hanley, J., Tan, T. L., Stadel, B., and Hoedemaker, F. S.: Psychophysiology, 5:208, 1968. 39. Oswald, I.: Sleep and dependence on amphetamine and other drugs. In A. Kales (Ed.), Sleep-Physiology and Pathology. Philadelphia: 1. B. Lippincott Company, 1969, pp. 317-330. 40. Carroll, D., Lewis, S. A., and Oswald, I.: Nalllre, 223: 865-866, 1969. 41. Kales, A., and Jacobson, A.: Exp. Neuro/., 19 (Suppl. 4) :81-91, 1967. 42. Greenberg, R., and Pearlman, C.: Am. J. Psychiatry, 124:133-142,1967. 43. Gresham, S. c., Webb, W. B., and Williams, R. L.: Science, 140: 1226-1227, 1963. 44. Gross. M. M.. and Goodenough, D. R.: Psycl,iatr. Rl's. Rep. Am. Psychiatr. Assoc., 24: 132-147, 1968. 45. Knowles, J. B., Laverty, S. G., and Kuechler, H. A.: Q. J. Stud. Alcohol, 29:342-349, 1968. 46. Yules, R. B., Freedman, D. X., and Chandler, K. W.: Electruellcephaloj.lr. Clin. Neurophysiol., 20:109-111. 1966. 47. Yules, R. B., Ogden, J. A., Gault, F. P., and Freedman, D. X.: Psychon. Sci., 5:97-98, 1966. 48. Yules, R. B., Lippman, M. E., and Freedman, D. X.: Arch. Gell. Psyclriat/y, 16:94-97, 1967. 49. Evans. J. I., and Ogunremi, O. 0.: Br. Med. J., 3:310-313, 1970. 50. Allen. c., Kales, A., and Berger, R. J.: PsycllOn. Sci., 12:329-330, 1968. 51. Goldstein, L., Graedon, J., Willard, D., Goldstein, F., and Smith, R. R.: J. Clin. Plrarmacol., 10:258-268, 1970. 52. Kales, A.. Malmstrom, E. J., Kee, H. K., Kales, J. D., and Tan. T. L.: Bioi. Psychiatry, 1:235-241, 1969. 53. Kales, A., Kales, J. D., Scharf, M. B., and Tan, T. L.: Arch. Gen. Psychiatry, 23:219-225, 1970. 54. Kales, J. D.. Kales, A., Bixler, E. 0., and Slye, E. S.: Clin. Plrarmacol. Ther., 12:691·697, 197\. 55. Kales, A., Allen, c., Scharf, M. B., and Kales, J. D.: Arch. Gen. Psychiatry, 23:226-232, 1970. 56. Goldstein, L., Stoltzfus, N. W., and Smith, R. R.: Res. Commull. Chem. Pathol. Pharmacol., 2:927933. 197\. 57. Johnson, L. c., Burdick, J. A., and Smith, J.: Arch. Gen. Psychiatry, 22:406-418, 1970. 58. Mello. N. K., and Mendelson, J. H.: Alterations in states of consciousness associated with chronic ingestion of alcohol. In J. Zubin and C. Shagass (Eds.), Neurobiological A spects of Psychopathology. New York: Grune and Stratton, 1969, pp. 183-218. 59. Mello, N. K., and Mendelson, J. H.: J. Pharmacol. Exp. Ther., 175:94-112, 1970. 60. Evans, J. I., and Lewis, S. A.: Electroencephalogr. Clin. Neurophysiol., 25:508-509, 1968. 6\. Gross, M. M., Goodenough, D., Tobin, M., Halpert, E., Lepore, D., Perlstein, A., Sirota, M., March-April, 1973
62. 63. 64. 65. 66. 67. 68.
69. 70. 7\. 72.
73. 74. 75. 76. 77. 78.
79. 80. 8\. 82. 83. 84.
85. 86.
87.
88. 89.
Dibianco, J., Fuller, R., and Kishner, I.: J. Nerv. Ment. Dis., 142:493-514, 1966. Haider, I., and Oswald, I.: Br. Med. J., 2:318322, 1970. Williams, H. L., Lester, B. K., and Coulter, J. D.: Psychopharmacologia, 15 :28-38, 1969. Sagales, T., Erill, S., and Domino, E. F.: Clin. Pharmacol. Ther., 10:522-529, 1969. Toyoda. J., Sasaki, K., and Kurihara, M.: Folia Psychiatr. Neurol. Jap., 20:275-289, 1966. Freemon, F. R., Agnew, H. W., and Williams, R. L.: Clin. Pharmacol. Ther., 6: 172-176, 1965. Haider, I.: Pakistan Med. FOT/IIII, 4:13-28,1969. Hishikawa, C., Nakai, K., Ida., H., and Kaneko, Z.: Electroencephalogr. Clin. Neurophysiol., 19: 518-521, 1965. Jewett, R. E., and Norton, S.: Exp. Neurol., 15:463·474, 1966. Lewis, S. A., and Evans, J. I.: Psychopharmacologia, 14:342-348, 1969. Shimizu, A., and Himwich, H. E.: Del'. Psychobioi., 2: 161-167, 1969. Wallach. M. B., Winters, W. D., Mandell, A. J., and Spooner, C. E.: Electroencephalogr. Clin. Neurophysiol., 27 :574-580, 1969. Tabushi, K.. and Himwich, H. E.: PsycllOpharmacologia, 16:240-252, 1969. Toyoda, J.: Folia Psychiatr. Neurol. Jap., 18: 198-221, 1964. Coulter, J. D., Lester, B. K., and Williams, H. L.: Psychopharmacologia, 19: 134-147, 197 \. Hartmann, E.: Psychopharmacologia. 9:242-247, 1966. Hoffman, 1. S., and Domino, E. F.: J. Pharmacol. Exp. Ther., 170:190-198, 1969. Reite, M., Pegram, G. V., Stephens, L. M., Bixler, E. c., and Lewis. O. L.: Psychopharmacologia, 14: 12-17, 1969. Tissot, R.: Prog. Braill Res., 18:175-177, 1965. Williams, H. L., Lester, B. K., and Coulter, J. D.: Psychophysiology, 5:210, 1968. Hartmann, E.: Psychophysiology, 5:207, 1968. Khazan, N., and Brown, P.: Life Sci., 9:279-284, 1970. Khazan, N., and Sulman, F. G.: Psychopharmacolol:ia, 10:89-95, 1966. Ritvo, E., Ornitz, E., LaFranchi, S., and Walters, R.: Electroencephalogr. Clin. Neurophysiol., 22: 465-468, 1967. Zung, W. W. K.: Exp. Med. Surg., 27: 124-137, 1969. Akindele, M. 0., Evans, J. I., and Oswald, I.: Electroencephalogr. Clin. Neurophysiol., 29:4756, 1970. Wyatt, R. J., Kupfer, D. J., Scott, J., Robinson, D. S., and Snyder, F.: Psychopharmacologia, 15: 236-244, 1969. Cramer, H., and Ohlmeier, D.: Arch. Psychiatr. NeTl'enkr., 210:182-197, 1967. Le Gassicke, J., Ashcroft, G. W., Eccleston, D., 117
PSYCHOSOMATICS
90. 91.
92.
93. 94. 95. 96. 97. 98.
Evans, J. I., Oswald, I., and Ritson, E. B.: Br. J. Psychiatry, 111:357-364, 1965. Oswald, I.: Pharmacol. Rev., 20:273-303, 1968. Oswald, I.: Effects on sleep of amphetamine and its derivatives. In E. Costa and S. Garrattini (Eds.), A mphetamines and Related Compounds. New York: Raven Press, 1970, pp. 865-871. Lewis, S. A.: Comparative effects of some amphetamine derivatives in human sleep. In E. Costa and S. Garrattini (Eds.), Amphetamines and Related Compounds. Raven Press: New York, 1970, pp. 873-888. Baekeland, F.: Psychopharmacologia, 10: 179183, 1966. Oswald, 1., Jones, H. S., and Mannerheim, J. E.: Br. Med. J., 1:796-799, 1968. Johnson, D. N., Funderburk, W. H., and Ward, J. W.: Psychopharmacologia, 20: 1-9, 1971. Riley, 1., Corson, J., Haider, I., and Oswald, I.: Lancet, 2: 1162-1163, 1969. Firth, H., Lewis, S. A., Ogunremi, O. 0., and Oswald, I.: Br. J. Pharmacal., 39:462-463, 1970. Oswald, I., and Thacore, V. R.: Br. Med. J., 2: 427-431, 1963.
118
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99. Oswald, I., Evans, J. I., and Lewis, S. A.: Addie· tive drugs cause suppression of paradoxical sleep with withdrawal rebound. In H. Steinberg (Ed.). Scientific Basis of Drug Dependence. London: J. & A. Churchill Ltd., 1969. pp. 243-257. 100. Isbell, H., Fraser, H. F., Wikler, A., Belleville, R. E., and Eisenman, A. J.: Q. J. Stud. Alcohol, 16: 1-33, 1955. 101. Victor, M., and Adams, R. c.: Res. Publ. Assoc. Res. Nerv. Ment. Dis., 32:526-573, 1953. 102. Wikler, A., Pescor, F. T., Fraser. H. F., and Isbell, H.: Am.J.PsyclJiatry.I13:106-114, 1956. 103. Fraser, H. E, Isbell, H .• Eisenman, A. J., Wik· ler, A., and Pescor, F. T.: Arch. [mem. Med., 94:34-41, 1954. 104. Isbell, H., Altschul, S., Kornetsky, C. H .• Eisen· man, A. J., Flanary, H. G., and Fraser, H. F.: Arch. Neural., 64: 1-28. 1950. 105. Connell, P. H.: Amphetamine Psychosis. London: Chapman and Hall, 1958. 106. Ellinwood, E. H.: J. Nerv. Ment. Dis., 144:273283, 1967. 107. Griffith, J. D., Cavanaugh, J., Held, J., and Oates, J. A.: Arch. Gen. Psychiatry, 26:97-100, 1972.
Volume XIV _.
creased early in the night and delta sleep was not affected by this dose. Morphine thus has an arousal effect on the sleep of several species. The only investigation which has studied the mechanism of this arousal effect3 ,4 has supported neither the antiserotonergic nor the noradrenergic hypotheses which were tested. Chronic opiate administration leads to a somewhat different pattern of effects on sleep. Khazan et al. 2 found that after 3 days of increasing intravenous dosage, rats showed tolerance to the decreases in SWS and PS. Self-in-
OPIATES
After Khazan and Sawyer! found that morphine reduces paradoxical sleep (PS) in rabbits, Khazan et al.~ demonstrated that morphine has an arousal effect in rats: continuous intravenous infusion of morphine initially increased wakefulness and decreased both slow wave sleep (SWS) and PS. Echols and Jewetfl,4 have also found that morphine decreases PS and SWS in cats. These effects of morphine in the rabbit. rat and cat parallel those effects found in the human postaddict by Kay et aP Single doses of morphine (7.5. 15 and 30mg/70 kg) increase wakefulness (Fig. I) and drowsiness, and decrease both delta sleep (Fig. 2) and rapid eye movement sleep (REMS: Fig. 3). Estimates from this study as to the acute dose of morphine required to abolish REMS measures range over 20-25 mg/70 kg. Morphine differentially affects various REMS measures: it decreases the number and mean duration of REMS episodes while increasing REMS latency and having indeterminate effect on the REMS ~ycle. Lewis et al. G found that 7.5 mg of heroin had comparable effects on nonaddicts: it decreased REMS and increased drowsiness. Sleep onset was delayed, but spindle sleep was inDr. Kay is from the National Institute of Mental Health, Addiction Research Center, Lexington, Kentucky, U.S.A. 108
MORPHINE EFFECT ON WAKING STATE DURING STANDARD NIGHT (WS/450minl 50
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Figure I. Morphine significantly (p < 0.01) increased waking state in the 7Y2 hours after lights out. Morphine dose is expressed on the abscissa in milligrams/70 kg. Waking state is expressed on the ordinate as percentage of the 450 minute standard night. Each X represents the total response of one subject, and each • represents the mean of 8 subjects. The arithmetic regression equation was calculated from the 4 dosage means.
Volume XIV
SLEEP AND SOME PSYCHOACTIVE DRUGS-KAY
jection then produces a characteristic pattern: wakefulness, with bursts of high voltage slow waves in the EEG,7 followed each injection, and sleep (especially PS) preceded each injection of morphine. After repeated doses of 7.5 mg of heroin for 3-7 nights, nonaddict humans also showed tolerance to the decrease of REMS. 6 Six men who chronically received 140-240 mg of morphine daily showed several significant phenomena: 8 ,9 wakefulness was no longer increased, even during the induction phase after the dose had been increasing for three weeks. Delta sleep tended to increase, and shifted toward later in the night. Delta bursts (4-20 sec in duration) increased significantly during drug administration, both in number and total time. REMS was still significantly decreased during both the induction phase and the stable phase. REMS measures varied in their response to chronic morphine: the number of REMS episodes remained low and the REMS cycle remained longer in period
c
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MORPHINE EFFECT ON DELTA SLEEP (STAGE 4) DURING A SUNDARD NIGHT (05/450)
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Morphine dose is expressed on the abscissa in milligrams/70 kg. Delta (stage 4) sleep is expressed on the ordinate as percentage of the 450 minute standard night. Each X represents the total response of one subject, and each • represents the mean of 8 subjects. The arithmetic regression equation was calculated from the 4 dosage means. March-April, 1973
during both induction and stabilization phases, while mean REMS episode duration was diminished only during the induction phase. REMS latency and REM density were not significantly different from control during either phase of drug administration. Chronic administration of methadone shows a comparable pattern. Henderson et al. tO found that tolerance developed to the initial decrease in REMS and delta sleep after stabilization on methadone, but some signs appeared of persistent arousal. Kay and Martin ll and Martin et al.l~ found that little difference could be seen in the sleep of 6 men between the control and drug phases, except that vocalization during REMS and nocturnal delta bursts were increased during drug administration. However, waking EEG showed a marked increase in slow wave activity during drug administration. The effects of chronic opiate administration appear to be a combination of varying degrees of tolerance to the arousal effects and the emergence or exaggeration of slowwave activity. It is not certain whether this slow wave activity is evidence of sleep and/or subconvulsive phenomena. Withdrawal of opiates produces sleep and EEG changes which have not been completely d~fined. There is inconclusive evidence for an increase in REMS in humans after the initial decrease by single doses,fl,G or soon after withdrawal of morphine in rats. 2 There are many reports from clinical studies that insomnia is a major symptom of early abstinence from opiates, and the only appropriate sleep study2 supports this impression in the rat. Integrated EEG voltage is decreased after drug withdrawal in both the sleep and wakefulness of rats experiencing early abstinence. 13 ,14 A more specific effect was seen in human waking EEG by Martin et al. 12 at 6 weeks after withdrawal of methadone (early abstinence): slow wave activity was decreased even with alpha activity present. The protracted abstinence syndrome after withdrawal of methadone from 5 humans showed two effects on sleep:ll an increase in REMS which peaked at t 3 weeks after withdrawal, and a later increase in delta sleep. 109
PSYCHOSOMATICS
barbiturates16,19,25,27,29 in a dose-related fashion. 25 REMS latency is increased by barbiturate;16,18,19.21,28,30 this effect is significant (p
Khazan and Colasantp5 have also found a change in the response of rats to single doses of morphine depending on the phase of the addiction cycle. Naive rats show a pattern of behavioral stupor with bursts of high voltage slow waves in the EEG for 60-90 min, followed by behavioral and EEG arousel for 60-90 min. This pattern was not distinct during chronic morphine administration or during early abstinence. During protracted abstinence, the rats showed a prolonged arousal to single doses of mcrphine, with the gradual return of the stupor plus EEG slowwave response as time increased after withdrawal. Henderson et al. 10 have described more nocturnal awakenings in 4 human ex-addicts when compared to control. Thus, growing evidence from quantified sleep studies supports the importance of persistent physiologic changes after drug withdrawal; these facts could support the concept of a pharmacologic factor in opiate drug abuse.
30
MORPHINE EFFECT ON REM STATE DURING STANDARD NIGHT
25
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3. Morphine significantly (p < 0.001) decreased REM sleep in the 7Y2 hours after lights out. Morphine dose is expressed on the abscissa in milligrams/70 kg. REMS is expressed on the ordinate as percentage of the 450 minute standard night. Each X represents the total response of one subject, and each • represents the mean of 8 subjects. The arithmetic regression equation was calculated from 3 dosage means (excluding the mean for 30 mg. of morphine).
Figure
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Volume XIV
SLEEP AND SOME PSYCHOACTIVE DRUGS-KAY
et aI. 22.2f interpreted the increase of spindle sleep as compensatory for the decrease in REMS, and most of the other studies did not see this effect as a primary drug effect. During the study by Kay et a1. 25 spindle burst incidence during spindle sleep was increased by pentobarbital (75, 150 and 300 mg/70 kg), especially in the middle and late thirds of the night when peak drug effect was probably occurring (Fig. 5). This increase in incidence of spindle bursts, as well as an increase in duration and amplitude of spindles, with a slowing of sigma frequency, would support the hypothesis that the increase of spindle sleep is a primary effect of barbiturate. However, Lester et al. 27 found an opposite effect: 200 mg of secobarbital decreased the incidence of spindle bursts from 6.0 bursts per minute (bpm) to 2.0 bpm. They used their finding to support the hypothesis that barbiturates selectively inhibit phasic events in sleep (e.g.: sigma waves in spindle sleep, eye movements in REMS, and spontaneous electrodermal responses in delta sleep). Feinberg et aJ.33 have reported data on total spindles which can be used to estimate an average of 4.6 bpm in normal young adults; this compares with placebo values of 3.5 bpm in the Kay et a1. 25 subjects and 6.0 bpm in the Lester et al. 27 subjects. Delta sleep has shown the most reported variability after barbiturate. Lester and Guer-
SPINDLE
SLEEP
AND
rero-Figueroa28 found that both thiopental and phenobarbital increased delta sleep; however, EEG slow waves after barbiturate have been reported as evidence for anesthesia,34 so this effect would require differentiation from delta sleep. Most studies I6,20,25,27,29 report no significant change in delta sleep after barbiturate. Feinberg et al.,19 and Kales et a1.2 2.24 found a decrease in delta sleep after barbiturate. This decrease becomes significant during the first week of continued drug use,24 with a gradual return toward normal after withdrawal. This pattern of effect is more typical of tolerance phenomena or chronic toxicity rather than of acute effects of a drug. Probably some of the variability in delta sleep response to barbiturate is due to the subject population: Bohlin et al. 35 found differences between normal and anxious subjects in their delta sleep response to sedatives. Sleep latency has been quantified in few studies; it is decreased by barbiturate,16,18,20,21,25 but is not dose-related. 25 Waking state. number of awakenings, body movement and/or muscle tension are decreased by barbiturate. 16,18.20,25,27,29 Difficulty in quantifying a decrease in total waking state or an increase in total sleep can be related in several studies to the use of normal subjects and to the necessity for a fixed bedtime and a limit to spontaneous AM arousal. Few studies have been done of the effects
RE MS
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March·April, 1973
(p < 0.001) decreased REMS and significantly (p < 0.001) increased spindle (stage 2) sleep. The mean of 8 subjects is expressed on the abscissa for each dose of pentobarbital in milligrams170 kg. Each measure is expressed on the ordinate as total minutes during the 450 minutes after lights out, and is paired with its arithmetic regression equation. III
PSYCHOSOMATICS
of chronic barbiturate administration on quantified sleep. Oswald and Priest36 were the first to quantify barbiturate withdrawal effects on sleep with continuous EEG monitoring. In their study, 2 subjects received 400 mg of oral amylobarbitone for 9 nights and then 600 mg for 9 nights. After an initial decrease in REMS and increase in REMS latency with each dosage increase, tolerance tended to develop over the 9 night sequence. Insomnia, poor sleep and nightmares dominated the first 2 weeks after drug withdrawal, with an increase in REMS up to 5-6 weeks after drug withdrawal (especially in the first 2 hours of sleep). Evans et al. IH found total sleep was reduced but REMS was increased after withdrawal from amylobarbitone. Evans and Lewis 37 claim that chlorpromazine will block these signs of abstinence. One subject dependent on 1.0 G of pentobarbital had a reduced level of REMS SPINDLE
BURST
INCIDENCE
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Figure 5. Spindle burst incidence was significantly
(p < 0.05) increased by pentobarbital. Each X rep· resents the value for one subject, and each • represents the mean of 8 subjects. The dose of pentobarbital is expressed on the abscissa in milligrams/ 70 kg. Spindle burst incidence is expressed on the ordinate as bursts per minute of spindle sleep during the 450 minutes after lights out. 112
while on drug, with an increase in REMS, vivid dreams and nightmares while the drug was reduced over two months. 22 ,::!3,38 REM density increases after withdrawal of barbiturate,23,39 which has been correlated with the vivid dreaming and nightmares. 22 ,4o,41 Delta sleep also shows change with chronic barbiturate use and withdrawal. It is decreased or absent with chronic use,19,22,24,38 and gradually returns to normal in a few months after withdrawal. 38 OTHER SEDATIVE-HYPNOTICS
Non-barbiturate sedative-hypnotics have also been studied for their effects on sleep. REMS decreases after single doses of alcohoJ,42.48 chloral hydrate,::!::!,49 glutethimide,22,24,:;o'52 methyprylon,::!::!,24,a2 methaqualone,2::!,a:l and flurazepam!',::!·a4 Spindle sleep increases after alcohol,H,46,4i chloral hydrate,4H glutethimide,24,:;1 methyprylon,24 methaqualone,',I,r'3 and flurazepam."3.":; Delta sleep is increased and then decrcased H or it is unchanged 4fi ,4i after alcohol; it is unchanged after chloral hydrate 26,49,53,,,,, or methyprylon.::!4 Delta sleep is decreased 24 or unchanged"1 by glutethimide, decreased"l or unchanged l .,49,r,:1 by methaqualone and decreased by flurazepam.":!·"" Waking state is unaffected by single doses of alcohol,4!>,4i decreased!!' or unaffected 5:!,:;" by chloral hydrate, decreased by glutethimide,"1 and methyprylon,24 decreased"I,"!> or unaffected l ',49 by methaqualone. and decreased by flurazepam.::!],;\4,r,a With chronic drug administration, delta sleep is persistently decreased by alcohol,H,,,. glutethimide,::!::! and flurazepam. 22 Chronic use of alcohol has also been associated with increased but fragmented sleep."8,59 Upon withdrawal of drug, an increase in REMS and/or an increase in REM density, as with barbiturates,2::!,:!!>,;;2 is found with alcohol,42,H,4!>'4H/",!>o,fil chloral hydrate,::!::! glutethimide,22,24,,,(1."2 methyprylon,::!::!,::!4,;,::!,fi2 methaqualone, 22,,,1,53,62 and flurazepam!'" An increased incidence of vivid dreaming and nightmares, similar to that seen with barbiturates,22,36,52 is seen upon withdrawal of alcohol,42,44,57,6o,61 glutethimide,22,24,52 methyprylon,22,24,52,62 and methaqualone. 62 The effects of other sedative-hypnotics (such as ethinimate, ethchlorvinyl or oxazepam) have not been quantified as yet. Volume XIV
SLEEP AND SOME PSYCHOACTIVE DRUGS-KAY
Although antihistamines have sedative actions, little is known of their quantified effects on sleep. Diphenhydramine decreases REMS in single doses, with an increase in delta sleep during chronic administration and an increase in REMS upon withdrawal.:!:! Alpha-chloralose is an anesthetic with unusual hypnotic characteristics: it decreases REMS and increases delta sleep,28,63 while not affecting spindle sleep or waking stateli.1 at the dose tried. Scopolamine has some effects on quantified sleep similar to barbiturate: in single doses it decreases REMS,1I4 increases spindle sleep,li4 and does not change delta sl eep1l4,115 or waking state. U4 MINOR TRANQUILIZERS
This group of psychoactive drugs has some actions quite similar to barbiturate. In quantified studies, REMS was decreased by meprobamate lill and nitrazepam,:!11,36,67 but was not affected by the doses tried of diazepam:!2 or chlordiazepoxide.:!l Spindle sleep is increased by single doses of nitrazepam 31i,07 and meprobamate.(Ill Delta sleep is unchanged by meprobamate,';t: and is unaffected:l5 or decreased:l5 ,li7 by nitrazepam. Waking state is decreased by chlordiazepoxide 21 and not affected by meprobamate';l1 or nitrazepam. 67 Delta sleep is decreased during chronic administration of diazepam:!:? or chlordiazepoxide. 22 Withdrawal from nitrazepam is associated with an increase in REMS and/or REM density,36,62 and an increase in vivid dreaming and nightmares. 31i Insufficient evidence is available to differentiate these drugs from barbiturate on the basis of quantified sleep studies. MAJOR TRANQUILIZERS
Chlorpromazine MI• 7:! and reserpine 73 decrease REMS at some doses, but both chlorpromazine 111 ,7U,H and reserpine 71i.8o have also increased REMS. Spindle sleep is decreased by single doses of chlorpromazine64 ,69,74 and resperine. 77 Delta sleep is increased by chlorpromazine,19,:?8, t:4,1I11,71,7:!,H but dec rea sed by reserpine. 75 ,77 Waking state is decreased 68.72,74 or unchangedt:4 by chlorpromazine; and it is unchanged,76 increased 7:!,77 or decreased 73 by
reserpine. Chronic reserpine administration is associated with no change,:!2 or with a persistent decrease in delta sleep.80 ANTIDEPRESSANTS
Single doses of imipramine,68,71,72,74,81.84 desipramine,H,8o amitriptyline,21,72,74,81 and phenelzine 8o,l
Oswald:19,lIlJ, III has reviewed the clinical data, much of which have come from his laboratory. REMS has been the sleep state most studied, and it is decreased by single doses of most stimulants: amphetamine,16,30,32,611,1I2 methamphetamine,7:! methylphenidate,32,113 diethylpropion,:l2,92,!14 chlorphentermine,32,\l2 phenmetrazine,32,!14 aminorex,32 benzphetamine,32 and phentermine.32 Fcnfluramine decreases REMS in cats:12 ,!11i and in humans at higher doses !lll or when added to amphetamine,ll2 but has no significant effect at some dosesll 2,1l4,117 except for an increase in REMS latency.92,1l7 A new amphetamine derivative JP 992 [(meta trifluoromethyl-phenyl)-l-(benzoyl oxy)eth yl amino-2-propane] decreases REMS early in the night at a higher dosell 1 but not at a lower dose.1I 7 Despite the fact of studying stimulants, several investigations do not quantify effects on waking state, or seek to minimize such effects. Amphetamine increases waking state in humans even with barbiturates,16 as well as in
March-April, 1973
113 _._~~.
.t
PSYCHOSOMATICS
cats.32,69 Diethylpropion also increases waking state in humans,94 and JP 992 increases shifts into drowsiness and waking state. 9l ,97 Several amphetamine derivatives increase waking state in cats,32,72 except for chlorphentermine which has no effect3 2 and fenfluramine which decreases waking state after single doses. 32 ,95 Drowsiness (stage 1) is increased by several stirn ul an ts: fenfluramine,92,94,97 diethylpropion,92,94 JP 992,97 chlorphentermine 92 and amphetamine. 92 Shifts into drowsiness were increased by JP 992. 91 ,97 Spindle (stage 2) sleep is increased by methylphenidate,93 amphetamine,16,92 and diethylpropion,94 but has been reported to be decreased by amphetamine in cats. 69 Delta sleep (stages 3 and/or 4) is decreased by amphetamine,16,69 fenfluramine,94 diethylpropion,94 and JP 992. 97 SWS is decreased by several derivatives in the cat32,72 except for chlorphentermine which has no effect~2 and fenfluramine which increases SWS.32,95
probably are an increase in waking state and/or drowsiness, plus a decrease in delta sleep and REM sleep; spindle sleep effects are not clear. The little evidence available would support the idea that sleep returns toward normal during chronic stimulant use, although no data are available to evaluate the degree of tolerance or persistent effect. Withdrawal appears to be correlated with an increase in REMS and total sleep(possibly including a delta sleep increase), accompanied by excessive dreaming and occasional nightmares. ADDICTION CORRELATES
From the facts reviewed above, one acceptable hypothesis would be that most opiates, stimulants, and sedative-hypnotics decrease REMS after acute administration (with sufficient dose) and show increased REMS after withdrawal. These facts led some investigators99 to postulate that all drugs are addictive which show these effects; however, this concept had to be modified after more drugs were investigated, I know of no sleep studies which have used and some with no obvious abuse problem, chronic stimulant administration to humans such as antidepressants, were discovered to preceded by a nondrug control. Oswald and significantly decrease REMS, with REMS inThacore 98 reported apparently normal sleep in 6 creased for several weeks after withdrawal. humans who had been chronically taking stimuSome investigators19,22,99 have proposed anlants (amphetamine, phenmetrazine) either other relationship of sleep disorder to drug alone, or in combination with barbiturate; abuse: chronic drug use leads to suppression of they found an increase in both REMS and the REMS system, and withdrawal of drug then total sleep upon withdrawal of the drug (s) . releases the eNS, with abnormal amounts of When Rechtschaffen and Maron30 gave 3 subREMS being associated with nightmares and/or jects amphetamine plus barbiturate for 3 nights delirium. This theory evolved from the study they noted a reduction in REMS which did not of withdrawal from alcohol or sedative hypnotreturn to control level in all subjects, followed ics in which the REMS increase and a delirium by an increase in REMS in 2 succeeding placeare correlated in time. Although withdrawal bo nights. from alcohol,100.102 barbiturates l03 ,104 and other Oswald et al. 94 found that 2 subjects had less sedative-hypnotics is known to be associated REMS while receiving phenmetrazine for 7 with seizures and delirium, this pattern is not nights, which was followed by a decreased seen with other psychoactive drugs. An acute REMS latency upon withdrawal. They also toxic psychosis or a paranoid psychosis is assofound a decreased REMS latency upon with- ciated with amphetamine abuse,105.107 but these drawal of diethylpropion from 2 other subjects, subside during withdrawal. Except for meperbut no such effect after a clinical dose of fenflu- idine and dextropropoxyphene (which can proramine in 4 subjects. Johnson et aJ.95 found duce a toxic psychosis during chronic abuse), that REMS returned toward control during toxic psychosis is not a consistent feature either chronic fenfluramine administration in cats, of chronic opiate abuse or of withdrawal from and increased upon drug withdrawal. opiates. These differing patterns of toxic psyThe acute effects of stimulants on sleep chosis must be contrasted with the apparent 114
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SLEEP AND SOME PSYCHOACTIVE DRUGS-KAY
increase in REMS and dreaming after withdrawal from compounds in all three drug classes. There might well be some causal relationship between changes in sleep and the phenomena of drug abuse, but it is not obvious. The finding of increased REMS and delta sleep during protracted abstinence after opiates appears important: sleep studies would thus be established as a sensitive method to quantify protracted abstinence effects" which might be correlated with drug-seeking behavior. Even if REMS effects are comparable, can addicth e or nonaddictive drugs be classified on the basis of the total pattern of their effects on ~Ieep? I have summarized in Table I my best estimate of some acute drug effects on sleep, based on the data reviewed above. This table includes a representative stimulant (amphetamine), opioid analgesic (morphine) and sedative-hypnotic (pentobarbital), as well as an antidepressant (imipramine) and two antipsychotic drugs (reserpine and chlorpromazine). REMS appears to differentiate only the anti-psychotics, which increase REMS at some doses. Delta sleep clearly differentiates only chlorpromazine, which increases delta sleep, although the effects of pentobarbital and imipramine are not well-established. Waking state is increased by amphetamine, morphine and reserpine, but is decreased by pentobarbital, imipram"r:e and chlorpromazine. This would appear lJ be a gross arousal/sedation classification, except that morphine and imipramine might have been expected to be reversed. Spindle sleep apparently is increased by pentobarbital and imipramine, decreased by reserpine and chlorpromazine, and variably affected by amphetamine and morphine. The grouping of pentobarbital with imipramine appears puzzling. Inspection of this table would indicate that the measures which best differentiate these drugs are waking state and spindle sleep; those have been the measures least investigated by sleep researchers. Many drugs cannot be easily classified within these 6 groups, which is to be expected. As our knowledge increases about drug effects on sleep, hopefully a pharmacologic classification will evolve which can differentiate compounds already known to have significantly different eNS effects. March-April, 1973
TABLE I ACUTE EFFECTS OF PSYCHOACTIVE DRUGS Drug Amphetamine Amphetamine Morphine Reserpine Pentobarbital Imipramine Chlorpromazine + Increase, -
=
Waking State
Spindle Sleep
Delta Sleep
+ + + +
+,+,-
0, -
+
0, -
o
REM Sleep
+,-
+?
+
+, -
= Decrease, 0 = No Change SUMMARY
Morphine in single doses increases wakefulness and drowsiness while decreasing REMS and delta sleep. Partial or complete tolerance to these effects develops after continued morphine administration; however, sleep then precedes and wakefulness follows each drug dosage and bursts of slowwave activity appear in sleep and waking EEG. Withdrawal from methadone in man is associated with an initial increase in dreaming and then several weeks of insomnia during early abstinence, with a decrease in slow wave activity in the waking EEG. Protracted abstinence is characterized by an increase in REM sleep, followed by an increase in delta sleep. Tolerance develops to morphine's initial synchronizing effect on the EEG, leaving a persistent arousal effect from morr"'ire for several months during protracted abstinence. Barbiturate in single doses increases total c!cep and EEG spindling while decreasing REM sleep. With continued barbiturate administration, some tolerance probably develops to the effect on REMS, but delta sleep becomes persistently decreased. Withdrawal from barbiturate is associated with insomnia and nightmares, the latter occurring during a marked increase in REM sleep. Delta sleep remains low during chronic barbiturate use and gradually returns to normal levels after withdrawal without known increase above normal. Alcohol and most other sedative-hypnotics appear to have the same general pattern as barbiturate. Both alcohol and barbiturate are associated with a psychosis during withdrawal, which appears to occur during the greatest increase in REMS. liS
PSYCHOSOMATICS
Amphetamine in single doses increases wakefulness and decreases all states of sleep. Tolerance apparently develops to these effects, since chronic amphetamine users are reported to have sleep patterns within normal limits. Withdrawal from chronic amphetamine is associated with increased sleep, especially REMS. Amphetamine is also associated with a psychosis during chronic use, which tends to disappear during withdrawal. Most other CNS stimulants appear to have the same general pattern as amphetamine. REM sleep apparently increases during withdrawal from opiates, sedative-hypnotics or stimulants; psychosis occurs during chronic use of stimulants, but only occurs upon withdrawal from sedative-hypnotics, and does not usually occur either during chronic use or during withdrawal from opiates. Delta sleep is increased late after withdrawal from opiates and possibly early after withdrawal from stimulants; no increase in delta sleep has yet been describ<:d after withdrawal from sedative-hypnotics. However, measures of sleep states apparently are sensitive indicators of CNS homeostasis, and might help to defiine pharmacologic factors in recurrent drug-seeking behavior.
13. 14. 15. 16. 17. 18. 19.
20. 21. 22.
23.
24. 25.
26. 1. 2. 3. 4.
5. 6.
7. 8. 9. 10. 11. 12. 116
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