The most commonly used class of hypnotics for insomnia are the benzodiazepines. Benzodiazepines are not significantly better for insomnia than antidepressants. Chronic users of hypnotic medications for insomnia do not have better sleep than chronic insomniacs not taking medications. In fact, chronic users of hypnotic medications have more regular nighttime awakenings than insomniacs not taking hypnotic medications. Many have concluded that these drugs cause an unjustifiable risk to the individual and to public 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. 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 of nonbenzodiazepines.

The benzodiazepine and nonbenzodiazepine hypnotic medications also have a number of side-effects such as day time fatigue, motor vehicle crashes and other accidents, cognitive impairments and falls and fractures. Elderly people are more sensitive to these side-effects. Some benzodiazepines have demonstrated effectiveness in sleep maintenance in the short term but in the longer term benzodiazepines can lead to tolerance, physical dependence, benzodiazepine withdrawal syndrome upon discontinuation, and long-term worsening of sleep, especially after consistent usage over long periods of time. Benzodiazepines, while inducing unconsciousness, actually worsen sleep as—like alcohol—they promote light sleep while decreasing time spent in deep sleep. A further problem is, with regular use of short-acting sleep aids for insomnia, daytime rebound anxiety can emerge. 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. 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 the long-term use of benzodiazepines and is recommended whenever possible.

Benzodiazepines all bind unselectively to the GABA receptor. Some theorize that certain benzodiazepines (hypnotic benzodiazepines) have significantly higher activity at the α subunit of the GABA receptor compared to other benzodiazepines (for example, triazolam and temazepam have significantly higher activity at the α subunit compared to alprazolam and diazepam, making them superior sedative-hypnotics – alprazolam and diazepam, in turn, have higher activity at the α subunit compared to triazolam and temazepam, making them superior anxiolytic agents). Modulation of the α subunit is associated with sedation, motor impairment, respiratory depression, amnesia, ataxia, and reinforcing behavior (drug-seeking behavior). Modulation of the α subunit is associated with anxiolytic activity and disinhibition. For this reason, certain benzodiazepines may be better suited to treat insomnia than others.

Drugs that may prove more effective and safer than benzodiazepines for insomnia is an area of active research. Nonbenzodiazepine sedative-hypnotic drugs, such as zolpidem (Ambien), zaleplon, zopiclone (Imovane), and eszopiclone (Lunesta), 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.

Suvorexant is FDA approved for insomnia, characterized by difficulties with sleep onset and/or sleep maintenance.

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.

Behavioral treatment can be effective in some cases. Sedative hypnotics may also help relieve the symptoms. Additionally, education about normal patterns of the sleep-wake cycle may alleviate anxiety in some patients. For patients with severe depression resulting from the fear of having insomnia, electroconvulsive therapy appears to be a safe and effective treatment.

In the 1980s and 1990s, several trials of melatonin administration to totally blind individuals without light perception produced improvement in sleep patterns, but it was unclear at that time if the benefits were due to entrainment from light cues. Then, using endogenous melatonin as a marker for circadian rhythms, several research groups showed that appropriately timed melatonin administration could entrain free-running rhythms in the totally blind. For example, Sack et al. found that 6 out of 7 patients treated with 10 mg melatonin at bedtime were normally entrained. When the dose was gradually reduced to 0.5 mg in three of the subjects, entrainment persisted. Subsequently, it was shown that treatment initiated with the 0.5 mg dose produced entrainment. One subject who failed to entrain at a higher dose was successfully entrained at a lower dose. A low dose produces melatonin blood levels that are similar to the concentrations naturally produced by nightly pineal secretion.

Products containing melatonin are available as dietary supplements in the United States and Canada, available over the counter. These "supplements" do not require FDA approval. As prescription drugs may be prescribed off-label, treatment recommendations for non-24 in the blind may vary.

There has been a constant growth in the field of melatonin and melatonin receptor agonists since the 1980s. In 2005 Ramelteon (Rozerem) was the first melatonin agonist to be approved in the United States (US), indicated for insomnia treatment in adults. Melatonin in the form of prolonged release (trade name Circadin) was approved in 2007 in Europe (EU) for use as a short-term treatment, in patients 55 years and older, for primary insomnia. Tasimelteon (trade name Hetlioz) received FDA-approval in January 2014 for persons diagnosed with non-24. TIK-301 (Tikvah Therapeutics, Atlanta, USA) has been in phase II clinical trial in the United States since 2002 and the FDA granted it orphan drug designation in May 2004, for use as a treatment for circadian rhythm sleep disorder in blind individuals without light perception as well as individuals with tardive dyskinesia.

Caffeine is the most widely used alerting drug in the world and has been shown to improve alertness in simulated night work. Caffeine and naps before a night shift reduces sleepiness during the shift. Modafinil and armodafinil are non-amphetamine alerting drugs originally developed for the treatment of narcolepsy that have been approved by the FDA (the US Food and Drug Administration) for excessive sleepiness associated with SWSD.

Enforcing a 24-hour sleep–wake schedule using alarm clocks or family interventions is often tried but usually unsuccessful. Bright light exposure on awakening to counteract the tendency for circadian rhythms to delay, similar to the treatment for delayed sleep phase disorder, and seasonal affective disorder (SAD) has been found to be effective in some cases, as has melatonin administration in the subjective late afternoon or evening. Light therapy involves at least 20 minutes of exposure to 3000 to 10000 lux light intensity. Going outside on a bright sunny day can accomplish the same benefit as special light fixtures (light boxes). Bright light therapy combined with the use of melatonin as a chronobiotic and avoidance of light before bedtime may be the most effective treatment. Melatonin administration shifts circadian rhythms according to a phase response curve (PRC) that is essentially the inverse of the light PRC. When taken in the late afternoon or evening, it resets the clock earlier; when taken in the morning, it shifts the clock later. Therefore, successful entrainment depends on the appropriate timing of melatonin administration. The accuracy needed for successfully timing the administration of melatonin requires a period of trial and error, as does the dosage. In addition to natural fluctuations within the circadian rhythm, seasonal changes including temperature, hours of daylight, light intensity and diet are likely to affect the efficacy of melatonin and light therapies since these exogenous zeitgebers would compete for hormonal homoeostasis. Further to this there are unforeseen disruptions to contend with even when a stabilised cycle is achieved; such as travel, exercise, stress, alcohol or even the use of light emitting technology close to a subjective evening/night.

Hypnotics and/or stimulants (to promote sleep and wakefulness, respectively) have sometimes been used. Typically a sleep diary is requested to aid in evaluation of treatment, though the emergence of modern actigraphy devices can also assist in the logging of sleep data. Additionally, graphs can now be generated using mobile phone applications, utilising internal accelerometers which are present in most smartphones in use today. The graphs and basic sleep diary records can be shared with a physician. However, due to the lack of clinical accuracy they should not be used for diagnosis, but instead to monitor the cycle and general progress of any medications in use.

The condition may worsen as a result of persistent attempts to treat the symptoms through conventional methods of dealing with insomnia. The prescription of hypnotics or stimulants may lead to drug dependency as a complication.

Nonetheless, chronic SSM may increase risk for depression, anxiety, and substance abuse. It has also been noted that patients with this condition may sometimes opt to take medications over other treatments "for the wrong reasons (e.g. because of euphoriant properties)."

In late 1983, Italian neurologist/sleep expert Dr. Ignazio Roiter received a patient at the University of Bologna hospital's sleep institute. The man, known only as Silvano, decided in a rare moment of consciousness to be recorded for future studies and to donate his brain for research in hopes of finding a cure for future victims. As of 2017, no cure or treatment has yet been found for FFI. Gene therapy has been thus far unsuccessful. While it is not currently possible to reverse the underlying illness, there is some evidence that treatments that focus solely upon the symptoms may improve quality of life.

It has been proven that sleeping pills and barbiturates are unhelpful; on the contrary, in 74% of cases, they have been shown to worsen the clinical manifestations and hasten the course of the disease.

One of the most notable cases is that of Michael (Michel A.) Corke, a music teacher from New Lenox, Illinois (born in Watseka, Illinois). He began to have trouble sleeping before his 40th birthday in 1991; following these first signs of insomnia, his health and state of mind quickly deteriorated as his condition worsened. Eventually, sleep became completely unattainable, and he was soon admitted to University of Chicago Hospital with a misdiagnosis of clinical depression due to multiple sclerosis. Medical professionals Dr. Raymond Roos and Dr. Anthony Reder, at first unsure of the nature of his illness, initially diagnosed multiple sclerosis; in a bid to provide temporary relief in the later stages of the disease, physicians attempted to induce a coma with the use of sedatives, to no avail as his brain still failed to shut down completely. Corke died in 1993, a month after his 42nd birthday, by which time he had been completely sleep-deprived for six months.

One person was able to exceed the average survival time by nearly one year with various strategies, including vitamin therapy and meditation, using different stimulants and hypnotics, and even complete sensory deprivation in an attempt to induce sleep at night and increase alertness during the day. He managed to write a book and drive hundreds of miles in this time but nonetheless, over the course of his trials, the person succumbed to the classic four-stage progression of the illness.

In the late 2000s, a mouse model was made for FFI. These mice expressed a humanized version of the PrP protein that also contains the D178N FFI mutation. These mice appear to have progressively fewer and shorter periods of uninterrupted sleep, damage in the thalamus, and early deaths, similar to humans with FFI.

As of 2016, studies are investigating whether doxycycline may be able to slow or even prevent the development of the disease.

Melatonin is a hormone secreted by the pineal gland in darkness, normally at night. Its production is suppressed by light exposure, principally blue light around 460 to 480 nm. Light restriction, or dark therapy, in the hours before bedtime allows its production. Dark therapy does not require total darkness. Amber or orange colored goggles eliminate blue light to the eyes while allowing vision.

Melatonin is also available as an oral supplement. In the US and Canada, the hormone melatonin is not classified as a drug; it is sold as a dietary supplement. In other countries it requires a prescription or is unavailable. Although it is not licensed by the FDA as a treatment for any disorder, there have been no serious side effects or complications reported to date.

Melatonin has been shown to accelerate the adaptation of the circadian system to a nighttime work schedule. Melatonin may benefit daytime sleep in night workers by an additional direct sleep promoting mechanism. Melatonin treatment may increase sleep length during both daytime and nighttime sleep in night shift workers.

Middle-of-the-night insomnia is often treated with medication, although currently Intermezzo (zolpidem tartrate sublingual tablets) is the only Food and Drug Administration-approved medication specifically for treating MOTN awakening. Because most medications usually require 6–8 hours of sleep to avoid lingering effects the next day, these are often used every night at bedtime to prevent awakenings. Medication may not be prescribed in some cases, especially if the cause turns out to be the patient ingesting too much fluid during the day or just before they go to sleep.

Sleep restriction therapy and stimulus control therapy as described in insomnia have shown significance in treating middle of night insomnia.

Some studies have shown that zaleplon, which has a short elimination half-life, may be suitable for middle-of-the-night administration because it does not impair next day performance.

Research suggests that hypnosis may be helpful in alleviating some types and manifestations of sleep disorders in some patients. "Acute and chronic insomnia often respond to relaxation and hypnotherapy approaches, along with sleep hygiene instructions." Hypnotherapy has also helped with nightmares and sleep terrors. There are several reports of successful use of hypnotherapy for parasomnias specifically for head and body rocking, bedwetting and sleepwalking.

Hypnotherapy has been studied in the treatment of sleep disorders in both adults and children.

A review of the evidence in 2012 concluded that current research is not rigorous enough to make recommendations around the use of acupuncture for insomnia. The pooled results of two trials on acupuncture showed a moderate likelihood that there may be some improvement to sleep quality for individuals with a diagnosis insomnia. This form of treatment for sleep disorders is generally studied in adults, rather than children. Further research would be needed to study the effects of acupuncture on sleep disorders in children.

Treatment for irregular sleep–wake rhythm tries to enable the body clock in the brain, such that a normal long sleep period at night can be achieved. Education about sleep hygiene is important, and counseling can be helpful. Melatonin, vitamin B, sleep aids, wake aids, and other medications may also be used. Light during the daytime, and activities occurring at regular times each day, may help to restore a normal rhythm.

Because there are different systems in the body that help establish regulation, it's helpful to employ a multi-modal approach. A 2008 review states that "...each clock is differentially sensitive to zeitgebers. The suprachiasmatic nucleus (SCN) is very responsive to light, the clock in the liver is very sensitive to food, and clocks in muscle are sensitive to exercise."

The following approaches are recommended by one source:

1. Spend <7–8 hours in bed.

2. Add environmental cues such as light and social interactions, regular meal times, and regular sleep–wake times.

3. Morning and eve light at 3000 lux for 2 hours have been shown to improve nocturnal sleep in institutionalized patients and reduce agitation in demented patients.

4. Melatonin at desired sleep time.

In general, there are two broad classes of treatment, and the two may be combined: psychological (cognitive-behavioral) and pharmacological. In situations of acute distress such as a grief reaction, pharmacologic measures may be most appropriate. With primary insomnia, however, initial efforts should be psychologically based, including discussion of good sleep hygiene. Other specific treatments are appropriate for some of the disorders, such as ingestion of the hormone melatonin, correctly timed bright light therapy and correctly timed dark therapy or light restriction for the circadian rhythm sleep disorders. Specialists in sleep medicine are trained to diagnose and treat these disorders, though many specialize in just some of them.

For those patients who have not been able to stop this disorder on their own, doctors have been working to discover a treatment that will work for everyone. One treatment that Schenck and Mahowald studied consisted of psychotherapy combined with "environmental manipulation". This was usually done separately from the weight-reducing diets. However, during this study only 10 percent of the patients were able to lose more than one third of their initial excess weight, which was not a viable percentage. In addition, they reported that many of the patients experienced "major depression" and "severe anxiety" during the attempted treatments. This was not one of the most successful attempts to help those with NSRED.

However, Dr. R. Auger reported on another trial treatment where patients were treated utilizing pramipexole. Those conducting the treatment noticed how the nocturnal median motor activity was decreased, as was assessed by actigraphy, and individual progress of sleep quality was reported. Nevertheless, Augur also said, "27 percent of subjects had RLS (restless legs syndrome, a condition known to respond to this medication), and number and duration of waking episodes related to eating behaviors were unchanged." Encouraged by the positive response verified in the above-mentioned trial treatment, doctors and psychiatrists conducted a more recent study described by Auger as "efficacy of topiramate [an antiepileptic drug associated with weight loss] in 17 consecutive patients with NSRED." Out of the 65 percent of patients who continued to take the medication on a regular basis, all confirmed either considerable development or absolute remission of "night-eating" in addition to "significant weight loss" being achieved. This has been one of the most effective treatments discovered so far, but many patients still suffered from NSRED. Therefore, other treatments were sought after.

Such treatments include those targeted to associated sleep disorders with the hope that it would play an essential part of the treatment process of NSRED. In Schenck and Mahowald's series, combinations of cardibopa/L-dopa, codeine, and clonazepam were used to treat five patients with RLS and one patient with somnambulism and PLMS (periodic limb movements in sleep). These patients all were suffering from NSRED as well as these other disorders, and they all experienced a remission of their NSRED as a result of taking these drugs. Two patients with OSA (obstructive sleep apnea) and NSRED also reported as having a "resolution of their symptoms with nasal continuous positive airway pressure (nCPAP) therapy." Clonazepam monotherapy was also found to be successful in 50 percent of patients with simultaneous somnambulism. Interestingly, dopaminergic agents such as monotherapy were effective in 25 percent of the NSRED subgroup. Success with combinations of dopaminergic and opioid drugs, with the occasional addition of sedatives, also was found in seven patients without associated sleep disorders. In those for whom opioids and sedatives are relatively contraindicated (e.g., in those with histories of substance abuse), two case reports were described as meeting with success with a combination of bupropion, levodopa, and trazodone. Notably, hypnotherapy, psychotherapy, and various behavioral techniques, including environmental manipulation, were not effective on the majority of the patients studied. Nevertheless, Auger argue that behavioral strategies should complement the overall treatment plan and should include deliberate placement of food to avoid indiscriminate wandering, maintenance of a safe sleep environment, and education regarding proper sleep hygiene and stress management. Even with their extensive studies, Schenck and Mahowald did not find the success as Auger found by treating his patients with topiramate.

There is currently a great deal of active research on various aspects of circadian rhythm; this often occurs at major universities in conjunction with sleep research clinics at major hospitals. An example is the program with Harvard Medical School and Brigham and Women's Hospital. This research includes programs that are staffed by researchers from various departments at the university, including psychiatry, neurology, chemistry, biology. Other major sleep research centers are in Tel Aviv in Israel, Munich in Germany and in Japan.

A wide variety of sleep disorders are actively being researched. Measuring body temperature or melatonin levels may be used. Some hospitals do blood tests for melatonin levels. Saliva tests for melatonin are now available for online purchase; its metabolites can also be tested in urine.

Although "there has been no cure of chronic hypersomnia", there are several treatments that may improve patients' quality of life, depending on the specific cause or causes of hypersomnia that are diagnosed.

Positive airway pressure therapy is similar to that in obstructive sleep apnea and works by stenting the airway open with pressure, thus reducing the airway resistance. Use of a CPAP mask can help ease the symptoms of UARS. Therapeutic trials have shown that using a CPAP mask with pressure between four and eight centimeters of water can help to reduce the number of arousals and improve sleepiness. CPAP masks are the most promising treatment for UARS, but effectiveness is reduced by low patient compliance.

Oral appliances to protrude the tongue and lower jaw forward have been used to reduce sleep apnea and snoring, and hold potential for treating UARS, but this approach remains controversial. Oral appliances may be a suitable alternative for patients who cannot tolerate CPAP.

In most of the reported cases, the treatment options were very similar. Plasmapheresis alone or in combination with steroids, sometimes also with thymectomy and azathioprine, have been the most frequently used therapeutic approach in treating Morvan’s Syndrome. However, this does not always work, as failed response to steroids and to subsequently added plasmapheresis have been reported. Intravenous immunoglobulin was effective in one case.

In one case, the dramatic response to high-dose oral prednisolone together with pulse methylprednisolone with almost complete disappearance of the symptoms within a short period should induce consideration of corticosteroids.

In another case, the subject was treated with haloperidol (6 mg/day) with some improvement in the psychomotor agitation and hallucinations, but even high doses of carbamazepine given to the subject failed to improve the spontaneous muscle activity. Plasma Exchange (PE) was initiated, and after the third such session, the itching, sweating, mental disturbances, and complex nocturnal behavior improved and these symptoms completely disappeared after the sixth session, with improvement in insomnia and reduced muscle twitching. However, one month after the sixth PE session, there was a progressive worsening of insomnia and diurnal drowsiness, which promptly disappeared after another two PE sessions.

In one case there high dose steroid treatment resulted in a transient improvement, but aggressive immuno-suppressive therapy with cyclophosphamide was necessary to control the disease and result in a dramatic clinical improvement.

In another case, the subject was treated with prednisolone (1 mg/kg body weight) with carbamazepine, propanolol, and amitriptyline. After two weeks, improvement with decreased stiffness and spontaneous muscle activity and improved sleep was observed. After another 7–10 days, the abnormal sleep behavior disappeared completely.

In another case, symptomatic improvement with plasmapheresis, thymectomy, and chronic immunosuppression provide further support for an autoimmune or paraneoplastic basis.

Although thymectomy is believed to be a key element in the proposed treatment, there is a reported case of Morvan’s Syndrome presenting itself post-thymectomy.

Seizures in Dravet syndrome can be difficult to manage but may be reduced by anticonvulsant medications such as clobazam, stiripentol, topiramate and valproate. Because the course of the disorder varies from individual to individual, treatment protocols may vary. A diet high in fats and low in carbohydrates may also be beneficial, known as a ketogenic diet. Although diet adjustment can help, it does not eliminate the symptoms. Until a better form of treatment or cure is discovered, those with this disease will have myoclonic epilepsy for the rest of their lives.

Certain anticonvulsant drugs that are classed as Sodium Channel Blockers are now known to make seizures worse in most Dravet patients. These drugs include carbamazepine, gabapentin, lamotrigine, and phenytoin.

Treatments include cognitive rehabilitation through psychomotor and speech therapy. In addition, valproate is often administered to prevent recurrence of febrile seizures and benzodiazapine is used for long lasting seizures, but these treatments are usually insufficient.

Stiripentol was the only drug for which a double-blind placebo trial was performed and this drug showed efficacy in trials. It acts as a GABAergic agent and as a positive allosteric modulator of GABA receptor. Stiripentol, can improve focal refractory epilepsy, as well as Dravet's syndrome, supplemented with clobazam and valproate was approved in Europe in 2007 as a therapy for Dravet syndrome and has been found to reduce overall seizure rate by 70%. In cases with more drug resistant seizures, topiramate and the ketogenic diet are used as alternative treatments.

Cannabidiol (CBD) has received orphan drug status in the United States, for treatment of Dravet syndrome which will allow it to be studied.

In general, alcohol abusers with withdrawal symptoms, such as alcoholic hallucinosis, have a deficiency of several vitamins and minerals and their bodies could cope with the withdrawal easier by taking nutritional supplements. Alcohol abuse can create a deficiency of thiamine, magnesium, zinc, folate and phosphate as well as cause low blood sugar. However, several tested drugs have shown the disappearance of hallucinations. Neuroleptics and benzodiazepines showed normalization. Common benzodiazepines are chlordiazepoxide and lorazepam. It has been shown that management has been effective with a combination of abstinence from alcohol and the use of neuroleptics. It is also possible to treat withdrawal before major symptoms start to happen in the body. Diazepam and chlordiazepoxide have proven to be effective in treating alcohol withdrawal symptoms such as alcoholic halluciniosis. With the help of these specific medications, the process of withdrawal is easier to go through, making alcoholic hallucinosis less likely to occur.

The medication that may be prescribed to someone who has a mental breakdown is based upon the underlying causes, which are sometimes more serious mental disorders. Antidepressants are given to treat depression. Anxiolytics are used for those with anxiety disorders. Antipsychotics are used for schizophrenia and mood stabilizers help with bipolar disorder. Depending upon what caused a person’s mental breakdown, any of these treatments can be helpful for them.

There are several different kinds of therapy that a patient can receive. The most common type of therapy is counseling. This is where the patient is able to talk about whatever is on their mind without worrying about any judgments. Psychotherapy is a very common type of therapy that addresses the current problems in someone’s life and helps them to deal with them. Past experiences may also be explored in this type of therapy. In psychoanalysis therapy, the main focus is a patient’s past experiences so that they can confront these issues and prevent breakdowns in the future. Cognitive behavioral therapy explores how a person behaves and what they are thinking and feeling. If there is anything negative in these three different categories, then this therapy will try to turn them around into positives. Hypnotherapy is where hypnosis is performed and used to help the patient relax. Hypnosis can also be used to figure out why a person acts or feels a certain way, by examining past events that may have caused the breakdown. Expressive therapy focuses on how the patient is able to express their feelings. If the patient has a hard time doing this, expression through the arts is highly recommended. There is also aromatherapy, which consists of herbs to help the patient relax and to try to relieve stress. Yoga and massage may also be included in this therapy that will help the muscles to relax. Meditation is also often recommended. All of these therapies help a person to relax and de-stress and also help to prevent future breakdowns.

Clonidine may be used in combination with benzodiazepines to help some of the symptoms. There is insufficient evidence to support the use of baclofen for alcohol withdrawal syndrome.

Antipsychotics, such as haloperidol, are sometimes used in addition to benzodiazepines to control agitation or psychosis. Antipsychotics may potentially worsen alcohol withdrawal as they lower the seizure threshold. Clozapine, olanzapine, or low-potency phenothiazines (such as chlorpromazine) are particularly risky; if used, extreme caution is required.

While intravenous ethanol could theoretically be used, evidence to support this use, at least in those who are very sick, is insufficient.

Secondary hypersomnias are extremely numerous.

Hypersomnia can be secondary to disorders such as clinical depression, multiple sclerosis, encephalitis, epilepsy, or obesity. Hypersomnia can also be a symptom of other sleep disorders, like sleep apnea. It may occur as an adverse effect of taking certain medications, of withdrawal from some medications, or of drug or alcohol abuse. A genetic predisposition may also be a factor. In some cases it results from a physical problem, such as a tumor, head trauma, or dysfunction of the autonomic or central nervous system.

Sleep apnea is the most frequent cause of secondary hypersomnia, affecting up to 4% of middle-aged adults, mostly men. Upper airway resistance syndrome (UARS) is a clinical variant of sleep apnea that can also cause hypersomnia. Just as other sleep disorders (like narcolepsy) can coexist with sleep apnea, the same is true for UARS. There are many cases of UARS in which EDS persists after CPAP treatment, indicating an additional cause, or causes, of the hypersomnia and requiring further evaluation.

Sleep movement disorders, such as restless legs syndrome (RLS) and periodic limb movement disorder (PLMD or PLMS) can also cause secondary hypersomnia. Although RLS does commonly cause EDS, PLMS does not. There is no evidence that PLMS plays "a role in the etiology of daytime sleepiness. In fact, two studies showed no correlation between PLMS and objective measures of EDS. In addition, EDS in these patients is best treated with psychostimulants and not with dopaminergic agents known to suppress PLMS."

Neuromuscular diseases and spinal cord diseases often lead to sleep disturbances due to respiratory dysfunction causing sleep apnea, and they may also cause insomnia related to pain. "Other sleep alterations, such as periodic limb movement disorders in patients with spinal cord disease, have also been uncovered with the widespread use of polysomnography."

Primary hypersomnia in diabetes, hepatic encephalopathy, and acromegaly is rarely reported, but these medical conditions may also be associated with the secondary hypersomnias sleep apnea and periodic limb movement disorder (PLMD).

Chronic fatigue syndrome and fibromyalgia can also be associated with hypersomnia. Regarding chronic fatigue syndrome, it is "characterized by persistent or relapsing fatigue that does not resolve with sleep or rest. Polysomnography shows reduced sleep efficiency and may include alpha intrusion into sleep EEG. It is likely that a number of cases labeled as chronic fatigue syndrome are unrecognized cases of upper airway resistance syndrome" or other sleep disorders, such as narcolepsy, sleep apnea, PLMD, etc.

Similarly to chronic fatigue syndrome, fibromyalgia also may be associated with anomalous alpha wave activity (typically associated with arousal states) during NREM sleep. Also, researchers have shown that disrupting stage IV sleep consistently in young, healthy subjects causes a significant increase in muscle tenderness similar to that experienced in "neurasthenic musculoskeletal pain syndrome". This pain resolved when the subjects were able to resume their normal sleep patterns.

Chronic kidney disease is commonly associated with sleep symptoms and excessive daytime sleepiness. For those on dialysis, approximately 80% have sleep disturbances. Sleep apnea can occur 10 times as often in uremic patients than in the general population and can affect up to 30-80% of patients on dialysis, though nighttime dialysis can improve this. About 50% of dialysis patients have hypersomnia, as severe kidney disease can cause uremic encephalopathy, increased sleep-inducing cytokines, and impaired sleep efficiency. About 70% of dialysis patients are affected by insomnia, and RLS and PLMD affect 30%, though these may improve after dialysis or kidney transplant.

Most forms of cancer and their therapies can cause fatigue and disturbed sleep, affecting 25-99% of patients and often lasting for years after treatment completion. "Insomnia is common and a predictor of fatigue in cancer patients, and polysomnography demonstrates reduced sleep efficiency, prolonged initial sleep latency, and increased wake time during the night." Paraneoplastic syndromes can also cause insomnia, hypersomnia, and parasomnias.

Autoimmune diseases, especially lupus and rheumatoid arthritis are often associated with hypersomnia, as well. Morvan's syndrome is an example of a more rare autoimmune illness that can also lead to hypersomnia. Celiac disease is another autoimmune disease associated with poor sleep quality (which may lead to hypersomnia), "not only at diagnosis but also during treatment with a gluten-free diet." There are also some case reports of central hypersomnia in celiac disease. And RLS "has been shown to be frequent in celiac disease," presumably due to its associated iron deficiency.

Hypothyroidism and iron deficiency with or without (iron-deficiency anemia) can also cause secondary hypersomnia. Various tests for these disorders are done so they can be treated. Hypersomnia can also develop within months after viral infections such as Whipple's disease, mononucleosis, HIV, and Guillain–Barré syndrome.

Behaviorally induced insufficient sleep syndrome must also be considered in the differential diagnosis of secondary hypersomnia. This disorder occurs in individuals who fail to get sufficient sleep for at least three months. In this case, the patient has chronic sleep deprivation although he or she is not necessarily aware of it. This situation is becoming more prevalent in western society due to the modern demands and expectations placed upon the individual.

Many medications can also lead to secondary hypersomnia. Therefore, a patient's complete medication list should be carefully reviewed for sleepiness or fatigue as side effects. In these cases, careful withdrawal from the possibly offending medication(s) is needed; then, medication substitution can be undertaken.

Mood disorders, like depression, anxiety disorder and bipolar disorder, can also be associated with hypersomnia. The complaint of EDS in these conditions is often associated with poor sleep at night. "In that sense, insomnia and EDS are frequently associated, especially in cases of depression." Hypersomnia in mood disorders seems to be primarily related to "lack of interest and decreased energy inherent in the depressed condition rather than an increase in sleep or REM sleep propensity". In all cases with these mood disorders, the MSLT is normal (not too short and no SOREMPs).