Clinical surveys and laboratory models of withdrawal indicate that sleep disturbance is common among frequent cannabis users and may directly contribute to either relapse to cannabis use or compensatory use of other drugs (Budney et al., 2004
; Budney et al., 2008
; Copersino et al., 2006
; Haney, 2009
; Peters and Hughes, 2010
). However, most studies of cannabis withdrawal have relied on self-reported sleep assessments, which do not always accurately reflect actual sleep quality and do not provide information about sleep architecture (Morgan et al., 2006
). The present study provides objective evidence that abrupt cessation of daily cannabis use can indeed result in disrupted sleep continuity and altered sleep architecture, with latency to sleep onset and REM sleep most notably affected. These findings confirm and extend previous studies indicating that abrupt marijuana cessation leads to sleep disruption, and provide the first data demonstrating that these effects can be attenuated with administration of hypnotic medication.
The decreased sleep efficiency and increased sleep latency observed during cannabis withdrawal in the present study is consistent with prior studies (Bolla et al., 2008
; Schierenbeck et al., 2008
). Mean sleep efficiency scores during the cannabis withdrawal period exceeded the cutoff (0.85) generally used to indicate clinically important sleep disturbance by the third day of abstinence. Chronic decreases in sleep continuity have been associated with a variety of negative sequelae including fatigue, cognitive decline, decreased pain thresholds and spontaneous pain, increased anxiety and negative mood (Stores, 2007
). Also, %REM sleep increased and REM latency decreased during withdrawal in this study. REM sleep is increasingly believed to play a role in affect regulation and memory related processes (Stickgold and Walker, 2007
; Wagner et al., 2001
; Walher, 2010
). Reduced REM latency and increased %REM, due to heritable or situational factors, have been linked to depression (Cartwright and Wood, 1991
) and heightened pain sensitivity (Smith et al., 2005
). Thus, it is possible that secondary effects of reduced sleep continuity (e.g. cognitive decline, anxiety, negative mood) and increased REM (depression, pain sensitivity) during cannabis withdrawal could put users at an increased risk for relapse. However, research is needed to determine whether or not these associations extend to changes in sleep induced by cannabis withdrawal.
Some differences between the findings of the present study and those reported by Bolla and colleagues (2008
warrant discussion. First, in contrast to the present study, Bolla et al. found no abstinence effects on %REM sleep, reported that %REM sleep declined over time, and that cannabis abstinence was associated with less Stage 3/4 (slow-wave) sleep. These differences could be accounted for by the possibility that the cannabis users in the study by Bolla and colleagues had lower REM and Stage 3/4 sleep compared with controls at baseline. For REM sleep, an increase during abstinence, consistent with what was observed in our study, would have resulted in more similarity to the control group (no difference observed), and the gradual reduction in REM sleep observed over time may reflect a return to baseline. Stage 3/4 sleep was stable within-subjects across both studies, but relatively large inter-subject variability was observed (mean %Stage 3/4 sleep across nights ranged from 4.4% to 26.5%) in the present study. Thus, it is possible that a larger percentage of cannabis users with low Stage 3/4 sleep was enrolled in the study by Bolla et al. That said, we cannot eliminate the possibility that factors other than cannabis use impacted the data in the present study because a control group of non-cannabis users was not included.
At this point it remains unclear whether the reduced Stage 3/4 sleep observed among a subset of daily cannabis users across studies is related to chronic use of cannabis, cannabis withdrawal, or an unrelated cause. That said, Stage 3/4 sleep is integral to the restorative effects of sleep and has been shown to predict relapse among those in treatment for alcohol use disorders (Brower et al., 1998
). Thus, it will be important for future studies to further delineate the effects of cannabis use and withdrawal on Stage 3/4 sleep, and, to identify heritable or substance use risk factors that predict the effects of cannabis withdrawal on Stage 3/4 sleep.
In this study, administration of extended-release zolpidem attenuated the effects of cannabis withdrawal on sleep. No differences were observed between periods of cannabis use and the zolpidem-abstinence condition for measures of sleep architecture (% time spent in different sleep stages). Also, zolpidem administration significantly reversed abstinence induced changes in Stage 2 and REM sleep relative to the placebo-abstinence condition. While sleep efficiency was worse during the zolpidem-abstinence condition compared with cannabis use, mean sleep efficiency scores were maintained in the range of normal sleep (>.85) on all three nights. Zolpidem did not reduce sleep latency as expected. This may be because it was administered when participants turned out the lights for the night, which likely did not allow enough time for the onset of clinical effects with the medication. Thus, it is possible that zolpidem administered 20–30 minutes prior to bedtime would improve sleep continuity (reduced sleep latency and increased sleep efficiency).
Study participants self-reported significantly better sleep quality when they received active medication compared with placebo. This suggests that zolpidem may be useful for the treatment of sleep disturbance associated with cannabis withdrawal. Additional research is warranted to determine whether the level of improvement in sleep quality obtained with zolpidem during cannabis withdrawal can translate to improved clinical outcomes for those trying to quit use of cannabis. Other medications that can improve sleep continuity and/or reverse the effects of cannabis withdrawal on REM sleep should also be explored.
With the exception of the speed with which responses were made on some tasks, cognitive performance assessed each morning remained stable throughout the study. On one hand, this indicates that there was no “hangover” effect of zolpidem on cognitive performance. This is consistent with prior research (cf. Blin et al., 2006
). On the other hand, clinically significant sleep deficits have been associated with impaired cognitive abilities (cf. Altena et al., 2008
; Edinger et al., 2008
). Because sleep continuity and REM measures were significantly degraded during the cannabis withdrawal period it was somewhat surprising that a corresponding decrease in cognitive performance was not observed. It is possible that the duration of abstinence was not long enough for the development of cognitive impairment associated with cumulative sleep loss, or that the tasks used were not sensitive to the type (e.g. sustained or shifting attention) or magnitude of change in cognitive ability associated with sleep loss. A recent literature review suggests that cognitive deficits among people with primary insomnia are subtle and inconsistently observed in controlled research studies not involving experimenter induced sleep deprivation (Shekleton et al., 2010
). Thus, the failure to find impairment on cognitive performance in the present study is not entirely unexpected or inconsistent with research on the cognitive consequences of poor sleep.
There are limitations of the present study that warrant discussion. The duration of abstinence studied was relatively short and there was a trend for sleep to become progressively worse over the three days of abstinence. Previous findings suggest that changes in sleep architecture persist for at least 2 weeks (Bolla et al., 2010
), and subjective ratings of sleep difficulty and strange dreams have been observed for up to 7 weeks in an outpatient study of continuous cannabis abstinence (Budney et al., 2003
). A study of longer duration is needed to determine the peak severity and time course of abstinence-induced alterations of sleep architecture in daily cannabis users. While extended-release zolpidem appears to have improved objective and subjective measures of sleep quality, this did not translate to a reduction in overall cannabis withdrawal severity or craving. That said, participant-rated withdrawal and craving scores were relatively low in this study, possibly because the duration of abstinence was short and the study was conducted in a residential setting devoid of the environmental cues associated with cannabis use that can exacerbate craving and withdrawal. Replication of these effects using ambulatory sleep collection methods will be important to validate the present findings and the inpatient model. Also, participants in the present study were not seeking treatment. Additional research is needed to prospectively assess the correlation between sleep and relapse in a clinical population, and to determine whether an improvement in sleep quality can positively impact treatment success among those with cannabis use disorders.
In summary, this study provides objective evidence of sleep disturbance during cannabis withdrawal and suggests that pharmacological, and, possibly, behavioral interventions known to reduce sleep latency and normalize REM could be useful in the treatment of cannabis use disorders. Significant sleep disruption appears to be a common feature of withdrawal across drugs of abuse, and it has been suggested that sleep disturbance is a universal risk factor for relapse among those with drug use disorders (Brower and Perron, 2010
). Additional research is recommended to 1) examine the time course of cannabis withdrawal effects on sleep continuity and architecture, 2) replicate these effects in outpatient clinical samples, 3) prospectively establish the association between sleep and relapse during a quit attempt, 4) determine whether alternative medications or doses of zolpidem can further attenuate sleep disturbance, and 5) examine the commonality and treatment implications of abstinence-induced sleep disturbance in drug use disorders more broadly.