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Temporal variations have been found in the survival rate of rats to lethal doses of Librium (Marte and Halberg 1961), the amount required for a lethal dose depending upon the time of administration.
Several studies have found that a rat's responsivity to morphine is partly a function of chronobiological rhythms. For example, Morris and Lutsch (1969) observed diurnal rhythms in response to morphine analgesia; later, they discovered that the effects of morphine could be manipulated by changes in the lighting period (Lutsch and Morris 1971 , 1972). More recently, Bornschein (1975) observed that the effective dose of morphine varied with the time of administration; morphine was most toxic at the end of the animal's active phase, and least toxic at the end of the animal's rest phase. Similarly, Bornschein et al. (1977) noted changes in the animal's central nervous system responsiveness to morphine; they detected a threefold difference in the efficacy of morphine as a function of time of day (i.e., morphine was 2.7 times more effective at 0300 hours than at 1500 hours). Unfortunately, there is very little research bearing on the relationship between chronobiological rhythms and human opiate use (e.g., Ghodse et al. 1977).
lt has been reported (Frederickson et al. 1977) that the administration of naloxone, a narcotic antagonist, will produce variable results in rats, depending upon the phase of circadian rhythm at administration.
Much of the previously cited research relating drug use to chronobiological factors has emphasized the administration of a drug during a specific time within the ongoing rhythmic period. Consequently, the experimental focus has been on how rhythmic activities affect the responsivity to a given drug. A complementary way of viewing the relationship between drug events and chronobiological events is to consider how the drug itself may affect the level of rhythmic functioning in the subject.
CHRONOBIOLOGY AND SELF-MEDICATION
lf one views drug abuse as a possible form of self-medication, then it is conceivable that some drug use represents an attempt on the part of the user to induce artificially certain rhythmic patterns where none have been before, or perhaps to reestablish such patterns when they have been lost. For example, Orr (1976) has suggested that amphetamine use may represent an attempt by the drug user to get back to a regulated sleep-wakefulness schedule. Can the "uppers" and "downers" taken by many drug users be compared to the "ups" and "downs" of chronobiological rhythm periods? An additional possibility would be for the drug to establish a "limit cycle," in which the motivation for drug use would not simply be the acquisition of a particular rhythm, but an attempt to avoid going too high or too low within the rhythm; as such, the drug would serve as a regulating device.
Should this hypothesis prove relevant, future research, rather than studying only retrospective patterns of drug use (what drug was taken, how often it had been used in the past) should focus upon when a given drug (or drugs) is used (Sinnet and Morris 1977), inasmuch as the timing of administration of a particular drug may be as significant as many of the other variables.
ln heroin addiction, for example, there is the increase in pleasure obtained after the injection, the gradual reduction of pleasure after several hours, the onset of unpleasant withdrawal symptoms, the injection of another dose of heroin, etc. Viewed in long-term chronobiological patterns, it seems possible that the heroin user might be taking heroin in an attempt to maintain some degree of rhythmicity in his or her physiological and psychological functioning.
As a final point, deaths from a heroin overdose might be due in part to when the heroin is taken; if injected at a time of maximal susceptibility within the chronobiological rhythm, the effect might be quite different (i.e., death) than if it were taken during a time of minimal susceptibility (i.e., survival).
Unfortunately, most chronobiological drug studies are bound to a relatively simplistic "time of day"; a more complex analysis arises from the possibility of "free running" rhythms that are not synchronized with the environmental cycles. ln such cases, the subject will drift in and out of phase with the chronobiological clock, experiencing periodic "jet lag" discomfort. Perhaps narcotic addicts have such discomforts and use heroin in an attempt to synchronize their internal rhythms to the environment.
CHRONOBIOLOGY AND CONTROL
As chronobiological rhythms are related to drug effects, so are they implicated in a number of different psychiatric problems. Recently, behavioral rhythms have been observed in several schizophrenics (Reynolds et al. 1978), and circadian rhythm disorders have been investigated in manic-depressive patients (Kripke et al. 1978). One important implication of this research is the possibility that such psychiatric problems may have a biological basis related to rhythmic activity within the brain. lndeed, it has been found (Philipp and Marneros 1978) that some patients with endogenous depression are treated more effectively with a single large dose of an antidepressant than with three smaller doses throughout the day. Such findings suggest that there may be circadian fluctuations within the neurotransmitter system, thus making the depression more (or less) susceptible to chemical treatment. Obviously, there are not only variations in chronobiological rhythms, but in consciousness and psychological factors as well (Broughton 1975).
One hypothesis concerning the motivation for drug use (and abuse) is that drugs may be consumed in an effort to self-medicate (e.g., Mellinger 1978). This analysis is particularly attractive in light of the research on chronobiological rhythms, since it suggests that (1) if an individual cannot predict or control his or her chronobiological rhythms (e.g., manic depression) or (2) if the amplitude of the manic-depressive behavior exceeds normal limits, the person may resort to licit and/or illicit drugs in an attempt to establish some control over these fluctuating moods. Thus, heroin use may be viewed as a way of coping with psychological problems (Khantzian et al. 1974) or, more specifically, with particularly stressful situations as assessed by life change units (Duncan 1977).
This use of drugs to control possible aberrant chronobiological rhythms is an important concept, especially as related to the concept of learned helplessness (Seligman 1975). A considerable amount of research, both with animals and with humans, has suggested that exposure to unpredictable and uncontrollable events may interfere with the individual's ability subsequently to master a learning task, even if such future tasks are controllable. That is, the individual becomes psychologically "helpless."
One intriguing aspect of this research has been the theoretical linkage between helplessness and depression. lt was assumed initially that helplessness might serve as a theoretical model of depression. Additional research, however (Huesmann 1978), has questioned the early concept of learned helplessness as a model of depression, and Seligman and his associates (Abramson et al. 1978) have recently reformulated the theory of learned helplessness to account for a wider range of cognitive processes (e.g., attribution). These modifications notwithstanding, the learned helplessness hypothesis is based primarily on learned experiences; if the evidence regarding chronobiological rhythms in depression is correct, however, then another phenomenon which might contribute to perceptions of helplessness would be the unpredictable and uncontrollable chronobiological rhythms that produce depression. As such, drugs may be used as agents of control (Hochhauser 1978a) which permit the individual user to exert some degree of internal control over his or her perceptions of helplessness.
Learned helplessness appears to play a role in alcohol and drug use (e.g., Sadava et al. 1978); moreover, the relationship between locus of control (Rotter 1966) and alcohol and/or drug use is one which has generated much research. Locus of control (whether one believes one's behavior to be internally or externally controlled) has been measured in a wide variety of drug-using populations (e.g., Plumb et al. 1975; Hall 1978): opiate addicts (Berzins and Ross 1973; Henik and Domino 1974; Obitz et al. 1974), alcoholics (Goss and Morosko 1970; Gozali and Sloan 1971; Oziel et al. 1972; Oziel and Obitz 1975; Obitz and Swanson 1976; Hinrichsen 1976; Weissbach et al. 1976; Rohsenow and O'Leary 1978a,b), and polydrug users (Segal 1974).
Such studies have often reported conflicting results. One reason for such discrepancies might be that the initial locus-of-control measure focused primarily on behavioral indices; it may be that a locus-ofcontrol concept which takes into account other factors, such as health (e.g., Strickland 1978), may be more appropriate for alcohol and drug problems.
DISTINCTIONS BETWEEN DRUG USE,
Assuming that drugs may be used as agents of control, it is argued that—
1. Drug use may represent an initial attempt to achieve some degree of internal control over perceptions of helplessness; moreover, drugs may be a relatively quick and effective means of obtaining such control, especially when other control measures are unavailable;
2. lf a drug is used for control and is found effective, then its use will probably escalate, as the individual may develop a relatively predictable and controllable method of coping;
3. Dependency may develop if there are no other effective coping mechanisms available;
4. Depending upon the addictive liability of the drug, addiction may occur with continued use, as the physiological consequences of the drug (e.g., withdrawal symptoms) may eventually establish control over the user. At this point, addicts may seek treatment, since they are no longer using the drug for control; rather, they are being controlled by the drug.
ACClDENTAL DEATH/SUlCl DE
Research on chronobiological rhythms suggests that there may be periods of minimal and maximal sensitivity to the lethal dose of a drug; consequently, problems such as heroin-overdose deaths or barbiturateoverdose deaths may be related to when (in the rhythmic cycle) a given drug is taken.
lt is difficult to determine if psychopathological behaviors (e.g., schizophrenia, manic-depressive behavior, etc.) lead to drug use (perhaps in an attempt to self-medicate such problems), or whether continued drug use (perhaps through changes in chronobiological rhythms associated with psychopathology) may cause subsequent psychopathology. Relationships between chronobiology, psychopathology, and drug abuse require additional clarification.
Significant psychological and physiological changes occur during adolescence, and the effect of drugs upon such developmental changes is largely unknown (Hochhauser 1978b). Studies of adolescent drug abuse suggest, however, that depression is often a characteristic variable associated with drug abuse (Braucht et al. 1973) and that the inability to cope with stressful experiences may play a significant role in the development of drug dependence (Duncan 1977). The interrelationship between changing chronobiological rhythms, perceptions of internal control, and drug abuse must be more clearly defined.
During the period of old age, there are often significant environmental changes (e.g., retirement, loss of a spouse, relocation) which may make the individual more helpless and possibly more susceptible to drugs as a way of coping. Moreover, important physiological changes are also taking place (e.g., reduced metabolism, changes in sleep patterns, hormone reduction) which may substantially affect chronobiological rhythms, thus making the elderly person more susceptible to drug effects.