Nonprescription Agents

Nonprescription Agents

While the efficacy of behavioral treatments has been established, the evidence supporting the efficacy of popular nonprescription or nutritional supplements is limited. Despite the lack of safety and efficacy data, many patients with insomnia (up to 25%) use over-the-counter (OTC) agents. A list of common OTC treatments for insomnia is shown in Table 10-1.

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Antihistamines

Sedating antihistamines are used by some patients to self-medicate for insomnia because of their wide availability and relatively low cost. The primary active ingredient in OTC sleep aids is a first-generation H₁ antihistamine (diphenhydramine or doxylamine), which produces mild to moderate sedation and may improve sleep latency and continuity for some individuals. Diphenhydramine, the most commonly used agent, is well absorbed and is widely distributed throughout the body, including the CNS.

Despite its possible roles in sleep regulation, H₁ antihistamines are also associated with morning grogginess since they may have long durations of action. In the case of diphenhydramine, peak serum concentration is at about 8 hours and the elimination half-life is about 8 hours. Daytime sleepiness can lead to impairment of driving ability. Other potential side effects include delirium, especially in vulnerable individuals such as the elderly, urinary retention, constipation, dry mouth, blurry vision, orthostasis, CNS depression, paradoxic excitement and tachycardia. Because of these risks, antihistamines with anticholinergic effects should be avoided in individuals ≥65 years of age. In addition, problems with chronic use, such as the development of tolerance to sedative-hypnotic actions and weight gain are possible, although not well studied. 

Dietary Supplements and Herbal Agents

Although their use is not regulated by the FDA, dietary supplements and herbal remedies also enjoy extensive use for sleep disorders owing to a variety of factors, including their widespread availability, lack of prescription requirements, relatively low cost and the widespread belief that they are safe and have a relatively low abuse risk. These include, among others, melatonin, valerian, kava kava (Piper methysticum), chamomile, passiflora, avena sativa, hops and humulus lupulus. Melatonin, which has received the widest evaluations, is not regulated by the FDA yet may be effective in the treatment of delayed sleep phase disorder and shift work disorder.

Melatonin

Melatonin is a neurohormone secreted by the pineal gland (Figure 10-1) that plays a major role in regulating circadian rhythm. Its secretion increases at night and is diminished by exposure to light. As melatonin blood levels increase in the evening, there is a gradual decline in alertness and arousal in preparation for sleep. The circadian rhythm of melatonin release in the body is highly synchronized with habitual hours of sleep, as start of secretion is well correlated with onset of the steepest increase in nocturnal sleepiness. Melatonin is involved in the regulation of sleep and various circadian rhythms by binding to specific receptors (MT₁ and MT₂) in the suprachiasmatic nucleus, the brain’s “master clock.”

Following administration of exogenous melatonin as a dietary supplement, it is rapidly absorbed, with peak levels occurring in <30 minutes. It has an elimination half-life of 40 to 50 minutes. Oral doses of 1 to 5 mg result in serum melatonin concentrations that are 10 to 100 times higher than the usual nighttime peak within 1 hour after ingestion, followed by a decline to baseline values in 4 to 8 hours.

The circadian rhythm changing (chronobiotic) effects of melatonin may be useful in subjects suffering from circadian rhythm sleep disorders such as DSPD and SWSD.

As noted above, melatonin may also have direct effects on sleep itself, yet there is a lack of consistency concerning its therapeutic value in treating insomnia. A 2020 umbrella review of 18 meta-analyses and systematic reviews found a modest but statistically significant improvement in sleep latency and total sleep time. Questions have also been raised regarding purity and composition of melatonin preparations.

Valerian

Valerian extract, derived from the root of Valeriana officinalis, a perennial that grows wildly in temperate areas of the Americas and Europe, has long been advocated and used for promoting sleep but until relatively recently, evidence for its efficacy and safety has been solely anecdotal. Valerian is used as a sedative and anxiolytic and is commonly available as an aqueous, alcohol, or dilute alcohol extract. However, the extraction method can strongly influence the active components in a formulation. These components include sesquiterpenes (volatile oil components that account for valerian’s unpleasant odor), valepotriates and amino acids (such as GABA and glutamine). The valepotriates, for example, are not present in aqueous extracts, are most common in dilute alcohol extracts and tend to have a more prominent anxiolytic rather than sleep-inducing effect.

Although its soporific mechanism of action is unknown, an in vitro study showed that valerian and valerenic acid are selective agonists of the dopamine 5-HT_5a receptor. However, preparations containing valerian often also contain multiple herbs that are touted to help in sleep. Therefore, interactions between these plant extracts, and/or their synergistic effects, may also play a role.

The typical recommended dose is 400 to 900 mg V officinalis root, 30 to 60 minutes before bedtime. However, data regarding efficacy are mixed. For example, Bent and colleagues analyzed the results of 16 randomized, controlled trials of valerian extract and found the results to be contradictory due to the inconsistency between trials in terms of patients, experimental design and procedures and methodologic quality. A 2015 systematic review and meta-analysis and systematic review of available evidence for herbal medicine in insomnia found no significant difference between valerian preparations and placebo in efficacy (sleep onset latency, sleep duration, sleep efficiency, and WASO), and an increase in adverse event rates.

Thus, the efficacy of valerian still needs to be determined; similarly, safety data are also limited. Side effects are thought to be generally mild, consisting mostly of gastrointestinal irritation and headaches. There have also been case reports of hepatotoxicity in persons taking herbal products containing valerian. The treatment duration depends on the specific symptoms of sleep disorder and herbalists recommend a 2- to 3-week break after a 4- to 6-week period of valerian treatment.

Other Herbs and Supplements

L-tryptophan is an essential amino acid that is a biochemical precursor to serotonin, and is thought to function by increasing serotonin in certain brain cells, thus inducing sleep. It has been reported to reduce sleep latency by increasing subjective “sleepiness” and also decreasing waking time. Systematic evidence supporting the use of L-tryptophan, an endogenous amino acid available in a variety of dietary supplements, in the treatment of insomnia is very limited and based on studies in small numbers of patients. In 1989, L-tryptophan was associated with cases of eosinophilic myalgia syndrome, attributed to contamination linked with bacterial fermentation methods used in processing. Consequently, L-tryptophan was recalled in the United States, and is now only available by prescription. 5-hydroxytryptophan (5-HTP) is an intermediate metabolite of L-tryptophan in the serotonin pathway, and is currently being used as a sleep aid, to treat depression, and as a weight loss tool.

Kava kava, derived from the root of a plant endogenous to the western Pacific (P methysticum), has long been used as a hypnotic and anxiolytic. Although it appears to have rapid pharmacological properties in animal models, there have been few clinical trials of kava kava. The 2015 systematic review and meta-analysis mentioned in the Valerian subsection above found no increased efficacy of kava compared to placebo. Reports of serious hepatotoxicity with this preparation have resulted in its being banned in many countries, and the issuance of a Consumer Advisory from the FDA in 2002. Several European countries have restricted the sale of kava-containing products based on incidences of adverse hepatic events. Given the potential for severe toxicity, kava-containing products should not be recommended to patients with pre-existing liver disease or who are at risk for liver injury.

Chamomile has been used traditionally as a sedative, although no data are available regarding its efficacy and safety in any disorder. There are two types of chamomile plants used in herbal preparations, German chamomile (Matricaria recutita) used for restlessness and insomnia and Roman chamomile (Chamaemelum nobile) used orally for a variety of digestive, menstrual and nasal-oral mucosal symptoms and topically for eczema, wounds and inflammation. The sedative effects of German chamomile may be due to the flavonoid, apigenin, that binds to benzodiazepine receptors in the brain. When used orally as highly concentrated tea, chamomile can induce vomiting.

Despite the common use of chamomile to improve sleep, there is limited clinical evidence of its sedative effect. Studies have observed few significant differences in the effects of chamomile on sleep architecture when compared to placebo, such as changes in total sleep time (TST), sleep efficiency, sleep latency, WASO, sleep quality and number of awakenings. However, chamomile did show modest advantage on daytime functioning and mixed benefits on sleep diary measures relative to placebo in adults with chronic primary insomnia. No significant effect of chamomile on insomnia treatment outcomes was found in the 2015 systematic review-and meta-analysis of herbal remedies mentioned above.

Other herbs, such as hops, California poppy, scullcap and lemon balm, have been used for their sedative effects, but have not been scrutinized in detail in the literature for efficacy and safety.

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Summary

In summary, dietary supplements and herbal remedies have shown potential to be used as over-the-counter treatments for sleep disturbances. However, these treatments suffer from a number of drawbacks, including their lack of strict regulation by the FDA, the paucity of studies of their efficacy and side effects, the lack of definitive data regarding optimal dosages, the unknown potential for interactions with other medications and questions regarding the purity of preparations.