Insomnia as a risk factor for substance use disorders in women

Introduction

In recent years, the scientific field has taken huge steps towards better understanding sex and gender differences in a variety of health conditions. After decades of male-centric research, studies finally started demonstrating how women are differentially – and often, more severely – affected than men by many disorders. Even before the focus on sex as a biological variable, the field of psychiatry already suggested that women are more likely to be affected by some psychiatric disorders than men. However, the definition of “woman” has changed over the years to incorporate more up-to-date science on sex vs gender differences. This vocabulary has allowed us to better understand the differences between biology and environmental determinants, such as social roles and cultural factors, in psychiatric disorders. It is now commonly accepted that sex refers to biological determinants of male and female based on a person’s reproductive organs determined by genetics, while gender is a person’s self-identification as man or woman¹.

The distinction between sex and gender is extremely important in psychiatry, especially for disorders that can be heavily influenced by environmental factors and personal experiences. Of note, gender differences have been shown for both insomnia and substance use disorders, with women more likely to have insomnia and showing increased susceptibility to the effects of drugs than men, despite social factors deterring drug use among women. Importantly, a growing body of evidence suggests that insufficient sleep predicts and puts individuals at a higher risk for substance use and associated psychosocial problems. However, the role of insomnia in substance use disorders among women remains poorly understood. The present manuscript discusses gender differences in insomnia and in substance use disorders, and reviews evidence suggesting that an increased prevalence of insomnia may be a risk factor for substance use disorders in women.

Insomnia: Diagnosis and Pathophysiology

Every human has experienced what is commonly referred to as “insomnia”, or being unable to fall or stay asleep at night, at least once in their lifetime. Globalization, busy lifestyles and the advent of the “24/7 society” have contributed to a generation of insomniacs, with society going as far as to glamourize lack of sleep and associate sleeping with lack of productivity. Because of the growing prevalence of sleep and insomnia complaints in the general population, the medical field has seen a major change in the diagnostic criteria for insomnia in recent years. The 10^th edition of the International Classification of Diseases (ICD-10), which went into effect in 1993² and was last updated in 2019, defined “nonorganic insomnia” as changes in sleep quantity and/or quality that persist for a “considerable period of time”. The most recent version of this manual, the ICD-11³, which is now in effect as of January 2022, brings a much more detailed definition of this sleep disorder, with two subclassifications: short-term and chronic insomnia. Short-term insomnia is defined as difficulty initiating or maintaining sleep despite adequate opportunity for sleep, leading to sleep dissatisfaction and daytime impairment (e.g. excessive daytime sleepiness, cognitive impairment), of less than 3 months duration. Chronic insomnia, on the other hand, is defined when the sleep disturbance and associated daytime symptoms occur several times per week for at least 3 months. This new definition and subclassification not only brings to light the different ways in which insomnia can be experienced by an individual, but also emphasizes the daytime consequences of this disorder, now a determinant symptom in its diagnosis. Based on its medical definition, insomnia is one of the most prevalent sleep disorders in the world, affecting 10–30% of the population, with a total estimated cost of $92.5 to $107.5 billion annually for the U.S. alone^4–8.

The pathophysiology of insomnia has been studied extensively in humans. Available evidence indicates increased activity of the hypothalamic-pituitary-adrenal axis and of the autonomic nervous system in insomnia, as well as circadian process misalignment (changes in melatonin secretion) and dysfunction of the homoeostatic process (changes in extracellular adenosine levels⁹). Specific sleep- and electroencephalography (EEG)-related changes also have been reported in patients with insomnia, with reduced amounts of both slow wave and rapid eye movement (REM) sleep¹⁰ and increased EEG β power during non-rapid eye movement (NREM) sleep in insomnia patients⁹. The sleep of many patients with insomnia is also characterized by an increased frequency of brief events such as shifts in sleep stages, brief periods of awakening and microarousals¹¹, indicating that changes in sleep-wake regulation at the neurochemical levels might also be affected in insomnia. Particularly, reduced GABA release and increased orexin activation at night have been proposed as neurobiological mechanisms underlying insomnia^9,12.

Several studies also have investigated the negative consequences of chronic insomnia, including decreased quality of life, increased likelihood of accidents, decreased work productivity, and physical health consequences, such as diabetes and cardiovascular disease^6,13. It is well known that sleep plays an integral role in health, and insufficient sleep – associated with insomnia or not – can have a negative impact on virtually every system in the body, with broad-ranging clinical and public health consequences. Importantly, while not as largely studied, a growing body of evidence indicates that lack of sleep predicts substance use and associated psychosocial problems, and puts individuals at a higher risk for substance use disorders.

Insomnia as a Risk Factor for Substance Use Disorders

Substance use disorders represent an important – and growing – public health concern. The 2022 World Drug Report estimates that more than 350 million people worldwide use illicit drugs, with nearly 35 million people meeting diagnostic criteria for substance use disorders¹⁴. As defined by the DSM-5, substance use disorder is a chronic, relapsing disorder characterized by a set of symptoms that determine the recurrent use of alcohol and/or drugs leading to significant health and life consequences. Symptoms include tolerance to the drug effects, abstinence syndrome, increased drug use over time, persistent and unsuccessful attempts to discontinue or reduce drug use, spending increasing amounts of time to obtain the drug and/or recover from drug effects, reduced social and work-related activities in order to seek and/or use drugs, and continued drug use despite significant negative consequences associated with its use¹⁵. According to the World Health Organization, over 180 thousand deaths were directly associated with substance use disorders in 2019¹⁶. While drug use is high worldwide, with general increased rates of cannabis, amphetamines, opioids and cocaine use in recent years, the type of drug most commonly used and available varies between different regions and countries¹⁴.

Many factors can contribute to initiation of and increased drug use, including adverse life experiences, psychiatric disorders, and socioeconomic and genetic factors^17–18. However, one commonly neglected contributor to drug use and abuse is insufficient sleep. Several aspects of substance use and sleep impairment have prompted researchers to investigate relationships between these two factors¹⁹. For example, individuals using drugs often show a pattern of nocturnal drug taking due to professional, academic and/or social demands. Conversely, individuals with substance use disorders who present sleep problems are more likely to relapse during treatment²⁰. Finally, and completing what likely is a vicious cycle, sleep impairment is frequent in individuals with substance use disorders, who are 5 to 10 times more likely to present with sleep problems than the general population²¹. In fact, most drugs of abuse impair sleep in all phases of addiction^22–27. Given this striking and seemingly bidirectional interaction, it has become clear that neurobiological mechanisms seem to link sleep impairment and stimulant abuse, although the specific mechanisms are yet to be elucidated. In accordance with studies showing altered dopaminergic neuroplasticity following sleep deprivation^28–29, the mesolimbic dopaminergic system has been proposed as the main pathway mediating drug-induced sleep impairment³⁰.

In addition to the nocturnal pattern of drug use, the fact that sleep impairment predisposes relapse and that drug use and abuse can affect sleep quality, recent studies also suggest that poor sleep predicts substance use and associated psychosocial problems, and puts individuals at a higher risk for substance use disorders. Initial evidence for this relationship was demonstrated in pre-clinical studies showing that sleep loss can potentiate many behaviors associated with the abuse-related effects of drugs of abuse. Studies in rodents show that sleep deprivation can potentiate the rewarding and locomotor stimulant effects of drugs^31–34, as well as drug intake^35–36 and drug-seeking behavior^37–38.

Clinically, most of the evidence linking insufficient sleep and an substance use disorders emerged from prospective clinical studies in children and adolescents investigating associations between sleep patterns at baseline and subsequent substance use. Childhood sleep problems during ages 3–5 have been associated with early onset use of alcohol, cannabis, illicit drugs and cigarettes³⁹. Wong and colleagues⁴⁰ also studied a relationship between insufficient sleep and substance use in the National Longitudinal Study of Adolescent Health, and showed that sleep difficulties and hours of sleep were significant predictors of substance-related problems in adolescents. Corroborating these findings, Pieters et al.⁴¹ showed that sleep problems seem to be important predictors of substance use in adolescence. Specifically, inconsistent sleep-wake patterns and greater daytime sleepiness mediate increased lifetime use of all substances in adolescents⁴². Of note, difficulty sleeping during childhood predicts sleep problems during adolescence, which then increases the risk for drug-related problems in young adulthood⁴³. In this latter study, the number of illicit drugs used and several alcohol-related problems in young adulthood were associated with increased childhood tiredness⁴³.

A direct relationship between insomnia and risk for substance use also has been shown both in adolescents and adults⁴⁴. Roane and Taylor⁴⁵ showed that adolescents with insomnia at baseline were more likely to use alcohol, cannabis and other drugs during a 6- to 7-year follow up. An association between insomnia symptoms and problematic drug use also has been reported among university students⁴⁶. In adults, an insomnia diagnosis has been associated with increased risk for next-year alcohol use⁴⁷, as well as increased risk of illicit substance use disorder and nicotine dependence⁴⁸. Insomnia also moderates drug-related problems in adults, including increased aggression associated with cocaine use⁴⁹ and alcohol-related consequences, such as public embarrassment, drinking on nights they had planned not to drink, and passing out from drinking⁵⁰.

Together, these studies indicate that insufficient sleep is a major predictor of future substance use and related problems, with a direct association between insomnia and increased risk for drug use. Importantly, gender differences may play a major role in the relationship between insomnia and drug use. While investigating gender differences in insomnia and substance use disorders may seem straightforward, many biological, psychological, cultural and social factors can differentially contribute to the emergence of sleep problems and to drug use in women compared to men.

Sex differences in Insomnia and Substance Use Disorders

Several potential risk factors have been identified in chronic insomnia, including gender and genetic factors^51–53, and it is well established that insomnia complaints are most prevalent in women^54–55. Gender differences in insomnia have been reported as early as in adolescence⁵⁶, with a peak in insomnia symptoms among girls ages 11 to 12 – likely associated with puberty⁵⁷. In fact, a study by Johnson and colleagues⁵⁸ showed that this increased risk for insomnia in adolescent girls is only observed after onset of menstruation, when girls show a 2.75-fold increased risk for insomnia. In adults, epidemiological studies show that as many as 48.6% of women present insomnia symptoms⁵⁵, in addition to a higher prevalence of objective (polysomnography-based) insomnia in women compared to men⁸. According to Castro and colleagues⁸, an epidemiological sleep study showed that 71.4% of participants who met DSM-4 criteria for insomnia diagnosis were women. A meta-analysis also confirmed a female predisposition for insomnia, showing that women are 1.5 times more likely to have insomnia than men⁵⁹. In addition to gender, population-based studies show family history as a predisposing factor to insomnia⁶⁰, indicating a potential role for genetic factors in the genesis and heritability of this sleep disorder. Several twin studies strongly suggest that genetic factors influence insomnia and account for approximately one third of the variance in insomnia complaints^61–63, with one study on 7,500 male and female twins showing that women have a higher genetic risk of developing insomnia than men⁶⁴.

While it is very clearly established that being a woman increases the risk for developing insomnia, this association is not as clear when it comes to substance use disorders. Generally, men are more likely to use most drugs than women¹⁴. However, gender differences in drug use vary by region, by country and by drug, which is likely associated with whether or not women have the opportunity to use drugs due to accessibility, social factors preventing women from using drugs and potential cultural barriers to drug use among women¹⁴. Yet, women consistently outnumber men in both medical and non-medical use of a specific class of drugs: sedatives and tranquilizers, such as benzodiazepines and benzodiazepine-type drugs¹⁴. The most recent World Drug Report showed an increase in the use of sedatives and tranquilizers in recent years, particularly among women¹⁴. Benzodiazepines and related drugs are commonly used for the treatment of anxiety and sleep disorders, being one of the most largely prescribed treatments for insomnia⁶⁵. Therefore, the increased prevalence of insomnia, as well as anxiety disorders⁶⁶, among women likely contributes to an increased prevalence of sedative/tranquilizer use in recent years. Women also show a high prevalence of non-medical use of other pharmaceutical drugs, particularly opioids, surpassing men in some regions¹⁴. The misuse of prescription opioids is often associated with self-medication for pain, which is also highly prevalent among women⁶⁷, and can contribute to – and be affected by – insomnia⁶⁸.

Despite the fact that gender differences in rates of drug use are not consistent across drug classes, significant gender differences have been reported in drug use patterns and in the progression from drug use to substance use disorders. Of major importance, women show a faster progression from drug use to abuse. Studies show a more rapid progression to treatment admission for women who are dependent on opioids, cannabis and alcohol, with women reporting more severe psychiatric and medical complications related to drug use than men⁶⁹. Studies also show that women are less sensitive to the effects of some drugs⁷⁰, which could contribute to higher drug intake, and develop drug-related brain damage more rapidly than men⁷¹. Westermeyer and Boedicker⁷² reported that despite women using drugs for a shorter period of time compared to men, women and men had similar dependence rates, indicating that women may develop dependence faster. The interval between first time drug use and treatment-seeking also seems to be shorter in women than men⁷³.

Women with substance use disorders also have more difficulty quitting drug use and are more likely to relapse compared to men. Studies have shown that women are more likely than men to engage in heavy alcohol drinking to deal with unpleasant emotions⁷⁴. Considering that preoccupation/anticipation is one of the final stages of substance use disorders, leading to relapse, this coping mechanism, combined with increased craving among women⁷⁵, might put women at a higher risk for relapse⁷⁶. Enhanced craving and relapse risk in women also have been reported for opioids, psychostimulants and nicotine⁷⁶. Yet, despite higher relapse rates, women are generally underrepresented when it comes to treatment for substance use disorders¹⁴. Studies suggest that several factors contribute to decreased treatment seeking among women, including fear of legal repercussions, such as losing child custody, in addition to social and cultural factors, such as increased stigma and heavier household responsibilities placed on women^14,77. Consequently, women with substance use disorders are more likely to be living with HIV and hepatitis C⁷⁸, and show higher mortality rates compared to men⁷⁹.

Several factors can contribute to increased vulnerability to insomnia and substance use disorders in women. Importantly, many of these risk factors are common between the two disorders. Specifically regarding sex differences, studies have shown a role for sex hormones in insomnia and substance use disorders. Female sex hormones, including luteinizing hormone and progesterone, can alter circadian rhythms and disrupt sleep⁸⁰. On the other hand, higher endogenous estrogen levels are associated with better sleep in women⁸¹, although the effects of estrogen on sleep may depend on the menstrual cycle phase⁸⁰. In fact, insomnia is highly prevalent among women undergoing menopause^82–83, when ovarian hormone production decreases, and hormone therapy with estrogen improves sleep in postmenopausal women⁸⁴. Estrogen also has been shown to contribute to the increased vulnerability to substance use disorders in females⁸⁵, with greater subjective effects of drugs experienced during high estrogen and low progesterone levels⁸⁶. It is important to note, however, that changes in reproductive hormones can only explain the biological role of sex in disease, but not gender differences. This is an important distinction considering that both insomnia and substance use disorders can be influenced by psychological, environmental and social factors, which emphasizes that sex differences alone cannot explain the increased vulnerability to these disorders in women and their relationship.

Psychological risk factors common to both insomnia and substance use disorders include anxiety, depression and stress^87–91. Insomnia is highly comorbid with other psychiatric disorders, with studies showing that individuals with two psychiatric disorders are 2.2–3.2 times more likely to have sleep problems, a rate that increases to 4.6–6.3 times for individuals with three or more psychiatric disorders⁹². In fact, psychiatric comorbidities seem to mediate the interaction between insomnia and substance use disorders. In patients with comorbid anxiety and substance use disorders, anxiety sensitivity was associated with symptoms of insomnia⁹³. Anxiety symptoms seem to mediate insomnia induced by emotional dysregulation in patients with alcohol use disorder⁹⁴. A social anxiety disorder diagnosis has been associated with an increased likelihood of both alcohol use disorder and insomnia diagnosis, with insomnia contributing for the interaction between anxiety and alcohol use disorder⁹⁵. Sleep also has been shown as a significant mediator between psychiatric symptoms (anxiety and depression) and drug use in epidemiological studies⁹⁶. Of note, anxiety and depression are more prevalent in women^97–98, and women are also more vulnerable to the effects of stress than men⁹⁹. Therefore, an increased prevalence of psychiatric risk factors for both insomnia and substance use disorders would place women at a higher risk for the development of these disorders.

Importantly, socioeconomic factors also contribute to both insomnia and substance use disorders. Studies show that a low socioeconomic status is a strong predictor of short sleep duration, with insomnia being more frequent among those with lower income and lower educational levels^100–101. Low income and education, and exposure to poverty during childhood, also are risk factors for the development of substance use disorders^102–103. Of note, a study by Abreu and colleagues¹⁰⁴ showed that lower family income, insomnia symptoms and long working hours were associated with an increased likelihood of substance use among truck drivers. Therefore, socioeconomic factors may mediate the relationship between insomnia and drug use, although further research is needed to investigate this relationship. Regarding gender differences, it is well known that women generally show lower education attainment and lower income regardless of education compared to men¹⁰⁵, which could contribute to gender differences in insomnia and substance use disorders. Importantly, black women are disproportionally affected by the influence of socioeconomic factors in sleep^106–107 and drug use¹⁰⁸.

Importantly, biological, psychiatric and socioeconomic risk factors may interact to mediate the relationship between insomnia and substance use disorders. In a recent study, Marees and colleagues¹⁰⁹ showed that high alcohol consumption quantity was genetically associated with low socioeconomic status and high risk of substance use disorders and other psychiatric disorders, including insomnia. A convergent model also showed that sleep quality, psychiatric symptoms (anxiety and depression) and socioeconomic factors interacted to mediate risk for tobacco consumption in an epidemiological sleep study⁹⁶. While no studies to date have investigated gender differences specifically in these interactions, it seems clear that the relationship between insomnia and substance use disorders is multifactorial, and involves factors that generally pose women at a higher risk for the development of substance use disorders.

Discussion: Insomnia as a Risk Factor for Substance Use Disorders in Women

Over the last century, we have seen an increase in the number of women participating in the economy and working outside the home. With an increased presence of women in the labor force, women have had to adjust to managing a work-life balance to juggle their professional and personal lives. Often times, women sacrifice their sleep to keep up with their many chores and responsibilities, which has led to a generation of women with insomnia. In fact, work characteristics and family responsibilities play a major role in the gender differences observed in insomnia, contributing to an increased prevalence of insomnia in women^110–112.

Of note, this increase in the number of women reporting insufficient sleep has been accompanied by a narrowing in the gender gap in substance use disorders¹¹³. Importantly, an increase in the prevalence of substance use disorders among women also seems to be associated with the increased presence and importance of women in contemporary society. Lack of access to drugs, less opportunities for substance use, and negative attitudes towards the appropriateness of substance use represented the main barriers for drug use among women^114–116. However, with a growth in the movement for gender equality, we also have seen an increase in the prevalence of substance use disorders among women.

This concomitant increase in the prevalence of insomnia and substance use disorders poses the possibility that insomnia may be a potential unique risk factor for substance use disorders among women. A causal relationship is difficult to determine, especially considering that both disorders have multiple contributing factors that also mediate each other. However, as reviewed in this manuscript, several of the risk factors for insomnia are common to substance use disorders, with many affecting women disproportionally. Also, a growing body of evidence shows that insomnia and insufficient sleep predict and put individuals at a higher risk for substance use and associated psychosocial problems. Importantly, gender differences in insomnia emerge during adolescence^56–57, emphasizing the importance of focusing on sleep promotion during prevention and early intervention strategies to reduce the impact of substance use.

Summary

Gender differences exist for both insomnia and substance use disorders. Women show a higher prevalence of insomnia and increased susceptibility to the effects of drugs than men. Importantly, a growing body of evidence suggests that insufficient sleep predicts and puts individuals at a higher risk for substance use and associated psychosocial problems. The current literature suggests that an increased prevalence of insomnia may be a risk factor for substance use disorders in women. Many risk factors are common between insomnia and substance use disorders, including psychiatric disorders (anxiety, depression) and low socioeconomic status, and disproportionally affect women. Considering that gender differences in insomnia emerge as early as during adolescence, prevention and early intervention strategies to reduce the impact of substance use should focus on sleep promotion and education among teenagers and young adults.