The present findings are the first indication of a functional sex difference in sleep in persons with substance dependence of any kind. The drops in sleep efficiency, total sleep time, and sleep-dependent procedural learning in male subjects are consistent with prior work (for review see(Morgan and Malison, 2007
)), and the present work confirms these findings in a relatively large sample of treatment seeking, cocaine dependent persons. However, the lack of such drops in female participants is unprecedented, as cocaine dependent women had not been appreciably included in objective sleep studies previously.
The possibility that male and female cocaine users have different sleep characteristics during abstinence and across the menstrual cycle is a reasonable hypothesis given the evidence that progesterone affects circadian rhythms and sleep(Baker and Driver, 2007
; Cagnacci et al., 1996
; Moore-Ede et al., 1982
), and is markedly elevated during the luteal phase. However, the finding is still somewhat surprising as healthy men and women matched for age tend to have similar sleep(Voderholzer et al., 2003
; Williams et al., 1974
) (but see also e.g. (Fukuda et al., 1999
; Goel et al., 2005
)), and fluctuations of neurosteroid levels within the menstrual cycle of healthy women have only modest effects on polysomnographic sleep measurement(Baker and Driver, 2007
; Steiger, 2003
). Nevertheless, there is considerable and growing evidence that progesterone has striking effects on sleep in susceptible populations such as postmenopausal women and men.
In postmenopausal women, progesterone may improve sleep efficiency and self-reported sleep quality(Gambacciani et al., 2005
; Montplaisir et al., 2001
). In men, progesterone administration decreases latency to slow-wave sleep, and increases non-REM sleep time(Friess et al., 1997
), consistent with the increased levels of the GABAA
receptor active metabolite allopregnanolone(Majewska et al., 1986
). Such effects are consistent with human and animal studies that show that progesterone and related neurosteroids have hypnotic effects, with decreased sleep latency, increased non-REM sleep, and in some respects a benzodiazepine-like effect on the sleep EEG profile(Rupprecht, 2003
; Steiger, 2003
) (but without the hangover effects on next morning cognitive performance(Gron et al., 1997
)). Although hormone levels were not measured at the relevant time points in this study, all female subjects entered the study in the menstrual or early follicular phase. Hence it is likely that the 20 days abstinent time point reflected luteal phase levels of progesterone in most of the female participants. That is, progesterone levels were likely highest and most different from male participants at 20 days abstinent. If so, then it is possible that the sleep-promoting effects of progesterone and its metabolites may have offset in female participants the deteriorating sleep and sleep-dependent learning seen in male participants. Although somewhat speculative, this interpretation would be consistent with work suggesting a protective role of progesterone in cocaine dependence(Evans and Foltin, 2006
; Fox et al., 2008
; Sinha et al., 2007
; Sofuoglu et al., 2002
; Sofuoglu et al., 1999
; Terner and de Wit, 2006
), and would support the study of progesterone or related compounds as possible therapies for cocaine dependence.
Several limitations of this study must be considered, most importantly the lack of hormonal data, data beyond one menstrual cycle, or data from women at different menstrual phases relative to abstinence that could have distinguished abstinence effects from menstrual phase effects. In addition, participants in this study had no restrictions on sleep outside of the three experimental days in this study. Although napping was not permitted on those three days, subjects could choose their own bedtime within the restrictions of inpatient unit. Furthermore, polysomnographic (PSG) sleep recording was not done, but rather an ambulatory sleep monitor was used that has shown good correlation with PSG-measured total sleep time and sleep efficiency(Ajilore et al., 1995
). Although the Nightcap sleep monitor is minimally intrusive, it is possible that the first night of recording may have been subject to a first night effect. However, in this study such an effect would have been more likely to diminish the observed results than augment them. Although time in bed was not fixed in this naturalistic study, male subjects spent less time in bed as abstinence progressed, so the drop in sleep efficiency was not a result of more time spent in bed. Rather, the drop in total sleep time observed in male subjects was greater than the drop in time in bed, leading to the deterioration in sleep efficiency, and suggesting severely compromised sleep.
Another potential limitation is the non-statistically significant age difference between controls and cocaine dependent participants. As sleep time and efficiency tend to deteriorate with age (Williams et al. 1974
), the 5-year difference in age might have had some effect on the results. In addition, unrecognized differences in why cocaine dependent men and women seek treatment may have influenced the results. For example, men in this study may have been more likely to seek treatment because of some awareness of the deleterious neurophysiological effects of chronic cocaine, whereas women may have been more likely to seek treatment to escape an abusive relationship or other untenable social situation. Such a difference could have amplified the apparent difference in sleep and learning observed between men and women; unfortunately, detailed assessment of these possible factors was not performed.
There is now evidence that sleep disturbance associated with cocaine dependence and abstinence has functional consequences and may be relevant to the development of effective treatments(Morgan and Malison, 2007
; Morgan et al., 2008
). The absence of this finding in women with cocaine dependence suggests that therapies that target sleep or cognitive consequence of cocaine use may be more helpful in men than women, and points to a possible direction in the development of such treatments. Indeed, in the absence of such treatments, there is some evidence that women may respond better to treatment than men. Two studies that reported gender differences in treatment outcomes in cocaine users found that women, despite having similar or worse prognostic factors (e.g. severity of use, comorbidity, demographics), were more likely to remain abstinent and/or have reduced cocaine use at 6-month follow-up (Kosten et al., 1993
; Weiss et al., 1997
). Hence, the current findings should be confirmed in future polysomnographic sleep studies and the mechanism of this sex difference should be explored.