Polysubstance use (PSU) implies using more than one drug of abuse either simultaneously or sequentially within a defined timeframe. PSU is common among illicit drug users with the desire to (1) obtain greater effects compared to use of either drug alone, (2) acquire a notable increase in the subjective response to a drug, or (3) alleviate the adverse side effects of one substance by the other (1). Most substance use research (including preclinical research) has not accounted for PSU as a variable.

Globally, sleep disturbances have become one of the commonly prevalent mental health disorders, wherein one-third of general adult individuals suffer from sleep problems (2). Estimates vary, but a large proportion of community-dwelling adults show sleep disturbances ranging from ~16 to 65.4% (3–5). Poor sleep and related sleep disturbances may lead to physiological, psychological, and social disturbances (6). For example, individuals with poor sleep have been associated with treatment-resistant hypertension (7), suicidal ideation (8), dysregulated circulating cholesterol and triglyceride levels (9), and diabetes mellitus (10). Moreover, individuals with poor sleep quality were more susceptible to neuropsychiatric complications, especially substance use and affective and cognitive disorders (11–15). Intriguingly, the relationship between sleep disturbances and substance use disorders may be bidirectional, wherein sleep disturbances increase the risk of substance misuse (11, 12), and substance use may trigger sleep complications (16).

Substance-using populations in Ethiopian demographics have pronounced sleep problems (16–20). Habitual khat (Catha edulis) is a plausible explanation for changes in sleep patterns. Khat has two important alkaloids, cathinone and cathine, that possess stimulant-like activity similar to amphetamines (17, 21, 22). Central nervous complications are associated with khat use, including deficits in memory, concentration, sleep, headache, migraine, motor coordination, and stereotypical behavior (21, 22). Alcohol is often concurrently misused in the Ethiopian population (17, 18). The effect of alcohol on sleep continuity is dose-dependent, with low dose increasing the sleep time and high dose leading to short-term withdrawal state, increased sympathetic activity, and sleep disruption, mainly in the second phase of the night (23). Smoking tobacco is associated with a constellation of sleep complications, including difficulty initiating sleep, staying asleep, daytime sleepiness, and affective dysregulation, including anxiety and depression (24, 25).

Metacognitive abilities do vary among insomnia patients in comparison to healthy people (26). Some of the identifiable features of circadian rhythm (a component in sleep regulation) are associated with dysfunctional metacognition and neuroticism (27). Sleep quality characteristics, and metacognition mediate between chorotype measures and poor well-being (27). These pieces of evidence do imply that PSU disorder is a comorbid disorder commonly associated with numerous influences such as poor sleep, stress, and other factors. However, no study has attempted to assess sleep, sleep-related symptoms, and their predictors in community-dwelling polysubstance users. There is a paucity of studies regarding these factors among polysubstance users. Therefore, this study explored the prevalence of poor sleep, poor sleep-related symptoms, severe dependence on khat, and level of metacognitive deficits in polysubstance-using community adults. We hypothesized that history of chronic conditions in polysubstance users/family members, lower metacognitive ability, and higher level of dependence on substance use may predict poor sleep outcome.

In the present study, an association was observed between poor sleep and increasing severity of khat dependence, lower metacognition ability, the presence of chronic conditions, the presence of chronic conditions of a family member, and lower educational status. Moreover, a high proportion of polysubstance users had sleep disturbances and severe dependence on khat. Consistent with the crosstalk between substance use and poor sleep, this is the first study to demonstrate further that polysubstance users have sleep complaints such as subjective sleep disturbances, short sleep duration, daytime complaints, and occupational problems related to sleep disturbances.

Mostly, psychostimulants like khat and nicotine are taken along with central nervous system (CNS) depressants like alcohol: either (a) to obtain greater subjective effects when using these drugs together or (b) administration of khat or nicotine may offset alcohol's depressant effects. Alcohol may temper khat and nicotine-induced stimulants effects like anxiety and impulsive behavior (37, 38). Given that the half-life of cathinone is 1.5 h (39), this combination may be worse, as the effects of khat may wear off quicker than alcohol (half-life is 4–5 h), triggering individuals to consume khat repeatedly. This may lead to a fatal inhibited state in these individuals when the effects of alcohol are felt in isolation. Indeed, polysubstance users have poor health outcomes than single-drug users (38). As such, the present study revealed that PSU of khat, alcohol, and nicotine significantly correlated with poor sleep, poor sleep-related disturbances, and metacognitive deficits.

This study showed that among polysubstance users, the majority of users chewed khat (97.5%), and ~56% of the total population showed poor sleep. This PSU behavior among khat users is similar to the findings of prior studies, which also reported that khat users often use other substances (19, 40). Neurobiological mechanisms of khat which mimic amphetamine-like effects on the sleep circadian system are just beginning to be understood. Dopamine is an important neurotransmitter that modulates the reward circuitry and regulates alertness, thus implicated in the sleep–wake cycle. It has been demonstrated that repeated use of amphetamine-like drugs led to increased sleep latency and a decrease in the total sleep time and slow-wave and rapid eye movement (REM) sleep (41). Sleep changes may further downregulate dopamine receptors, thereby increasing vulnerability to drug misuse (42). Indeed, PSU may elevate the risk of comorbid psychopathology and cognitive dysfunction (13). In support, we and others have previously demonstrated that concurrent use of khat and tobacco smoking (43) and concurrent use of alcohol, khat, and tobacco smoking were associated with poor sleep (18). In animal models of behavioral sensitization, which is a model of drug addiction, nicotine potentiated the amphetamine behavioral response and dopaminergic efflux in rats (44); in the drug reinforcement animal model, nicotine enhanced incentive motivational effects of amphetamine (45). In the light of the dynamic interaction effects between nicotine, amphetamine, and alcohol on hypocretin/orexin, GABAergic, dopaminergic, and cholinergic neurotransmission, it is imperative to systematically study the neurological comorbidities in polydrug users to reveal new insights into the management of these addicts (41).

The present study also identified poor sleep-related disturbances in polysubstance users with the binary logistic regression models that were significantly associated with a subjective report of sleep disturbances and three and more months of sleep complaints. These findings are consistent with a previous study, which demonstrated that adolescents' substance use is significantly associated with sleep disturbances, especially in maintaining sleep regularity, timing, efficiency, and duration (46). Recent evidence support changes in the gene expression level of Per2 with heavy drinking in alcoholics (47). These changes are modulated by the dopaminergic transmission between the ventral tegmental area and nucleus accumbens involving melatonin hormone, levels of which promote circadian rhythm, or via gene expression by the CLOCK protein (48, 49). Moreover, drugs of abuse mediate direct changes in the circadian rhythm independent of suprachiasmatic nucleus (SCN) or light/dark cycle (50, 51) and also changes the sensitivity of various drugs of abuse like opiates, nicotine, stimulants, and alcohol based on the diurnal cycle (51).

As most study participants were khat users, it is possible to speculate that repeated use of khat, alcohol, and tobacco may have adverse consequences on attention and psychomotor function. Chronic amphetamine use promoted deficits in psychomotor functioning, attention, and sleep disruption (52, 53). Moreover, the concurrent use of nicotine and amphetamine in female rats demonstrated potentiation of behavioral response with an increase in the dopamine concentrations in the striatal slices rich in dopaminergic receptors (44).

Alcohol, on the other hand, is a cytochrome p450 inhibitor; chronic alcohol use may downregulate GABAergic receptors and stimulate the glutamatergic receptors, thereby leading to hyperarousal impulsive behavior state and further increase vulnerability to affective and substance use disorders (54, 55). Sleep disorders may confer vulnerability to future neuropsychiatric complications and cognitive dysfunction (56). Concurrent use of alcohol and methamphetamine (METH) showed impairment of learning and memory compared to METH alone in rats (57). Additional evidence in rats demonstrated that the use of alcohol and METH produced synergy to impair hippocampal-mediated spatial memory compared to using METH alone (58). Alcohol administration alone did not impair the spatial memory, suggesting synergistic effects when these drugs were combined (58). Furthermore, when rat hippocampus was assessed for markers of oxidative stress, the use of alcohol and METH showed a synergistic increase in reactive oxygen species, which are detrimental for the cell compared to the use of either drug alone. Hence, concurrent use of drugs may cause the drugs to interact with each other and may have additive or synergistic effects on the physiological system.

Consistent with the predisposition to sleep changes, cognitive deficits may also interplay, albeit concurrently, following substance use (59, 60). In the present study lower metacognition score predicted the presence of all four sleep complaints in polydrug users. This is in line with previous preclinical and clinical neuroimaging studies, which showed that differential substance users have differential changes in the gray matter volume that are associated with psychomotor, affective, and cognitive deficits (22, 61–64). Furthermore, long-term use of drugs with abuse potential may produce excitotoxicity by over-activation of glutamatergic and dopaminergic synapses, thus leading to neuronal damage and associated behavioral changes (65–67).

In the present study increasing severity of khat dependence was significantly associated with sleep complaints, namely, subjective reports of sleep disturbances, sleep duration complaints (3 or more months), daytime restlessness, irritability, and tiredness. This is in line with other studies, which demonstrated that drug users struggle with internalizing and externalizing problems including difficulty in sleep maintenance, sleep efficiency, and sleep duration (46, 68). Family social support buffers the effects of internalizing problems observed in substance users. Therefore, family involvement may moderate the risk factors associated with substance use and related emotional and behavioral challenges (69). However, if family members of substance users have chronic conditions, then they are less likely to buffer the effects of internalizing problems. This possibly explains the relationship of chronic conditions in family members with various sleep complaints and overall poor sleep because family members with chronic conditions may be less likely to constructively contribute to moderate the effects of internalizing problems (69).

The current study's results must be viewed in light of the study's cross-sectional nature. Also, the present study only focused on poor sleep and associated sleep disturbances and metacognition. Other factors that may impact sleep were not considered. The collection of data was done by using a validated questionnaire, which lacked objective sleep metrics. Also, illicit drug users were questioned about their drug use (duration in months) with a recall period of 1 month which may be associated with recall bias. Future studies should explore longitudinal study design in a cohort group of individuals who may use CNS stimulants and depressants together and compare to single-drug users or normal subjects. Nevertheless, our study is the first to report a high prevalence of sleep complaints and their association with dependence, metacognitive deficit, and socio-demographic factors in polysubstance users. From the data presented in this study, it is not possible to discern differences in associated factors of poor sleep/poor sleep-related symptoms in discrete groups of polysubstance users. Future studies with case–control designs involving distinct groups of polysubstance users with longitudinal data collection may help in identifying relationships between sub-groups of polysubstance users and sleep.

This study demonstrates that poor sleep, khat dependence, and metacognitive deficits are highly prevalent in community polysubstance users. Moreover, poor sleep is associated with higher khat dependence, lower metacognitive ability, lower educational status, and the presence of chronic conditions in polysubstance users or their families.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Human Institutional Ethics Committee, College of Health Sciences, Mizan-Tepi University, Mizan-Aman, Ethiopia. The patients/participants provided their written informed consent to participate in this study.

MM, MS, HH, AMA, DN, ET, SS, SRP, and AB conceptualized the study and its methodology and were involved in data collection and curation also. MM and MK did the data analysis and wrote and edited the manuscript. AHA, MS, HH, AMA, and AB were involved in supervision. All authors reviewed and approved the manuscript.

Researchers Supporting Project number (RSP-2021/382), King Saud University, Riyadh, Saudi Arabia. The authors extend their appreciation to the Deanship of Scientific Research at Majmaah University for funding this work under Project Number (R-2022-113).

SRP is employed by Somnogen Canada Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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