Insomnia, also known assleeplessness, is asleep disorder where people have troublesleeping.[1][11] They may have difficulty falling asleep, or staying asleep for as long as desired.[1][9][12] Insomnia is typically followed by daytimesleepiness, low energy,irritability, and adepressed mood.[1] It may result in an increased risk of accidents of all kinds as well as problems focusing and learning.[9] Insomnia can be short term, lasting for days or weeks, or long term, lasting more than a month.[1] The concept of the wordinsomnia has two distinct possibilities: insomnia disorder (ID) or insomnia symptoms, and many abstracts of randomized controlled trials and systematic reviews often underreport on which of these two possibilities the word refers to.[13]
Although their efficacy as first line treatments is not unequivocally established,[16]sleep hygiene and lifestyle changes are typically the first treatment for insomnia.[5][7] Sleep hygiene includes a consistent bedtime, a quiet and dark room, exposure to sunlight during the day and regularexercise.[7]Cognitive behavioral therapy may be added to this.[6][17] Whilesleeping pills may help, they are sometimes associated withinjuries,dementia, andaddiction.[5][6] These medications are not recommended for more than four or five weeks.[6] The effectiveness and safety ofalternative medicine is unclear.[5][6]
Between 10% and 30% of adults have insomnia at any given point in time, and up to half of people have insomnia in a given year.[8][9][10] About 6% of people have insomnia that is not due to another problem and lasts for more than a month.[9] People over the age of 65 are affected more often than younger people.[7] Women are more often affected than men.[8] Descriptions of insomnia occur at least as far back asancient Greece.[18]
Feeling tired or having low energy during the day[22]
Trouble concentrating
Being irritable, acting aggressive or impulsive
Sleep onset insomnia is difficulty falling asleep at the beginning of the night, often a symptom ofanxiety disorders.Delayed sleep phase disorder can be misdiagnosed as insomnia, as sleep onset is delayed to much later than normal while awakening spills over into daylight hours.[23]
It is common for patients who have difficulty falling asleep to also have nocturnal awakenings with difficulty returning to sleep.[24] Two-thirds of these patients wake up in the middle of the night, with more than half having trouble falling back to sleep after amiddle-of-the-night awakening.[25]
Early morning awakening occurs earlier (more than 30 minutes) than desired with an inability to go back to sleep and before total sleep time reaches 6.5 hours. Early morning awakening is often a characteristic ofdepression.[26] Anxiety symptoms may well lead to insomnia. Some of these symptoms includetension, compulsive worrying about the future, feeling overstimulated, and overanalyzing past events.[27]
Poor sleep quality can occur as a result of, for example,restless legs,sleep apnea, ormajor depression. Poor sleep quality is defined as the individual not reachingstage 3 or delta sleep, which has restorative properties.[28]
Major depression leads to alterations in the function of thehypothalamic–pituitary–adrenal axis, causing excessive release ofcortisol, which can lead to poor sleep quality.
Nocturnalpolyuria, excessive night-time urination, can also result in a poor quality of sleep.[29]
Some cases of insomnia are not insomnia in the traditional sense because people experiencingsleep state misperception often sleep for a normal amount of time.[30] The problem is that, despite sleeping for multiple hours each night and typically not experiencing significant daytime sleepiness or other symptoms of sleep loss, they do not feel like they have slept very much, if at all.[30] Because their perception of their sleep is incomplete, they incorrectly believe it takes them an abnormally longtime to fall asleep, and they underestimate how long they stay asleep.[30]
In August 2018,Sleep Science and Practice published a systematic review and meta-analysis of 19 studies comprising 253,904 adolescent subjects that found that excessive technology use had a strong and consistent association with reduced sleep duration and prolongedsleep onset latency for adolescents 14 years of age or older.[31] Also in August 2018,Sleep Science published a systematic review of 12 studies investigating associations between exposure to video games, sleep outcomes, and post-sleep cognitive abilities that found the data present in the studies indicated associations between a reduction in sleep duration, increased sleep onset latency, modifications torapid eye movement sleep andslow-wave sleep, increased sleepiness and self-perceivedfatigue, and impaired post-sleepattention span andverbal memory.[32] In October 2019,Sleep Medicine Reviews published a systematic review and meta-analysis of 23 studies comprising 35,684 subjects that found a statistically significantodds ratio for sleep problems and reduced sleep duration for subjects with internet addiction.[33] In February 2020,Psychiatry Research published a systematic review and meta-analysis of 14 studies that found positive associations between problematic smartphone use and poor sleep quality and between higher levels of problematic smartphone use and elevated risk of poor sleep quality.[34]
Also in February 2020,Sleep Medicine Reviews published a systematic review of 31 studies examining associations between screen time and sleep outcomes in children younger than 5 years and found that screen time is associated with poorer sleep outcomes for children under the age of 5, with meta-analysis only confirming poor sleep outcomes among children under 2 years.[35] In March 2020,Developmental Review published a systematic review of 9 studies that found a weak-to-moderate association between sleep quantity and quality and problematic smartphone use among adolescents.[36] In October 2020, theInternational Journal of Environmental Research and Public Health published a systematic review and meta-analysis of 80 studies that found that greater screen time was associated with shorter sleep duration among toddlers and preschoolers,[37] while theJournal of Behavioral Addictions published a systematic review and meta-analysis of 40 studies with 33,650 post-secondary student subjects that found a weak-to-moderate positive association between mobile phone addiction and poor sleep quality.[38] In April 2021,Sleep Medicine Reviews published a systematic review of 36 cross-sectional studies and 6 longitudinal studies that found that 24 of the cross-sectional studies and 5 of the longitudinal studies established significant associations between more frequent social media use and poor sleep outcomes.[39]
In June 2021,Frontiers in Psychiatry published a systematic review and meta-analysis of 34 studies comprising 51,901 subjects that established significant associations between problematic gaming and sleep duration, poor sleep quality, daytime sleepiness, and other sleep problems.[40] In September 2021,BMC Public Health published a systematic review of 49 studies investigating associations between electronic media use and various sleep outcomes among children and adolescents 15 years of age or younger that found a strong association with sleep duration and stronger evidence for an association with sleep duration between the ages of 6 and 15 years than for 5 years of age or younger, while evidence for associations between electronic media use with other sleep outcomes was more inconclusive.[41] In December 2021,Frontiers in Neuroscience published a systematic review of 12 studies published from January 2000 to April 2020 that found that adult subjects with higher gaming addiction scores were more likely to have shorter sleep quantity, poorer sleep quality, delayed sleep timing, and greater daytime sleepiness and insomnia scores than subjects with lower gaming addiction scores and non-gamer subjects.[42] In January 2022,Early Childhood Research Quarterly published a systematic review and meta-analysis of 26 studies that found a weak but statistically significant association with increased smartphone and tablet computer use and poorer sleep in early childhood.[43]
In May 2022, theJournal of Affective Disorders published a meta-analysis of 29 studies comprising 20,041 subjects that found a weak-to-moderate association between mobile phone addiction and sleep disorder and that adolescents with mobile phone addiction were at higher risk of developing sleep disorder.[44] In August 2022, theInternational Journal of Environmental Research and Public Health published a systematic review and meta-analysis of 16 studies comprising 8,077 subjects that established a significant association between binge-watching and sleep problems and a stronger association between binge-watching and sleep problems was found during the COVID-19 pandemic than pre-pandemic.[45] In October 2022,Reports in Public Health published a systematic review of 23 studies that found that excessive use of digital screens by adolescents was associated with poor sleep quality, nighttime awakenings, long sleep latency, and daytime sleepiness.[46] In December 2022,Sleep Epidemiology published a systematic review of 18 studies investigating associations between sleep problems and screen time duringCOVID-19 lockdowns that found that the increased screen time during the lockdowns negatively impacted sleep duration, sleep quality, sleep onset latency, and wake time.[47] In March 2023, theJournal of Clinical Sleep Medicine published a systematic review and meta-analysis of 17 studies comprising 36,485 subjects that found that smartphone overuse was closely associated with self-reported poor sleep quality,sleep deprivation, and prolonged sleep latency.[48]
In April 2023,Sleep Medicine Reviews published a systematic review of 42 studies that found digital media use to be associated with shorter sleep duration and poorer sleep quality and bedtime or nighttime use with poor sleep outcomes, but only found associations for general screen use, mobile phone use, computer and internet use, internet, and social media and not for television, game console, and tablet use.[49] In July 2023,Healthcare published a systematic review and meta-analysis of 16 studies that established a correlation coefficient of 0.56 between nomophobia and insomnia.[50] In September 2023,PLOS One published a systematic review and meta-analysis of 16 studies of smartphone addiction and sleep among medical students found that 57% of subjects had poor sleep and 39% of subjects had smartphone addiction with a correlation index of 0.3,[51] whileComputers in Human Behavior published a meta-analysis of 23 longitudinal studies comprising 116,431 adolescent subjects that found that adolescent screen time with computers, smartphones, social media, and television are positively associated with negative impacts on sleep health later in life.[52]
While insomnia can be caused by many conditions, it can also occur without any identifiable cause. This is known as Primary Insomnia.[53] Primary Insomnia may also have an initial identifiable cause but continues after the cause is no longer present. For example, a bout of insomnia may be triggered by a stressful work or life event. However, the condition may continue after the stressful event has been resolved. In such cases, the insomnia is usually perpetuated by the anxiety or fear caused by the sleeplessness itself, rather than any external factors.[54]
Symptoms of insomnia can be caused by or be associated with:
Restless legs syndrome, which can cause sleep onset insomnia due to the discomforting sensations felt and the need to move the legs or other body parts to relieve these sensations[58]
Pain:[60] an injury or condition that causes pain can preclude an individual from finding a comfortable position in which to fall asleep, and can also cause awakening.
Disturbances of thecircadian rhythm, such asshift work andjet lag, can cause an inability to sleep at some times of the day and excessive sleepiness at other times of the day. Chroniccircadian rhythm disorders are characterized by similar symptoms.[56]
Sleep studies usingpolysomnography have suggested that people who have sleep disruption have elevated night-time levels of circulatingcortisol andadrenocorticotropic hormone.[71] They also have an elevated metabolic rate, which does not occur in people who do not have insomnia but whose sleep is intentionally disrupted during a sleep study. Studies of brain metabolism usingpositron emission tomography (PET) scans indicate that people with insomnia have higher metabolic rates by night and by day. The question remains whether these changes are the causes or consequences of long-term insomnia.[72]
Heritability estimates of insomnia vary between 38% in males to 59% in females.[73] Agenome-wide association study (GWAS) identified 3 genomic loci and 7genes that influence the risk of insomnia and showed that insomnia is highly polygenic.[74] In particular, a strong positive association was observed for theMEIS1 gene in both males and females. This study showed that the genetic architecture of insomnia strongly overlaps with psychiatric disorders and metabolic traits.
It has been hypothesized that epigenetics might also influence insomnia through a controlling process of both sleep regulation and brain-stress response having an impact as well on the brain plasticity.[75]
Alcohol is often used as a form of self-treatment of insomnia to induce sleep. However, alcohol use to induce sleep can be a cause of insomnia.Long-term use of alcohol is associated with a decrease inNREM stage 3 and 4 sleep as well as suppression ofREM sleep and REM sleep fragmentation. Frequent moving between sleep stages occurs with awakenings due to headaches,the need to urinate,dehydration, andexcessive sweating.Glutamine rebound also plays a role when someone is drinking; alcohol inhibits glutamine, one of the body's natural stimulants. When the person stops drinking, the body tries to make up for lost time by producing more glutamine than it needs.
The increase in glutamine levels stimulates the brain while the drinker is trying to sleep, keeping them from reaching the deepest levels of sleep.[76] Stopping chronic alcohol use can also lead to severe insomnia with vivid dreams. During withdrawal, REM sleep is typically exaggerated as part of arebound effect.[77]
Some people experience sleep disruption or anxiety if they consume caffeine.[78] Doses as low as 100 mg/day, such as a 6 oz (170 g) cup of coffee or two to three 12 oz (340 g) servings of caffeinated soft-drink, may continue to cause sleep disruption, among other intolerances. Non-regular caffeine users have the least caffeine tolerance for sleep disruption.[79] Some coffee drinkers develop tolerance to its undesired sleep-disrupting effects, but others apparently do not.[80]
Like alcohol,benzodiazepines, such asalprazolam,clonazepam,lorazepam, anddiazepam, are commonly used to treat insomnia in the short-term (both prescribed and self-medicated), but worsen sleep in the long-term. While benzodiazepines can put people to sleep (i.e., inhibit NREM stage 1 and 2 sleep), while asleep, the drugs disruptsleep architecture: decreasing sleep time, delaying time to REM sleep, and decreasing deepslow-wave sleep (the most restorative part of sleep for both energy and mood).[81][82][83]
Opioid medications such ashydrocodone,oxycodone, andmorphine are used for insomnia that is associated withpain due to theiranalgesic properties andhypnotic effects. Opioids can fragment sleep and decreaseREM andstage 2 sleep. By producinganalgesia andsedation, opioids may be appropriate in carefully selected patients with pain-associated insomnia.[60] However, dependence on opioids can lead to long-term sleep disturbances.[84]
Two main models exist regarding the mechanism of insomnia: cognitive and physiological. The cognitive model suggests that rumination and hyperarousal contribute to preventing a person from falling asleep and might lead to an episode of insomnia.
The physiological model is based upon three major findings in people with insomnia; firstly, increased urinarycortisol andcatecholamines have been found suggesting increased activity of the HPA axis and arousal; second, increased global cerebral glucose utilization during wakefulness and NREM sleep in people with insomnia; and lastly, increased full body metabolism and heart rate in those with insomnia. All these findings taken together suggest a deregulation of the arousal system, cognitive system, andHPA axis, all contributing to insomnia.[9][89] However, it is unknown if the hyperarousal is a result of, or cause of insomnia. Altered levels of the inhibitoryneurotransmitterGABA have been found, but the results have been inconsistent, and the implications of altered levels of such a ubiquitous neurotransmitter are unknown. Studies on whether insomnia is driven by circadian control over sleep or a wake-dependent process have shown inconsistent results, but some literature suggests a deregulation of the circadian rhythm based on core temperature.[90] Increased beta activity and decreased delta wave activity has been observed onelectroencephalograms; however, the implication of this is unknown.[91]
Around half of post-menopausal women experience sleep disturbances, and generally, sleep disturbance is about twice as common in women as men; this appears to be due in part, but not completely, to changes in hormone levels, especially in post-menopause.[61][92]
Changes insex hormones in both men and women as they age may account in part for an increased prevalence ofsleep disorders in older people.[93]
In medicine, insomnia is measured using theAthens insomnia scale.[94] It measures eight parameters related to sleep, represented as an overall scale which assesses an individual's sleep quality.
A medical history and a physical examination can identify other conditions that could be the cause of insomnia. A comprehensive sleep history should include sleep habits and sleep environment, medications (prescription and non-prescription including supplements), alcohol, nicotine, and caffeine intake, and co-morbid illnesses.[95] Asleep diary can be used to track time to bed, total sleep time, time to sleep onset, number of awakenings, use of medications, time of awakening, and subjective feelings in the morning.[95] The sleep diary can be replaced or validated by the use of out-patientactigraphy for a week or more, using a non-invasive device that measures movement.[96]
Not everyone who suffers from insomnia should routinely have apolysomnography study to screen for sleep disorders,[97] but it may be indicated for those with risk factors forsleep apnea, including obesity, a thick neck diameter, or fullness of the flesh in theoropharynx.[97] For most people, the test is not needed to make a diagnosis, and insomnia can often be treated by changing their schedule to make time for sufficient sleep and by improvingsleep hygiene.[97]
Some patients may need an overnight sleep study in a sleep lab. Such a study will commonly involve assessment tools including a polysomnogram and themultiple sleep latency test. Specialists insleep medicine are qualified to diagnose disorders within the, according to theICSD, 81 major sleep disorder diagnostic categories.[98] Patients with some disorders, includingdelayed sleep phase disorder, are often mis-diagnosed with primary insomnia; when a person has trouble getting to sleep and awakening at desired times, but has a normal sleep pattern once asleep, a circadian rhythm disorder is a likely cause.
In many cases, insomnia is co-morbid with another disease, side-effects from medications, or a psychological problem. Approximately half of all diagnosed insomnia is related to psychiatric disorders.[99] For those who have depression, "insomnia should be regarded as a co-morbid condition, rather than as a secondary one;" insomnia typically predates psychiatric symptoms.[99] "In fact, it is possible that insomnia represents a significant risk for the development of a subsequent psychiatric disorder."[9] Insomnia occurs in between 60% and 80% of people with depression and can be a side effect of medications that treat depression.[100]
The determination of causation is not necessary for a diagnosis.[99]
TheDSM-5 criteria for insomnia include the following:[101]
"Predominant complaint of dissatisfaction with sleep quantity or quality, associated with one (or more) of the following symptoms:
Difficulty initiating sleep. (In children, this may manifest as difficulty initiating sleep without caregiver intervention.)
Difficulty maintaining sleep, characterized by frequent awakenings or problems returning to sleep after awakenings. (In children, this may manifest as difficulty returning to sleep without caregiver intervention.)
Early-morning awakening with inability to return to sleep.
In addition:
The sleep disturbance causes clinically significant distress or impairment in social, occupational, educational, academic, behavioral, or other important areas of functioning.
The sleep difficulty occurs at least three nights per week.
The sleep difficulty has been present for at least three months.
The sleep difficulty occurs despite adequate opportunity for sleep.
The insomnia is not better explained by and does not occur exclusively during the course of another sleep-wake disorder (e.g., narcolepsy, a breathing-related sleep disorder, a circadian rhythm sleep-wake disorder, a parasomnia).
The insomnia is not attributable to the physiological effects of a substance (e.g., adrug of abuse, a medication)."
TheDSM-IV TR includes insomnia but does not fully elaborate on the symptoms compared to the DSM-5. Instead of early-morning waking as a symptom, the DSM-IV-TR listed “nonrestorative sleep” as a primary symptom. The duration of the experience was also vague in the DSM-IV-TR. The DSM-IV-TR stated that symptoms had to be present for a month, whereas in the DSM-5, it stated symptoms had to be present for three months and occur at least 3 nights a week (Gillette).
Insomnia can be classified as transient, acute, or chronic.
Transient insomnia lasts for less than a week. It can be caused by another disorder, by changes in the sleep environment, by the timing of sleep, severedepression, or bystress. Its consequences – sleepiness and impaired psychomotor performance – are similar to those ofsleep deprivation.[102]
Acute insomnia is the inability to consistently sleep well for less than a month. Insomnia is present when there is difficulty initiating or maintaining sleep or when the sleep that is obtained is non-refreshing or of poor quality. These problems occur despite adequate opportunity and circumstances for sleep, and they must result in problems with daytime function.[103] Hyperarousal can be linked to acute insomnia since it activates the body's fight-or-flight response. When we encounter stress or danger, our bodies naturally become more alert, which can interfere with our capacity to both fall asleep and remain asleep. This heightened state of arousal can be useful in the short term during threatening situations, but if it continues over an extended period, it can result in acute insomnia.[104] Acute insomnia is also known asshort term insomnia orstress related insomnia.[105]
Chronic insomnia lasts for longer than a month. It can be caused by another disorder, or it can be a primary disorder. Common causes of chronic insomnia include persistent stress, trauma, work schedules, poor sleep habits, medications, and other mental health disorders.[106] When an individual consistently engages in behaviors that disrupt their sleep, such as irregular sleep schedules, spending excessive time awake in bed, or engaging in stimulating activities close to bedtime, it can lead to conditioned wakefulness contributing to chronic insomnia.[104] People with high levels of stress hormones or shifts in the levels ofcytokines are more likely than others to have chronic insomnia.[107] Its effects can vary according to its causes. They might include muscular weariness,hallucinations, and/ormental fatigue.[102]
Among lifestyle practices, going to sleep and waking up at the same time each day can create a steady pattern which may help to prevent insomnia.[12] Avoidance of vigorousexercise andcaffeinated drinks a few hours before going to sleep is recommended, while exercise earlier in the day may be beneficial.[109] Other practices to improvesleep hygiene may include:[109][110]
It is recommended to rule out medical and psychological causes before deciding on the treatment for insomnia.[111]Cognitive behavioral therapy is effective for chronic insomnia.[112][17] The beneficial effects, in contrast to those produced by medications, may last well beyond the stopping of therapy.[113]
Medications have been used mainly to reduce symptoms in insomnia of short duration; their role in the management of chronic insomnia remains unclear.[8] Several different types of medications may be used.[114][115][108] Many doctors do not recommend relying on prescription sleeping pills for long-term use.[109] It is also important to identify and treat other medical conditions that may be contributing to insomnia, such as depression, breathing problems, and chronic pain.[109][116] As of 2022, many people with insomnia were reported as not receiving overall sufficient sleep or treatment for insomnia.[117][118]
Non-medication-based strategies have comparable efficacy tohypnotic medication for insomnia, and they may have longer lasting effects. Hypnotic medication is only recommended for short-term use becausedependence withrebound withdrawal effects upon discontinuation ortolerance can develop.[119]
Non-medication-based strategies provide long-lasting improvements to insomnia and are recommended as a first line and long-term strategy of management. Behavioral sleep medicine offers non-medication strategies to address chronic insomnia includingsleep hygiene,stimulus control, behavioral interventions,sleep-restriction therapy,paradoxical intention, patient education, andrelaxation therapy.[120] Some examples are keeping a journal, restricting the time spent awake in bed, practicingrelaxation techniques, and maintaining a regular sleep schedule and a wake-up time. Behavioral therapy can assist a patient in developing new sleep behaviors to improve sleep quality and consolidation. Behavioral therapy may include learning healthy sleep habits to promote sleep relaxation, undergoing light therapy to help with worry-reduction strategies, and regulating the circadian clock.[116]
Music may improve insomnia in adults (seemusic and sleep).[121]EEG biofeedback has demonstrated effectiveness in the treatment of insomnia with improvements in duration as well as quality of sleep.[122] Self-help therapy (defined as a psychological therapy that can be worked through on one's own) may improve sleep quality for adults with insomnia to a small or moderate degree.[123]
Stimulus control therapy is a treatment for patients who have conditioned themselves to associate the bed, or sleep in general, with a negative response. As stimulus control therapy involves taking steps to control the sleep environment, it is sometimes referred to interchangeably with the concept ofsleep hygiene. Examples of such environmental modifications include using the bed for sleep and sex only, not for activities such as reading or watching television; waking up at the same time every morning, including on weekends; going to bed only when sleepy and when there is a high likelihood that sleep will occur; leaving the bed and beginning an activity in another location if sleep does not occur in a reasonably brief period after getting into bed (commonly ~20 min); reducing the subjective effort and energy expended trying to fall asleep; avoiding exposure to bright light during night-time hours, and eliminating daytime naps.[124]
A component of stimulus control therapy is sleep restriction, a technique that aims to match the time spent in bed with the actual time spent asleep. This technique involves maintaining a strict sleep-wake schedule, sleeping only at certain times of the day and for specific amounts of time to induce mild sleep deprivation. Complete treatment usually lasts up to 3 weeks and involves making oneself sleep for only a minimum amount of time that they are actually capable of on average, and then, if capable (i.e. whensleep efficiency improves), slowly increasing this amount (~15 min) by going to bed earlier as the body attempts to reset its internal sleep clock.Bright light therapy may be effective for insomnia.[125]
Paradoxical intention is a cognitive reframing technique where the insomniac, instead of attempting to fall asleep at night, makes every effort to stay awake (i.e., essentially stops trying to fall asleep). One theory that may explain the effectiveness of this method is that by not voluntarily making oneself go to sleep, it relieves the performance anxiety that arises from the need or requirement to fall asleep, which is meant to be a passive act. This technique has been shown to reduce sleep effort and performance anxiety and also lower subjective assessment of sleep-onset latency and overestimation of the sleep deficit (a quality found in many insomniacs).[126]
Sleep hygiene is a common term for all of the behaviors that relate to the promotion of good sleep. They include habits that provide a good foundation for sleep and help to prevent insomnia. However, sleep hygiene alone may not be adequate to address chronic insomnia. Sleep hygiene recommendations are typically included as one component ofcognitive behavioral therapy for insomnia (CBT-I).[96][6] Recommendations include reducing caffeine, nicotine, and alcohol consumption, maximizing the regularity and efficiency of sleep episodes, minimizing medication usage and daytime napping, the promotion of regular exercise, and the facilitation of a positive sleep environment.[127] The creation of a positive sleep environment may also help reduce the symptoms of insomnia.[128]On the other hand, a systematic review by the AASM concluded that clinicians should not prescribe sleep hygiene for insomnia due to the evidence of absence of its efficacy and potential delaying of adequate treatment, recommending instead that effective therapies such as CBT-i should be preferred.[16]
There is some evidence that cognitive behavioral therapy for insomnia (CBT-I) is superior in the long-term tobenzodiazepines and thenonbenzodiazepines in the treatment and management of insomnia.[129] In this therapy, patients are taught improved sleep habits and relieved of counter-productive assumptions about sleep. Common misconceptions and expectations that can be modified include:[citation needed]
Unrealistic sleep expectations.
Misconceptions about insomnia causes.
Amplifying the consequences of insomnia.
Performance anxiety after trying for so long to have a good night's sleep by controlling the sleep process.
Numerous studies have reported positive outcomes of combining cognitive behavioral therapy for insomnia treatment with treatments such as stimulus control and relaxation therapies.Hypnotic medications are equally effective in the short-term treatment of insomnia, but their effects wear off over time due totolerance. The effects ofCBT-I have sustained and lasting effects on treating insomnia long after therapy has been discontinued.[130][131] The addition of hypnotic medications with CBT-I adds no benefit in insomnia. The long-lasting benefits of a course of CBT-I shows superiority over pharmacological hypnotic drugs. Even in the short term, when compared to short-term hypnotic medication such as zolpidem, CBT-I still shows significant superiority. Thus, CBT-I is recommended as a first-line treatment for insomnia.[132]
Common forms of CBT-I treatments include stimulus control therapy, sleep restriction, sleep hygiene, improved sleeping environments, relaxation training, paradoxical intention, and biofeedback.[133]
CBT is the well-accepted form of therapy for insomnia since it has no known adverse effects, whereas taking medications to alleviate insomnia symptoms has been shown to have adverse side effects.[134] Nevertheless, the downside of CBT is that it may take a lot of time and motivation.[135]
Treatments based on the principles ofacceptance and commitment therapy (ACT) andmetacognition have emerged as alternative approaches to treating insomnia.[136] ACT rejects the idea that behavioral changes can help insomniacs achieve better sleep, since they require "sleep efforts" - actions which create more "struggle" and arouse the nervous system, leading tohyperarousal.[137] The ACT approach posits that acceptance of the negative feelings associated with insomnia can, in time, create the right conditions for sleep.Mindfulness practice is a key feature of this approach, although mindfulness is not practised to induce sleep (this in itself is asleep effort to be avoided) but rather as a longer-term activity to help calm the nervous system and create the internal conditions from which sleep can emerge.
A key distinction between CBT-I and ACT lies in the divergent approaches to time spent awake in bed. Proponents of CBT-i advocate minimizing time spent awake in bed, on the basis that this creates cognitive association between being in bed and wakefulness. The ACT approach proposes that avoiding time in bed may increase the pressure to sleep and arouse the nervous system further.[137]
Research has shown that "ACT has a significant effect on primary and comorbid insomnia and sleep quality, and ... can be used as an appropriate treatment method to control and improve insomnia".[138]
Despite the therapeutic effectiveness and proven success of CBT, treatment availability is significantly limited by a lack of trained clinicians, poor geographical distribution of knowledgeable professionals, and expense.[139] One way to potentially overcome these barriers is to use the Internet to deliver treatment, making this effective intervention more accessible and less costly. The Internet has already become a critical source of health-care and medical information.[140] Although the vast majority of health websites provide general information,[140][141] there is growing research literature on the development and evaluation of Internet interventions.[142][143]
These online programs are typically behaviorally based treatments that have been operationalized and transformed for delivery via the Internet. They are usually highly structured; automated or human supported; based on effective face-to-face treatment; personalized to the user; interactive; enhanced by graphics, animations, audio, and possibly video; and tailored to provide follow-up and feedback.[143]
There is good evidence for the use of computer-based CBT for insomnia.[144]
Many people with insomnia usesleeping tablets and othersedatives. In some places, medications are prescribed in over 95% of cases.[145] They, however, are a second line treatment.[146] In 2019, the USFood and Drug Administration stated it is going to require warnings foreszopiclone,zaleplon, andzolpidem, due to concerns about serious injuries resulting from abnormal sleep behaviors, includingsleepwalking or driving a vehicle while asleep.[147]
The percentage of adults using a prescription sleep aid increases with age. During 2005–2010, about 4% of U.S. adults aged 20 and over reported that they took prescription sleep aids in the past 30 days. Rates of use were lowest among the youngest age group (those aged 20–39) at about 2%, increased to 6% among those aged 50–59, and reached 7% among those aged 80 and over. More adult women (5%) reported using prescription sleep aids than adult men (3%). Non-Hispanic white adults reported higher use of sleep aids (5%) than non-Hispanic black (3%) and Mexican-American (2%) adults. No difference was shown between non-Hispanic black adults and Mexican-American adults in use of prescription sleep aids.[148]
As an alternative to taking prescription drugs, some evidence shows that an average person seeking short-term help may find relief by takingover-the-counterantihistamines such asdiphenhydramine ordoxylamine.[149] Diphenhydramine and doxylamine are widely used in nonprescription sleep aids. They are the most effective over-the-counter sedatives currently available, at least in much of Europe, Canada, Australia, and the United States, and are more sedating than some prescriptionhypnotics.[150] Antihistamine effectiveness for sleep may decrease over time, andanticholinergic side-effects (such as dry mouth) may also be a drawback with these particular drugs. While addiction does not seem to be an issue with this class of drugs, they can induce dependence and rebound effects upon abrupt cessation of use.[151] However, people whose insomnia is caused by restless legs syndrome may have worsened symptoms with antihistamines.[152]
While insomnia is a common symptom of depression,antidepressants are effective for treating sleep problems whether or not they are associated with depression. While all antidepressants help regulate sleep, some antidepressants, such asamitriptyline,doxepin,mirtazapine,trazodone, andtrimipramine, can have an immediate sedative effect and are prescribed to treat insomnia.[153] Trazodone was at the beginning of the 2020s the biggest prescribed drug for sleep in the United States despite not being indicated for sleep.[154]
Amitriptyline, doxepin, and trimipramine all haveantihistaminergic,anticholinergic,antiadrenergic, andantiserotonergic properties, which contribute to both their therapeutic effects and side effect profiles, while mirtazapine's actions are primarily antihistaminergic and antiserotonergic and trazodone's effects are primarily antiadrenergic and antiserotonergic. Mirtazapine is known to decrease sleep latency (i.e., the time it takes to fall asleep), promoting sleep efficiency and increasing the total amount of sleeping time in people with both depression and insomnia.[155][156]
Agomelatine, a melatonergic antidepressant with claimed sleep-improving qualities that does not cause daytime drowsiness,[157] is approved for the treatment of depression though not sleep conditions in the European Union[158] andAustralia.[159] After trials in the United States, its development for use there was discontinued in October 2011[160] byNovartis, who had bought the rights to market it there from the European pharmaceutical companyServier.[161]
A 2018Cochrane review found the safety of taking antidepressants for insomnia to be uncertain with no evidence supporting long term use.[162]
Melatonin receptor agonists such asmelatonin andramelteon are used in the treatment of insomnia. The evidence for melatonin in treating insomnia is generally poor.[163] There is low-quality evidence that it may speed the onset of sleep by 6minutes.[163] Ramelteon does not appear to speed the onset of sleep or the amount of sleep a person gets.[163]
The usage of melatonin as a treatment for insomnia in adults has increased from 0.4% between 1999 and 2000 to nearly 2.1% between 2017 and 2018.[164]
While the use of melatonin in the short-term has been proven to be generally safe and is shown to not be a dependent medication, side effects can still occur.[165]
Most common side effects of melatonin include:[165]
Studies have also shown that children who are on theautism spectrum or have learning disabilities,attention-deficit hyperactivity disorder (ADHD) or relatedneurological diseases can benefit from the use of melatonin. This is because they often have trouble sleeping due to their disorders. For example, children with ADHD tend to have trouble falling asleep because of theirhyperactivity and, as a result, tend to be tired during most of the day. Another cause of insomnia in children with ADHD is the use of stimulants to treat their disorder. Children who have ADHD then, as well as the other disorders mentioned, may be given melatonin before bedtime to help them sleep.[168]
The most commonly used class of hypnotics for insomnia are thebenzodiazepines.[63]: 363 Benzodiazepines arenot significantly better for insomnia thanantidepressants.[170] Chronic users ofhypnotic medications for insomnia do not have better sleep than chronic insomniacs not taking medications. In fact, chronic users of hypnotic medications have more regular night-time awakenings than insomniacs not taking hypnotic medications.[171] Many have concluded that these drugs cause an unjustifiable risk to the individual and topublic health and lack evidence of long-term effectiveness. It is preferred that hypnotics be prescribed for only a few days at the lowest effective dose and avoided altogether wherever possible, especially in the elderly.[172] Between 1993 and 2010, the prescribing of benzodiazepines to individuals with sleep disorders has decreased from 24% to 11% in the US, coinciding with the first release ofnonbenzodiazepines.[173]
Thebenzodiazepine andnonbenzodiazepinehypnotic medications also have several side effects, such as daytime fatigue, motor vehicle crashes and other accidents, cognitive impairments, and falls and fractures. Elderly people are more sensitive to these side effects.[174] Some benzodiazepines have demonstrated effectiveness in sleep maintenance in the short term but in the longer term benzodiazepines can lead totolerance,physical dependence,benzodiazepine withdrawal syndrome upon discontinuation, and long-term worsening of sleep, especially after consistent usage over long periods. Benzodiazepines, while inducing unconsciousness, actually worsen sleep as – like alcohol – they promote light sleep while decreasing time spent in deep sleep.[175] A further problem is, with regular use of short-acting sleep aids for insomnia, daytimerebound anxiety can emerge.[176] Although there is little evidence for benefit of benzodiazepines in insomnia compared to other treatments and evidence of major harm, prescriptions have continued to increase.[177] This is likely due to their addictive nature, both due to misuse and because – through their rapid action, tolerance and withdrawal they can "trick" insomniacs into thinking they are helping with sleep. There is a general awareness that long-term use of benzodiazepines for insomnia in most people is inappropriate and that a gradual withdrawal is usually beneficial due to the adverse effects associated with thelong-term use of benzodiazepines and is recommended whenever possible.[178][179]
Benzodiazepines all bind unselectively to theGABAA receptor.[170] Some theorize that certain benzodiazepines (hypnotic benzodiazepines) have significantly higher activity at the α1 subunit of the GABAA receptor compared to other benzodiazepines (for example, triazolam and temazepam have significantly higher activity at the α1 subunit compared to alprazolam and diazepam, making them superior sedative-hypnotics – alprazolam and diazepam, in turn, have higher activity at the α2 subunit compared to triazolam and temazepam, making them superior anxiolytic agents). Modulation of the α1 subunit is associated with sedation, motor impairment, respiratory depression, amnesia, ataxia, and reinforcing behavior (drug-seeking behavior). Modulation of the α2 subunit is associated with anxiolytic activity and disinhibition. For this reason, certain benzodiazepines may be better suited to treat insomnia than others.[128]
Nonbenzodiazepine orZ-drug sedative–hypnotic drugs, such aszolpidem,zaleplon,zopiclone, andeszopiclone, are a class of hypnotic medications that are similar to benzodiazepines in their mechanism of action, and indicated for mild to moderate insomnia. Their effectiveness at improving time to sleeping is slight, and they have similar—though potentially less severe—side effect profiles compared to benzodiazepines.[180] Prescribing of nonbenzodiazepines has seen a general increase since their initial release on the US market in 1992, from 2.3% in 1993 among individuals with sleep disorders to 13.7% in 2010.[173]
Certainatypical antipsychotics, particularlyquetiapine,olanzapine, andrisperidone, are used in the treatment of insomnia.[183][184] However, while common, the use of antipsychotics for this indication is not recommended as the evidence does not demonstrate a benefit, and the risk of adverse effects is significant.[183][185][186][187] A major 2022 systematic review and network meta-analysis of medications for insomnia in adults found that quetiapine did not demonstrate any short-term benefits for insomnia.[188] Some of the more serious adverse effects may also occur at the low doses used, such asdyslipidemia andneutropenia.[189][190] Such concerns of risks at low doses are supported by Danish observational studies that showed an association of use of low-dose quetiapine (excluding prescriptions filled for tablet strengths >50 mg) with an increased risk of major cardiovascular events as compared to use ofZ-drugs, with most of the risk being driven by cardiovascular death.[191] Laboratory data from an unpublished analysis of the same cohort also support the lack of dose-dependency of metabolic side effects, as new use of low-dose quetiapine was associated with a risk of increased fasting triglycerides at one-year follow-up.[192] Concerns regarding side effects are greater in the elderly.[193]
Gabapentinoids likegabapentin andpregabalin have sleep-promoting effects but are not commonly used for the treatment of insomnia.[194] Gabapentin is not effective in helping alcohol related insomnia.[195][196]
Barbiturates, while once used, are no longer recommended for insomnia due to the risk of addiction and other side effects.[197]
A survey of 1.1 million residents in the United States found that those who reported sleeping about 7 hours per night had the lowest rates of mortality, whereas those who slept for fewer than 6 hours or more than 8 hours had higher mortality rates. Severe insomnia – sleeping less than 3.5 hours in women and 4.5 hours in men – is associated with a 15% increase in mortality, while getting 8.5 or more hours of sleep per night was associated with a 15% higher mortality rate.[206]
With this technique, it is difficult to distinguish lack of sleep caused by a disorder, which is also a cause of premature death, versus a disorder which causes a lack of sleep, and the lack of sleep causing premature death. Most of the increase in mortality from severe insomnia was discounted after controlling forassociated disorders. After controlling for sleep duration and insomnia, the use of sleeping pills was also found to be associated with an increasedmortality rate.[206]
The lowest mortality was seen in individuals who slept between six and a half and seven and a half hours nightly. Even sleeping only 4.5 hours per night is associated with a very little increase in mortality. Thus, mild to moderate insomnia for most people is associated with increasedlongevity, and severe insomnia is associated only with a very small effect on mortality.[206] It is unclear why sleeping longer than 7.5 hours is associated with excess mortality.[206]
Between 10% and 30% of adults have insomnia at any given point in time and up to half of people have insomnia in a given year, making it the most common sleep disorder.[9][8][10][207] About 6% of people have insomnia that is not due to another problem and lasts for more than a month.[9] People over the age of 65 are affected more often than younger people.[7] Females are more often affected than males.[8] Insomnia is 40% more common in women than in men.[208]
Thepopular press have published stories about people who supposedly never sleep, such as that ofThái Ngọc andAl Herpin.[210] Horne writes "everybody sleeps and needs to do so", and generally this appears true. However, he also relates from contemporary accounts the case of Paul Kern, who was shot in 1915 fighting inWorld War I and then "never slept again" until he died in 1955.[211] Kern appears to be a completely isolated, unique case.
^Jiaxin Y, Xi F, Xiaoli L, Yamin L (2020). "Association of problematic smartphone use with poor sleep quality, depression, and anxiety: A systematic review and meta-analysis".Psychiatry Research.284. Elsevier: 112686.doi:10.1016/j.psychres.2019.112686.PMID31757638.S2CID207974088.
^Mac Cárthaigh S, Griffin C, Perry J (2020). "The relationship between sleep and problematic smartphone use among adolescents: A systematic review".Developmental Review.55. Elsevier: 100897.doi:10.1016/j.dr.2020.100897.S2CID213952365.
^Mallawaarachchi SR, Anglim J, Hooley M, Horwood S (2022). "Associations of smartphone and tablet use in early childhood with psychosocial, cognitive and sleep factors: a systematic review and meta-analysis".Early Childhood Research Quarterly.60. Elsevier:13–33.doi:10.1016/j.ecresq.2021.12.008.
^Zhang J, Zhang X, Zhang K, Lu X, Yuan G, Yang H, et al. (2022). "An updated of meta-analysis on the relationship between mobile phone addiction and sleep disorder".Journal of Affective Disorders.305. Elsevier:94–101.doi:10.1016/j.jad.2022.02.008.PMID35149136.S2CID246738576.
^Brautsch LA, Lund L, Andersen MM, Jennum PJ, Folker AP, Andersen S (2023). "Digital media use and sleep in late adolescence and young adulthood: A systematic review".Sleep Medicine Reviews.68. Elsevier: 101742.doi:10.1016/j.smrv.2022.101742.PMID36638702.
^Pagano M, Bacaro V, Crocetti E (2023). ""Using digital media or sleeping … that is the question". A meta-analysis on digital media use and unhealthy sleep in adolescence".Computers in Human Behavior.146. Elsevier: 107813.doi:10.1016/j.chb.2023.107813.hdl:11585/950006.
^"What causes insomnia?". National Heart, Lung, and Blood Institute.Archived from the original on 3 July 2013. Retrieved11 July 2013.
^abGeddes J, Price J, McKnight R, Gelder M, Mayou R (2012).Psychiatry (4th ed.). Oxford: Oxford University Press.ISBN978-0-19-923396-0.
^Bendz LM, Scates AC (January 2010). "Melatonin treatment for insomnia in pediatric patients with attention-deficit/hyperactivity disorder".The Annals of Pharmacotherapy.44 (1):185–91.doi:10.1345/aph.1M365.PMID20028959.S2CID207263711.
^Ouellet MC, Beaulieu-Bonneau S, Morin CM (2006). "Insomnia in patients with traumatic brain injury: frequency, characteristics, and risk factors".The Journal of Head Trauma Rehabilitation.21 (3):199–212.doi:10.1097/00001199-200605000-00001.PMID16717498.S2CID28255648.
^Palagini L, Biber K, Riemann D (June 2014). "The genetics of insomnia – evidence for epigenetic mechanisms?".Sleep Medicine Reviews.18 (3):225–35.doi:10.1016/j.smrv.2013.05.002.PMID23932332.
^Perry L (12 October 2004)."How Hangovers Work".HowStuffWorks. Archived fromthe original on 15 March 2010. Retrieved20 November 2011.
^"Information about caffeine dependence".Caffeinedependence.org. Johns Hopkins Medicine. 9 July 2003. Archived from the original on 23 May 2012. Retrieved25 May 2012.
^Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE (March 1999). "Actions of caffeine in the brain with special reference to factors that contribute to its widespread use".Pharmacological Reviews.51 (1):83–133.PMID10049999.
^Morin CM, Bélanger L, Bastien C, Vallières A (January 2005). "Long-term outcome after discontinuation of benzodiazepines for insomnia: a survival analysis of relapse".Behaviour Research and Therapy.43 (1):1–14.doi:10.1016/j.brat.2003.12.002.PMID15531349.
^Poyares D, Guilleminault C, Ohayon MM, Tufik S (1 June 2004). "Chronic benzodiazepine usage and withdrawal in insomnia patients".Journal of Psychiatric Research.38 (3):327–34.doi:10.1016/j.jpsychires.2003.10.003.PMID15003439.
^Asaad TA, Ghanem MH, Samee AM, El-Habiby MM (2011). "Sleep Profile in Patients with Chronic Opioid Abuse".Addictive Disorders & Their Treatment.10:21–28.doi:10.1097/ADT.0b013e3181fb2847.S2CID76376646.
^Lichstein KL, Taylor DJ, McCrae CS, Ruiter ME (November 2010). "Insomnia: epidemiology and risk factors.".Principles and Practice of Sleep Medicine (Fifth ed.). Elsevier Inc. pp. 827–837.doi:10.1016/B978-1-4160-6645-3.00076-1.
^Lord C, Sekerovic Z, Carrier J (October 2014). "Sleep regulation and sex hormones exposure in men and women across adulthood".Pathologie-Biologie.62 (5):302–10.doi:10.1016/j.patbio.2014.07.005.PMID25218407.
^Soldatos CR, Dikeos DG, Paparrigopoulos TJ (June 2000). "Athens Insomnia Scale: validation of an instrument based on ICD-10 criteria".Journal of Psychosomatic Research.48 (6):555–60.doi:10.1016/S0022-3999(00)00095-7.PMID11033374.
^abPassarella, S, Duong, M. "Diagnosis and treatment of insomnia." 2008.
^abcWilson SJ, Nutt DJ, Alford C, Argyropoulos SV, Baldwin DS, Bateson AN, et al. (November 2010). "British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders".Journal of Psychopharmacology.24 (11):1577–1601.doi:10.1177/0269881110379307.PMID20813762.S2CID16823040.
^"NIH State-of-the-Science Conference Statement on manifestations and management of chronic insomnia in adults".NIH Consensus and State-Of-The-Science Statements.22 (2):1–30. 2005.PMID17308547.
^Riemann D, Perlis ML (June 2009). "The treatments of chronic insomnia: a review of benzodiazepine receptor agonists and psychological and behavioral therapies".Sleep Medicine Reviews.13 (3):205–14.doi:10.1016/j.smrv.2008.06.001.PMID19201632.
^van Straten A, Cuijpers P (February 2009). "Self-help therapy for insomnia: a meta-analysis".Sleep Medicine Reviews.13 (1):61–71.doi:10.1016/j.smrv.2008.04.006.PMID18952469.
^Lande RG, Gragnani C (December 2010). "Nonpharmacologic approaches to the management of insomnia".The Journal of the American Osteopathic Association.110 (12):695–701.PMID21178150.
^Ellis J, Hampson SE, Cropley M (May 2002). "Sleep hygiene or compensatory sleep practices: An examination of behaviours affecting sleep in older adults".Psychology, Health & Medicine.7 (2):156–161.doi:10.1080/13548500120116094.S2CID143141307.
^ab"Insomnia".The Lecturio Medical Concept Library.Archived from the original on 2021-06-24. Retrieved2021-06-24.
^Krystal AD (August 2009). "A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for insomnia: the empirical basis for U.S. clinical practice".Sleep Medicine Reviews.13 (4):265–74.doi:10.1016/j.smrv.2008.08.001.PMID19153052.
^Edinger JD, Means MK (July 2005). "Cognitive-behavioral therapy for primary insomnia".Clinical Psychology Review.25 (5):539–58.doi:10.1016/j.cpr.2005.04.003.PMID15951083.
^abFox S, Fallows D (5 October 2005)."Digital Divisions".Internet health resources. Washington, DC: Pew Internet & American Life Project. Archived fromthe original on 21 October 2005.
^Marks IM, Cavanagh K, Gega L (2007).Hands-on Help: Computer-Aided Psychotherapy. Hove, England and New York: Psychology Press.ISBN978-1-84169-679-9.
^abRitterband LM, Gonder-Frederick LA, Cox DJ, Clifton AD, West RW, Borowitz SM (2003). "Internet interventions: In review, in use, and into the future".Professional Psychology: Research and Practice.34 (5):527–34.doi:10.1037/0735-7028.34.5.527.S2CID161666.
^Cheng SK, Dizon J (2012). "Computerised cognitive behavioural therapy for insomnia: a systematic review and meta-analysis".Psychotherapy and Psychosomatics.81 (4):206–16.doi:10.1159/000335379.PMID22585048.S2CID10527276.
^Charles J, Harrison C, Britt H (May 2009)."Insomnia"(PDF).Australian Family Physician.38 (5): 283.PMID19458795. Archived fromthe original(PDF) on 12 March 2011.
^Bertschy G, Ragama-Pardos E, Muscionico M, Aït-Ameur A, Roth L, Osiek C, et al. (January 2005). "Trazodone addition for insomnia in venlafaxine-treated, depressed inpatients: a semi-naturalistic study".Pharmacological Research.51 (1):79–84.doi:10.1016/j.phrs.2004.06.007.PMID15519538.
^Winokur A, DeMartinis NA, McNally DP, Gary EM, Cormier JL, Gary KA (October 2003). "Comparative effects of mirtazapine and fluoxetine on sleep physiology measures in patients with major depression and insomnia".The Journal of Clinical Psychiatry.64 (10):1224–29.doi:10.4088/JCP.v64n1013.PMID14658972.
^Schittecatte M, Dumont F, Machowski R, Cornil C, Lavergne F, Wilmotte J (2002). "Effects of mirtazapine on sleep polygraphic variables in major depression".Neuropsychobiology.46 (4):197–201.doi:10.1159/000067812.PMID12566938.S2CID25351993.
^Le Strat Y, Gorwood P (September 2008). "Agomelatine, an innovative pharmacological response to unmet needs".Journal of Psychopharmacology.22 (7 Suppl):4–8.doi:10.1177/0269881108092593.PMID18753276.S2CID29745284.
^"VALDOXAN® Product Information"(PDF).TGA eBusiness Services. Servier Laboratories Pty Ltd. 23 September 2013.Archived from the original on 24 March 2017. Retrieved14 October 2013.
^abcBrasure M, MacDonald R, Fuchs E, Olson CM, Carlyle M, Diem S, et al. (December 2015). "Management of Insomnia Disorder".AHRQ Comparative Effectiveness Reviews. Rockville (MD): Agency for Healthcare Research and Quality (US).PMID26844312.
^Lemoine P, Zisapel N (April 2012). "Prolonged-release formulation of melatonin (Circadin) for the treatment of insomnia".Expert Opinion on Pharmacotherapy.13 (6):895–905.doi:10.1517/14656566.2012.667076.PMID22429105.S2CID23291045.
^Lader M, Cardinali DP, Pandi-Perumal SR (2006).Sleep and sleep disorders: a neuropsychopharmacological approach. Georgetown, Tex.: Landes Bioscience/Eurekah.com. p. 127.ISBN978-0-387-27681-6.
^Authier N, Boucher A, Lamaison D, Llorca PM, Descotes J, Eschalier A (2009). "Second meeting of the French CEIP (Centres d'Evaluation et d'Information sur la Pharmacodépendance). Part II: benzodiazepine withdrawal".Therapie.64 (6):365–70.doi:10.2515/therapie/2009051.PMID20025839.
Maglione M, Maher AR, Hu J, Wang Z, Shanman R, Shekelle PG, et al. (Sep 2011). "Off-Label Use of Atypical Antipsychotics: An Update".AHRQ Comparative Effectiveness Reviews. Rockville (MD): Agency for Healthcare Research and Quality (US).PMID22132426.
Nasrallah HA (January 2008). "Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles".Molecular Psychiatry.13 (1):27–35.doi:10.1038/sj.mp.4002066.PMID17848919.S2CID205678886.
^Coe HV, Hong IS (May 2012). "Safety of low doses of quetiapine when used for insomnia".The Annals of Pharmacotherapy.46 (5):718–722.doi:10.1345/aph.1Q697.PMID22510671.S2CID9888209.
^Maglione M, Maher AR, Hu J, Wang Z, Shanman R, Shekelle PG, et al. (2011).Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Reviews, No. 43. Rockville: Agency for Healthcare Research and Quality.PMID22973576.
^abLeach MJ, Page AT (December 2015). "Herbal medicine for insomnia: A systematic review and meta-analysis".Sleep Med Rev.24:1–12.doi:10.1016/j.smrv.2014.12.003.PMID25644982.
^abKim J, Lee SL, Kang I, Song YA, Ma J, Hong YS, et al. (May 2018). "Natural Products from Single Plants as Sleep Aids: A Systematic Review".J Med Food.21 (5):433–444.doi:10.1089/jmf.2017.4064.PMID29356580.
^Bhagavan C, Kung S, Doppen M, John M, Vakalalabure I, Oldfield K, et al. (December 2020). "Cannabinoids in the Treatment of Insomnia Disorder: A Systematic Review and Meta-Analysis".CNS Drugs.34 (12):1217–1228.doi:10.1007/s40263-020-00773-x.PMID33244728.S2CID227174084.
^Suraev AS, Marshall NS, Vandrey R, McCartney D, Benson MJ, McGregor IS, et al. (October 2020). "Cannabinoid therapies in the management of sleep disorders: A systematic review of preclinical and clinical studies".Sleep Med Rev.53: 101339.doi:10.1016/j.smrv.2020.101339.PMID32603954.S2CID219452622.
^Gates PJ, Albertella L, Copeland J (December 2014). "The effects of cannabinoid administration on sleep: a systematic review of human studies".Sleep Med Rev.18 (6):477–87.doi:10.1016/j.smrv.2014.02.005.PMID24726015.
^Jiang XL, Zheng XY, Yang J, Ye CP, Chen YY, Zhang ZG, et al. (December 2015). "A systematic review of studies on the prevalence of insomnia in university students".Public Health.129 (12):1579–84.doi:10.1016/j.puhe.2015.07.030.PMID26298588.
