Sleep abnormalities associated with alcohol, cannabis, cocaine, and opiate use: a comprehensive review

Alcohol is widely used as a sleep-promoting agent. However, as the consumption of alcohol becomes chronic, alcohol has less of an hypnotic effect [196]. Significant, self-reported sleep problems are highly prevalent among alcohol users with rates of clinical insomnia between approximately 35 and 70 % depending on the setting and stage of use, among other parameters [35, 48]. These rates are substantially higher than those observed in the general population (i.e. ~15 to 30 %) [32]. Complaints typically include difficulty falling asleep, frequent awakenings, daytime sleepiness, and abnormal sleep quality [15, 34, 196], but could also include hypersomnia [196]. Notably, sleep complaints associated with alcohol use disorders are one of the most refractory problems to resolve [34, 69, 82], and insomnia is the most frequent complaint among alcoholics after they stop drinking [132].

Objective measurement of sleep in persons with alcohol use disorders confirms self-reported sleep problems in many respects, and provides additional insight into the nature of the underlying sleep abnormalities.

Although there is limited published data on the relationship between subjective and objective sleep measurement in persons with alcohol use disorders, one group studied 172 individuals with alcohol use disorders of whom 104 had insomnia as determined by the Sleep Disorders Questionnaire [35]. They found that participants with baseline insomnia had longer sleep latency and lower sleep efficiency at an average of approximately 1 month abstinent than those without, suggesting a correspondence between self-report and objective measurement.

In a small study, increased sleep latency associated with chronic alcohol use was linked with lower overall melatonin levels as well as with a delay in the onset and peak of melatonin [123]. A much larger study found an association between increased sleep latency and decreased sleep efficiency among persons with AUD and sleep disorder breathing [6].

In patients with AUD, insomnia is also correlated with amount of alcohol use [22], severity of alcohol use disorder [35], and self-report of alcohol use as a sleep aid [35]. An association between insomnia and severity of self-reported depression symptoms has also been recognized [35].

Because of the profound effects of chronic alcohol use and sleep and the apparent connection between sleep measures and clinical outcome, several studies have examined the role of sleep-promoting medications in treating persons with AUD (for review see [119]). In double-blind, placebo-controlled and other trials, gabapentin has been studied with largely [112, 136, 137] but not entirely [39] positive results. These studies suggest that gabapentin may promote both sleep outcomes and abstinence [137] in persons with alcohol use disorders.

Given the suggestion that melatonin levels are decreased in alcoholics [177, 212], the melatonin receptor agonists ramelteon and agomelatine have been examined in case series. Among patients who had been abstinent for 2–13 weeks, ramelteon was associated with decreased scores on the Insomnia Severity Index (ISI),decreased sleep latency, and increased total sleep time measured by actigraphy [36]. Similarly, agomelatine was associated with improved sleep as measured by the Pittsburgh Sleep Quality Index after 6 weeks [87].

Another potential pharmacotherapeutic agent that has been studied in this population is quetiapine. In a double-blind, placebo-controlled trial, quetiapine was associated with improvements in time awake after sleep onset and subjective insomnia [53]. In addition, a retrospective study showed an improvement on the insomnia subscale of the HAM-D [173] with quetiapine. The effect of quetiapine on alcohol-related clinical outcomes has been mixed, with evidence for improvement in abstinence rates in one study [142], and increased risk of re-hospitalization in another [143].

Trazodone is widely prescribed as a sleep aid in persons with addictions because of its lack of addictive potential. Although studies of trazodone in persons with AUD has shown benefits in sleep measurements [125] in a large, placebo-controlled trial, those benefits on sleep quality did not result in clinical improvement, but rather trazodone was associated with less abstinence during treatment and an increase in drinking after cessation of treatment [79]. Findings like these suggest that the relationship between sleep physiology and alcohol use and relapse is not simple. Rather, treatments directed at sleep that improve qualitative sleep but do not address the underlying physiological changes associated with chronic alcohol use may not be expected to promote abstinence.

Unlike trazodone, the popular benzodiazepine and benzodiazepine-like agents are often avoided in persons with alcohol use disorders because of their addictive potential and the increased risk of toxicity or overdose when these medications are mixed with alcohol [16, 90].

Like alcohol, cannabis may improve subjective sleep complaints [56], particularly when used over short periods of time. For instance; in studies using self-report questionnaires (e.g., Leeds Sleep Evaluation Questionnaire) participants report greater ease in getting to sleep [50]. However, like alcohol, chronic cannabis use is associated with negative subjective effects on sleep that are manifested most prominently during withdrawal. Notably, these subjective effects are present during discontinuation of cannabis use even among persons who were exposed to low dosages [97], and are common among regular users [61, 188]. Symptoms reported include sleep difficulties [61] such as strange dreams, insomnia, and poor sleep quality. Such symptoms occur in anywhere from 32 % [58] to 76 % [27, 222] of persons experiencing withdrawal. These studies have been conducted in both the inpatient (residential) [61, 97, 98] and outpatient levels of care [42, 44], and in studies with as many as 450 participants [222]. Placebo-controlled studies have examined what happens after discontinuation of oral THC use [97] or after discontinuation of smoked marijuana [98]. Regardless of design, studies of the effects of chronic use have consistently shown reliable and significant changes in subjective reports of sleep during abstinence in comparison to baseline [42].

Among the problems with sleep in chronic cannabis users is the presence of strange dreams [44]. Such dreams typically begin 1–3 days after cannabis discontinuation—when sleep quality is particularly poor [42, 44, 195], peak after 2–6 days, and last 4–14 days [44], coincident with other subjective sleep complaints. However, large studies have found sleep difficulties lasting for longer periods, such 43 days [58], and strange dreams in particular lasting for as long as 45 days [44]. Returning to cannabis use (or using alcohol or other sedatives) to promote sleep is commonly observed [58].

However, the sleep-promoting effect of cannabis is lessened in the chronic user compared to naïve users [50‐52, 91], while the negative effects of cannabis on sleep intensify with chronic use as noted above. This scenario leaves the chronic user in a potential catch-22: heavier use of cannabis may be necessary to receive its subjective sleep-promoting effects in the chronic user, but at the same time this increased use contributes to worsening overall sleep and therefore leads to continued and greater use.

Studies examining the effect of cannabis on objective sleep measurements obtained either by an experienced observer rating sleep by polysomnography (PSG) largely confirm the subjective reports. For instance, an observer-rated study showed that administration of 10, 20, or 30 mg of THC decreased total time to fall asleep [60], and a PSG study showed both shorter sleep latency (SL) [150], and decreased time awake after sleep onset (WASO) [160]. However, other studies have not observed a decrease in sleep latency or wake time after sleep onset [75]. One possible explanation for the difference in findings may be related to disparate effects of THC (sleep promoting) and cannabidiol (a non-euphorigenic cannabinoid preferred in some medical preparations), which may increase alertness [150].

Several studies of PSG-measured sleep report increased SWS [25, 75], decreased REM sleep [74, 75, 160], and decreased REM density (e.g., number of eye movements during REM sleep) [74, 75]. However, this pattern is not always replicated [150].

In chronic users of cannabis, the effects of cannabis on objectively measured sleep are notably different. With chronic use, individuals develop tolerance to most of the effects observed in naïve users, including its sleep-inducing effects and slow-wave sleep enhancement [25, 78, 111, 163]. Sleep efficiency is similarly unimproved [163] or worsens [111]. The tolerance to REM sleep changes, however, appears to be relatively muted [75]. However, no consensus exists with respect to REM time and studies have reported decreased, no change [163], or increased [111] REM time.

PSG studies of cannabis withdrawal have demonstrated increases in sleep onset latency and wakefulness after sleep onset [27, 28, 75, 77, 78, 175] (Table 2). Total sleep time, sleep efficiency, and slow-wave sleep time is reduced [1, 27, 28, 75, 78] (Table 1), and REM sleep is increased (REM rebound) [74, 75, 77, 108, 160, 175]. Shorter REM latency has also been reported [27, 77].

Changes in the objective PSG measurements during withdrawal can start as soon as the first night of abstinence (e.g., the decrease in SWS time [74]). Changes during withdrawal are more noticeable among heavy marijuana users (marijuana use ≥5 times per week over the past 3 months) [27]. With continued abstinence, TST, SE, and amount of REM sleep decline (Table 2), while WASO increases. These disturbances progress over the first 2 weeks of abstinence [28, 44, 120] and persist for more than 45 days into a marijuana abstinence period [44].

There are conflicting reports with regard to REM sleep in sustained abstinence. Initially it appears that REM sleep time increases/rebounds early in abstinence, but decreases as abstinence progresses [28] (Table 2). The reason for this continued worsening of sleep with decreasing REM sleep during abstinence is unclear, but could reflect a pre-existing, underlying sleep problem and/or the long-term effects of chronic use.

As noted above, the desirable effects of cannabis on sleep are reported less frequently in chronic cannabis users compared to naïve users [91], Chronic users also report difficulty sleeping and strange dreams among other symptoms associated with abstinence [11, 28, 43, 58, 175, 194]. These subjective findings have been correlated to longer sleep onset latency, reduced slow-wave sleep, and REM rebound observed in PSG studies [27, 198].

Sleep difficulties appear to be a predisposing factor for cannabis use, and baseline sleep problems are a significant predictor of later cannabis use, doubling the risk of future use [139, 155, 166, 211, 214]. This latter finding has led some to describe cannabis use as “coping oriented use” [21].

The sleep disturbances encountered in marijuana withdrawal may play a crucial role in treatment outcomes. Higher rates of relapse have been correlated with sleep problems and other withdrawal symptoms [43]. In a study focused on military veterans, Babson et al. showed that poor sleep quality prior to the quit attempt was a predictor of higher rates of later cannabis use [19‐21]. Similarly, poor sleep quality during abstinence also contributes to relapse [44, 46, 195]. Evidence from a limited number of studies suggests that objective findings, like increased periodic limb movements during abstinence, are correlated with quantity and duration of cannabis use [28].

Sleep disturbances associated with withdrawal improve with oral administration of THC or resumption of cannabis use [42, 44, 45, 95, 97, 108]. THC exerts a dose-dependent effect in reducing withdrawal symptoms [45], but as noted above, the beneficial effects of THC on sleep diminish with chronic use, and chronic use leads to more severe problems with sleep.

Haney et al. found the greatest benefit regarding sleep symptoms and relapse using combination therapy with lofexidine (an alpha-2 agonist) and oral THC. However they did not report any benefit from 10 days of oral THC alone [94]. Nabilone, a FDA-approved synthetic analog of THC, has the potential to reverse withdrawal-related irritability and disruptions in sleep, and promotes abstinence [92]. Nabiximols, a synthetic combination of THC and cannabidiol has a non-significant positive effect on these parameters [10].

The use of valproic acid resulted in no benefit and even some worsening of symptoms in chronic cannabis users [95, 128]. No definitive benefits have been reported with Lithium [107], nefazodone [96], or bupropion [49, 99].

Subjective and/or objective sleep parameters have been shown to improve with the use of zolpidem [195], mirtazapine [93], gabapentin [135], and quetiapine [57], but none of these agents have conclusively reduced the relapse rate.

Withdrawal from cocaine is characterized by numerous subjective complaints, including sleep and sleep-related complaints. The first several days to 1 week after cocaine cessation are characterized by sleep disturbances, hypersomnia, bad dreams, depressed mood, psychomotor agitation and retardation, fatigue, and increased appetite [38, 59, 80]. With continued abstinence, however, there is subjective improvement of sleep as well as improvements in other cocaine withdrawal measures [209], with apparent normalization of subjective sleep over the course of several weeks [80].

Numerous studies have indicated an improvement in self-reported sleep quality over the first few weeks of abstinence [13, 55, 81, 138, 147, 148, 153, 172, 209], with improvements in measures such as overall sleep quality, daytime alertness, concentration/confusion, depth of sleep, and energy/fatigue. However, the possibility that such improvements may be related to acclimation to a new environment (e.g., the treatment setting [209]) and not actually reflect good sleep relative to healthy persons [55] has been raised. Possibly providing some answers to these questions, a laboratory study that included self-administration of cocaine either early or late in a 3-week period of abstinence showed that subjective sleep quality was at its worst in the first few days following cocaine use and improved with continued abstinence [148]. In addition, whereas chronic cocaine users show impairment in self-reported but quasi-objective sleep measurement like the Pittsburgh Sleep Quality Index (PSQI), visual analog scale ratings of subjective sleep quality in the third week of abstinence are no different from healthy sleepers [147]. Hence there is evidence that chronic cocaine users have chronically impaired sleep as measured by instruments like the PSQI, that self-reported sleep quality improves with continued abstinence, and that self-reported sleep quality after an extended period of abstinence is similar to that in healthy sleepers. However, this last finding may only show that chronic cocaine users’ intrinsic scale for self-report of sleep quality is different from healthy sleepers, with ‘good’ subjective sleep in chronic cocaine users seemingly good only in comparison with the much worse sleep experience they have at other times.

Although self-reported sleep improves following the initial withdrawal from cocaine, polysomnographic findings have consistently shown deterioration in sleep to insomnia-like levels in the same period [13, 81, 104, 121, 138, 145, 148, 152, 192]. The co-occurring deterioration in PSG-measured sleep and improvement in self-reported sleep quality was termed ‘occult insomnia,’ as poor sleep as measured by PSG was associated with poor performance on sleep-dependent learning and other cognitive tasks [148, 149]. These findings suggest that the PSG-measured deterioration in sleep and not the subjective improvement in sleep better reflects what is happening during abstinence from chronic cocaine use, and supports the notion that the intrinsic, subjective scale used by chronic cocaine users to report sleep quality is altered relative to healthy persons.

What is now clearly shown to be a mismatch in subjective and objective experience during acute and subacute abstinence was once perceived as an inconsistency [104, 153]. One possible cause for the mismatch may be dysregulation of the homeostatic sleep drive in chronic cocaine users, wherein the ‘sleepiness’ and other negative effects of increased wakefulness are not experienced subjectively [148]. Additionally, or alternatively, the rebound in delta power after acute withdrawal [148], despite poor sleep and decreased slow-wave sleep time, may improve the subjective experience of sleep quality [122, 148]. The poor subjective experience in acute withdrawal may also be related to the decreased REM latency and increased REM sleep time, leading to increased dreaming [38, 59] and correlated with symptoms of withdrawal [13].

Although several medications such as modafinil, topiramate, tiagabine, gaboxadol and vigabatrin [145] have been suggested as potential options for targeting the sleep abnormalities associated with chronic cocaine use, few studies have examined the effects of medications on sleep in chronic cocaine users, and several of the suggested medications have potentially significant safety issues (i.e. tiagabine, gaboxadol, and vigabatrin). Hypothesizing that the REM rebound associated with initial withdrawal from cocaine was caused by dopamine insufficiency [62], Gillin et al. [81, 82] examined the effect of lisuride, a high affinity dopamine D2,3,4 receptor agonist, on sleep. While lisuride had the desired effect on REM sleep (decreasing REM% and increasing REM latency), it had no effects on other withdrawal-related phenomenon [81]. In light of the clinical findings in Angarita et al. [13] and the effect of prolonged abstinence on REM sleep, it seems unlikely that reduction in REM sleep time would be beneficial during extended abstinence, but increasing REM to normal values could be beneficial.

Another medication that has been tested is tiagabine, a GABA-reuptake inhibitor. Since tiagabine is known to increase slow-wave sleep time, which is implicated in improved cognitive performance in sleep-restricted persons [203], it was hypothesized that tiagabine may improve slow-wave sleep time in chronic cocaine users [146]. While tiagabine had dramatic effects on slow-wave sleep time, sleep architecture appeared unnatural, with slow-wave sleep occurring throughout the sleep period. Additionally, there was no apparent benefit to total sleep time, and no consistent benefit in cognitive performance [146].

Perhaps the most promising, and most studied medication to be tested for correcting sleep abnormalities related to cocaine is modafinil. A stimulant and cognitive enhancer that appears to act at least partially through dopamine transporter blockade, modafinil appears to share some important properties with cocaine while being a relatively safe medication with low abuse potential [140]. In chronic cocaine users, modafinil has been shown to normalize slow-wave sleep time, as well as other sleep parameters [147]. Though effects of modafinil on clinical outcome have been mixed (e.g., [12, 63, 64, 176]), its effects on sleep and its pro-cognitive effects position it as the best candidate at present for a viable pharmacotherapy for cocaine use disorders.

Short-term opioid use can cause sedation and daytime drowsiness [130, 159, 216, 217]. Dizziness and sleepiness are common side effects of opioid pain medications [41, 109]. With a stable dose, tolerance to the subjective, sedative effects of opioids develops within 2–3 days and some studies find that cognition normalizes after that [103, 129], supporting the notion of tolerance to the sedative effects. However, there is also evidence that unpleasant sedative effects, decreased alertness and increased reaction time in a variety of cognitive tasks continue to be experienced by some patients on a stable dose of narcotic medication [23, 24, 54, 181]. These differences in findings may be related to inconsistencies in how the sedative effects are defined [217].

Xiao et al. [215] studied the quality of sleep in persons with heroin use disorder on early methadone maintenance therapy (MMT) after a median of 5.4 days of treatment [215]. Patients without pre-existing chronic sleep disturbances demonstrated lower ratings of sleep (Pittsburgh Sleep Quality Index [PSQI]) and daytime sleepiness (Epworth Sleepiness Scale [ESS]) compared to healthy sleepers. Oyefeso et al. [151] reported inadequate sleep quality and quantity as well as difficulty initiating and maintaining sleep in persons with opioid use disorders in early stages of methadone detoxification. Similar studies have shown some increased daytime drowsiness and below normal sleep measures in this patient population [113, 114, 134, 204]. After longer periods of MMT, however, there is some degree of tolerance to these effects [206], and sleep difficulty is shown to be present only in the first 6–12 months of MMT [158, 193].

There is a limited number of reports studying the effects of withdrawal and abstinence from chronic opiate use. Asaad et al. reported insomnia, hypersomnolence, increased sleep latency, and reduced sleep duration in individuals with opioid use disorder after 3 weeks of abstinence [17].

Sleep architecture in healthy adults can be significantly altered even after a single dose of oral opioids [67]. Using electroencephalography (EEG) and electromyography (EMG), Kay et al. [117] reported that acute intoxication with heroin, morphine, or methadone resulted in dose-dependent enhancements in arousal during sleep–wake periods. Heroin use demonstrated a stronger effect particularly on reduction of theta waves and REM sleep [117, 204]. Morphine and methadone reduce slow-wave sleep and in-crease stage 2 sleep [67]. Several studies have shown that acute use of various opioids results in increased REM latency [115, 159], decreased REM sleep time [113‐117, 130, 159, 180], increased stage 1 [67, 130, 180] and stage 2 sleep [67], and decreased slow-wave sleep [113‐117, 159]. Acute use of opioids also leads to increased sleep latency [116, 130], increased wakefulness after sleep onset (WASO) [113‐117, 130, 159, 215], and concomitant decreases in total sleep time (TST) [116, 215] and sleep efficiency (SE) [116, 159, 215].

There is a partial tolerance to the effects of opioids with some evidence for increased REM sleep time in acute use [113, 114, 130], and less pronounced changes in SWS, wakefulness, and arousal observed after chronic use. However, vocalization during REM sleep, delta bursts, and increased daytime sleepiness may be observed in this phase [204]. Tolerance to sleep problems is more prominent in MMT [113, 134, 159, 204], with evidence that persons in treatment for more than 12 months exhibit better recovery sleep following sleep deprivation than persons in shorter-term treatment [193].

Nevertheless, abnormal PSG findings are commonly reported in chronic opioid users despite development of tolerance. These abnormalities include increased sleep latency [100, 185], increased awakening [100, 113, 185, 190], decreased total sleep time [100, 185], and decreased sleep efficiency [100, 190]. Slow-wave sleep time [113, 114, 185, 190] and REM sleep are decreased compared to baseline [113, 185, 190, 205], while duration of stage 2 sleep is increased similar to acute use [190, 205]. Analysis of actigraphy data from patients with prescription opioid use disorders indicated poor sleep in terms of total sleep time, sleep efficiency, sleep latency, total time awake, and time spent moving [100].

Several studies have reported changes in patterns of sleep with progressive abstinence from opiates. At around 5–7 days of acute abstinence from chronic heroin use, Howe et al. reported decreased total sleep time, slow-wave sleep, REM, and stage 2 sleep and increased sleep latency, wake after sleep onset, and REM latency compared to healthy sleepers [101] (Table 2). During the first 3 weeks of abstinence, prolonged sleep latency, decreased sleep efficiency, decreased TST, increased arousal index, increased stage 1 and 2, and decreased slow-wave sleep (SWS) were prominent compared to healthy sleepers [17] (Table 2). After 6 weeks and up to 6 months of abstinence from methadone, there is a rebound increase in SWS and REM time to a higher level than baseline [113, 114, 134].

Using PSG data, Xiao et al. showed an inverse relationship between the Epworth Sleepiness Scale (ESS) scores and SWS time in patients with heroin use disorder who were in early methadone treatment [215]. They reported poor initial quality of sleep based on the PSQI scores which were significantly correlated with their methadone dosages [102]. PSQI score were also found to be significantly correlated with average diary-reported sleep time, subjective ratings of feeling rested, and PSG sleep efficiency in MMT patients [179]. Overall the high prevalence of sleep complaints in this population along with documented abnormal objective findings argue that these complaints are more likely to be secondary to pathology rather than sleep misperception.

Modifiable psychological and medical risk factors associated with sleep disturbance should be identified and corrected in order to improve quality of life in drug treatment. Treatment of sleep disorders among MMT patients, particularly in those with psychiatric disorders, benzodiazepine abuse, chronic pain, and patients who are on high methadone dose is of crucial importance.