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CPRC non Rx treatment insomnia.qxp 4/8/2005 4:17 PM Page 173 Oral Nonprescription Treatment for Insomnia: An Evaluation of Products With Clinical Practice Review Committee, American Academy of Sleep Medicine Amy Lynn Meoli, M.D.1; Carol Rosen, M.D.2; David Kristo, M.D.3; Michael Kohrman, M.D.4; Nalaka Gooneratne, M.D.5; Robert Neal Aguillard, M.D.6; Robert Fayle, M.D.7; Robert Troell, M.D.8; Don Townsend, Ph.D.9; David Claman, M.D.10; Timothy Hoban, M.D.11; Mark Mahowald, M.D.12 1St. John's Regional Medical Center, Joplin, MO; 2Rainbow Babies and Children's Hospital, Department of Pediatrics, Case Western Reserve University, Cleveland, OH; 3Walter Reed Army Medical Center, Pulmonology/Critical Care, Washington, DC; 4University of Chicago, PediatricNeurology, Chicago, IL; 5University of Pennsylvania, Ralston House/Institute on Aging, Philadelphia, PA; 6Methodist Hospital, Methodist SleepDisorders Center, Memphis, TN; 7University of Texas Medical School, Houston, TX; 8Summerlin Medical Towers, Las Vegas, NV; 9Metropolitan Sleep Disorders Center, St. Paul, MN; 10UCSF—Mt. Zion Hospital, San Francisco, CA; 11University of Michigan Department of Pediatrics, Ann Arbor, MI; 12Hennepin County Medical Center, Minneapolis, MN Purpose: To evaluate the level of evidence regarding the safety and effica-
a beneficial effect were not found for the majority of herbal supplements, cy of nonprescription therapies used for insomnia. dietary changes, and other nutritional supplements popularly used for treat- Reviewers: Members of the American Academy of Sleep Medicine's
ing insomnia symptoms. Nevertheless, such treatments are described as Clinical Practice Review Committee. alternative remedies for insomnia. Studies are limited by small numbers of Methods: A search of the World Wide Web was conducted using the terms
participants and, in some instances, inadequate design, lack of statistical insomnia, herbal remedies, and alternative treatments to develop a list of thera- analysis, and sparse use of objective measurements. Sparse or no scientif- pies. Therapies in this review include passionflower, valerian, Jamaican dog- ic data were found to support the efficacy of most products as hypnotics, wood, hops, California poppy, chamomile, lemon balm, St. John's wort, kava including chamomile and St. John's wort. There is preliminary but conflicting kava, wild lettuce, scullcap, Patrinia root, first-generation histamine-1-receptor evidence suggesting Valerian officinalis L. and first-generation histamine-1- antagonists, alcohol, calcium, vitamin A, nicotinamide, magnesium, vitamin B12, receptor antagonists have efficacy as mild hypnotics over short-term use.
l-tryptophan, 5-hydroxytryptophan, dietary changes, Natrum muriaticum, and There are significant potential risks associated with the use of Jamaican Yoku-kan-san-ka-chimpi-hange. A search of the PubMed database was con- dogwood, kava kava, alcohol, and l-tryptophan. Physicians may find this ducted in October 2002 using MeSH terms insomnia and each product listed in information useful in counseling their patients. this paper, including only articles published in English between 1980 and 2002.
Key Words: Herbal sedatives, dietary supplements, hypnotics and seda-
Additional relevant articles from reference lists were also reviewed. Given the tives, herbal medicine, sleep disorders, insomnia.
paucity of pediatric publications, this age group was excluded from this review.
Citation: Meoli AL; Rosen C; Kristo D et al. Oral nonprescription treatment
Results and Conclusions: Although randomized, placebo-controlled stud-
for insomnia: an evalutation of products with limited evidence. J Clin Sleep ies were available for a few compounds, rigorous scientific data supporting The treatment of primary insomnia may include cognitive- Further, if these treatments are ineffective or harmful, the costs of behavioral therapies, sometimes in association with judicious treating a disease may increase. The assumption that nutritional use of hypnotic agents. While the efficacy of behavioral treatments supplements are inherently safe is dangerous. There are several is well established,1-5 the evidence supporting popular nonpre- examples of lethal toxicity associated with some products.10-13 scription or nutritional supplements has received less attention.6 Prescription drugs are subject to significant control of the manu- Expenditures on alternative medical therapies are substantial.7-9 facturing process, so that the active component is standardizedbetween different drug preparations. In contrast, nutritional sup-plements are not regulated, so efficacy with 1 specific product may not be generalized to other commercially available products pur- Dr. Rosen was the medical director for a centralized pediatric PSG and actigra- porting to be the same compound. For some products, the active phy reading center for a phase I study looking at pediatric labeling for a pre- component may not be known. This article provides a review of scription hypnotic medication; has received research support from Sanofi- most of the available scientific data on the safety and efficacy of Synthelabo. Dr. Townsend has received research support from Medtronic. Dr.
nonprescription therapies popularly used to treat insomnia symp- Meoli has participated in speaking engagements supported by Sanofi- toms. (NOTE: Melatonin, marketed as a nutritional supplement, Synthelabo. Dr. Fayle has received honoraria from Cephalon, Orphan, andNovartis. Drs. Aguillard, Hoban, Gooneratne, Claman, Troell, Kristo, Kohrman, has undergone extensive evaluation as to its hypnotic properties and Mahowald have indicated no financial conflicts of interest. and circadian-shifting effects and is not included in this review.) Submitted for publication July 2004
Accepted for publication July 2004

Address correspondence to: Amy Meoli, M.D., St. John's Regional MedicalCenter, 2727 McClelland Boulevard, Joplin, MO 64804; Tel: (417) 659-6807; Fax: A search of the World Wide Web was conducted using the (417) 659-6806; E-mail: terms insomnia, herbal remedies, and alternative treatments. A Journal of Clinical Sleep Medicine, Vol. 1, No. 2, 2005 CPRC non Rx treatment insomnia.qxp 4/8/2005 4:17 PM Page 174 AL Meoli, C Rosen, D Kristo et al list of nutritional supplements, dietary changes, and nonprescrip- 30 days, although oxazepam had a more-rapid onset of anxiolyt- tion medications that were listed by more than one Web site is ic effect.15 No scientific studies regarding efficacy for insomnia included in the review (see Table 1). Medications, such as anal- were found. Safety is also not well established, based on the gesics, that are not approved by the Federal Drug Administration reviewed literature. A case of a woman suffering prolonged QT (FDA) for use as nonprescription hypnotics or listed by public- interval and nonsustained ventricular tachycardia after ingestion oriented Web sites were not included. Literature searches of passionflower has been reported.16 (PubMed) limited to English language from 1980 to 2002 wereconducted for each list item. Additional relevant articles from ref- erence lists were also reviewed. Members of the Clinical PracticeReview Committee, an American Academy of Sleep Medicine Mechanism of Action committee comprising a multidisciplinary group of clinicians, Valerian is derived from plants of the species Valeriana, most extracted the data from the search results. Given the limited num- commonly V. officinalis L. It is used as a sedative and anxiolytic ber of publications for each therapy, studies were reviewed in addition to having purported uses in other conditions. It can be regardless of scientific caliber. In the case of first-generation his- marketed in powdered form, but it is most commonly sold as an tamine-1 (H1)-receptor antagonists, studies of antihistamines aqueous, alcohol, or dilute alcohol extract. However, the extrac- unavailable in the United States market were included because of tion method can strongly influence the active components in a the potential similarities in mechanism of action. Given the particular formulation. These components can be divided into the paucity of pediatric publications, this age group was excluded following categories: sesquiterpenes (volatile oil components that from this review. A consensus of committee members was used account for valerian's unpleasant odor), valepotriates, and amino to formulate the conclusions.
acids (such as GABA and glutamine). The valepotriates, forexample, are not present in aqueous extracts, are most common in dilute alcohol extracts, and tend to have a more prominent anxi- olytic than sleep-inducing effect.17 Because they degrade quickly,they are usually present in dry formulations. Most likely, the The aerial parts of passionflower are cultivated and used for its effects of valerian are due to the individual effects of each of these sedative and anxiolytic effects. The main components of pas- constituents on different pathways, along with possible interac- sionflower are flavonoids, indole alkaloids, maltol, ethyl-maltol, tions among them. This was extensively reviewed by Houghton.17 and cyanogenic glycosides. A dose-dependent sedative effect of Recent in vitro research suggests that an additional mechanism of an aqueous extract has been found in mice.14 A double-blind ran- action may be related to binding at A1 adenosine receptors.18 domized trial of passionflower and oxazepam in 36 patients withgeneralized anxiety disorder showed no significant difference in Efficacy and Safety Hamilton Anxiety Rating Scale between treatment groups after Several studies have examined the effects of valerian on sleep, many of which have used a randomized placebo-controlled Table 1—Oral Nonprescription Treatments for Insomnia Included
design. Only placebo-controlled studies will be included in this discussion because of the more extensive literature base. Most studies have administered valerian 30 to 60 minutes before bed- Passionflower (3.1) time at doses ranging from 400 to 900 mg. An aqueous extract of valerian, comprised predominantly of sesquiterpenes and without Jamaican dogwood (3.3) valepotriates, was given to 18 subjects without sleep disturbances in a randomized, crossover, double-blind, placebo-controlled California poppy (3.5) trial.19 Eight of these subjects had attended polysomnographic studies and received placebo or valerian 900 mg for 1 night; 10 had wrist-activity measured at home and received placebo, vale- St. John's wort (3.8) rian 450 mg, or valerian 900 mg over 2 nights. During the labo- Kava kava (3.9)Wild lettuce (3.10) ratory study, when treatment response on 3 nights of placebo was compared to 1 night of valerian 900 mg, polysomnographic-mea- Patrinia root (3.12) sured latency to stage 2 sleep was reduced from an average of First-generation histamine-1-receptor antagonists (4.0) 25.4 minutes to 19.2 minutes and wakefulness after sleep onset decreased from an average of 29.6 minutes to 19.0 minutes.
Vitamins and supplements (6.0) These findings were not statistically significant, possibly due to the small sample size. During the home study, subjective sleep latency and wake time after sleep onset significantly improved in Nicotinamide (6.3) a dose-dependent manner when comparing valerian doses of 450 Magnesium (6.4)Vitamin B12 (6.5) and 900 mg (P < .05). However, subjective sleep quality did not Tryptophans (6.6) change, and objective measures, such as wrist activity, were less Dietary changes (7.0) conclusive. Subjects had a statistically significant increase in Miscellaneous (8.0) nighttime activity in the middle third of the night when they usedvalerian 900 mg, relative to placebo, but decreased nighttime *Section numbers are in parentheses activity in the latter third of the night. A significant limitation of Journal of Clinical Sleep Medicine, Vol. 1, No. 2, 2005 CPRC non Rx treatment insomnia.qxp 4/8/2005 4:17 PM Page 175 Oral Nonprescription Treatment for Insomnia the study was the use of valerian for only 1 or 2 study nights in a using a visual analogue scale were 7.4 ± 0.9 on valerian com- study population without sleep problems. A second study that pared to 5.4 ± 0.8 on placebo (P < .001). While the placebo group compared valerian aqueous extract (450-mg and 900-mg doses) had a significant decrease in objective sleep latency from base- and placebo in 8 insomniacs using objective measures (wrist line to posttreatment, the valerian group had a slight increase in actigraphy) found that 450 mg of valerian significantly reduced sleep latency after treatment. Wakefulness after sleep onset, how- sleep latency (from 15.8 ± 5.8 minutes to 9.0 ± 3.9 minutes, P < ever, decreased in the valerian group while it increased in the .01).20 In contrast to the prior study, an increased dose of 900 mg placebo group such that the overall sleep efficiency remained had no additional benefit. In addition, the 900-mg dose was asso- similar in both groups after treatment. The authors postulated that ciated with a statistically significant increase in subjective morn- the decreased wakefulness after sleep onset explained the ing sleepiness, a possible "hangover" effect.
improved subjective interpretation of sleep with valerian, despite The effects of 1 night of valerian in comparison to a 14-day reg- the increased sleep latency.
imen were assessed by Donath et al21 using polysomnographic Another placebo-controlled study, using polysomnography, measures in a randomized, double-blind, placebo-controlled trial sought to further clarify the role of valerian in older adults with in 16 insomniacs using 600 mg of valerian-root extract. A single sleep problems.26 Eight elderly insomniacs were randomly assigned dose of valerian had no significant effects on subjective or objec- to receive valerian and were compared to 6 elderly insomniacs tive measures of sleep. However, a 14-day course was associated given placebo in a parallel-group design. Subjects took valerian with the following significant changes (P < .05): a shorter subjec- (450 mg) or placebo 1 hour before bedtime on study day 1, and on tive sleep latency (60 minutes with placebo vs 45 minutes with study days 2 through 8, they took valerian or placebo 3 times daily valerian) and a shorter objective latency to slow-wave sleep rela- with meals but not at bedtime. When compared to pretreatment tive to placebo (21.3 minutes with placebo vs 13.5 minutes with baseline, subjects on valerian had no significant change in sleep valerian). There were no significant changes in subjective sleep efficiency but did have an increased slow-wave sleep time (7.7% quality and no changes in other objective parameters such as sleep compared to 12.5%, P = .027), a finding similar to that noted by efficiency (88.4% with placebo vs 89.6% with valerian). While Donath et al,21 and an increased total sleep time (319 minutes com- slow-wave sleep time increased with valerian relative to baseline pared to 370 minutes, P = .039). However, when valerian treatment values (8.1% to 9.8%), slow-wave sleep time also increased with was compared directly to placebo, there were no differences in placebo (8.1% to 9.2%), and there was no statistically significant these or other polysomnographic parameters and there was no difference between valerian and placebo in this regard.22 change in self-reported sleep quality and day or evening alertness.26 The largest study (n = 128) of valerian found in the English lit- This study is limited by its small sample size and the fact that sev- erature evaluated the effects of 400 mg of aqueous valerian eral essential sleep parameters, such as sleep latency, were not sim- extract on self-rated "good sleepers" (52%) and "poor sleepers" ilar between the subjects randomly assigned to placebo or valerian.
(48%) in a randomized, double-blinded, placebo-controlled An additional special population studied with valerian was that crossover design.23 Statistically significant improvements in sub- of children with intellectual deficits (IQ < 70) and sleep distur- jective sleep latency (22% on placebo vs 36% on valerian) and bances.27 Five children were studied in a randomized, double- sleep quality (28% on placebo vs 41% on valerian) were found (P blind, placebo-controlled trial relying on the parents' report of < .05). In subgroup analysis, the population that reported the their children's sleep. There were statistically significant improve- largest improvement (63%) in sleep quality was older adult poor ments in time spent awake, total sleep time, and sleep quality with sleepers. However, 43% reported subjective improvement with valerian at a dose of 20 mg/kg. The greatest benefit was noted dur- placebo, and the difference was not statistically significant. In ing the second week of treatment. While promising, the lack of young poor sleepers, there was a statistically significant improve- physiologic measurements limits the clinical utility of this study.
ment with valerian treatment (45% reported better sleep with These and other studies have found that valerian has a rela- valerian vs 16% with placebo; P < .01). There was no significant tively benign side-effect profile. Rarely reported side effects are difference in subjective daytime sleepiness between placebo and gastrointestinal upset, contact allergies, headache, restless sleep, valerian. This study is limited by the lack of objective measure- and mydriasis.28 Although one study reported increased subjec- ment of sleep parameters. tive morning sedation after ingesting 900 mg of valerian the prior Lindahl and Lindwall24 studied valerian (400 mg, predomi- evening,20 a randomized double-blind, placebo-controlled, paral- nantly sesquiterpenes) in 27 insomniacs using a double-blind, lel-group study in 99 subjects specifically designed to identify crossover design. Subjective sleep quality improved in 78% after "hangover" cognitive/vigilance effects found no difference 1 night of valerian treatment, which was greater than that report- between evening placebo and valerian 600 mg.29 Valepotriates ed with placebo (P < .001). The study is limited, however, by the also have the potential to alkylate DNA, thus raising the concern short duration of treatment, limited sample, and lack of objective that they may have cytotoxic and carcinogenic potential.17 For this reason, valerian is not recommended for use during pregnan- Alternative sleep-related uses for valerian have also been cy.30 One case report of a postoperative patient who had been tak- explored. Poyares et al25 considered the possible role of valerian ing high doses of valerian, 530 mg to 2.0 grams per dose up to 5 as a method to facilitate benzodiazepine withdrawal. In a double- times daily for several years, cited valerian withdrawal symptoms blind study of 19 chronic benzodiazepine users, subjects were characterized by delirium and high-output cardiac failure.
asked to taper their benzodiazepines while being randomly Symptoms improved with benzodiazepine treatment.31 In one assigned to receive either a placebo or valerian compound (pre- study of 23 overdose cases with a valerian-containing compound dominantly valepotriates, 100 mg 3 times daily). Sleep patterns, (dose range 0.5-12 g), the main side effects noted were drowsi- after a course of either placebo or valerian, were also compared ness or confusion, which may have been in part due to the anti- to those of healthy controls. Subjective reports of sleep quality cholinergic properties of the other components of the product.32 Journal of Clinical Sleep Medicine, Vol. 1, No. 2, 2005 CPRC non Rx treatment insomnia.qxp 4/8/2005 4:17 PM Page 176 AL Meoli, C Rosen, D Kristo et al Of note, no patients developed hepatotoxicity; another study in Lemon balm is a perennial herb alleged to have efficacy as a which 4 cases reported hepatotoxicity from valerian may have hypnotic. A randomized, double-blind, crossover study of lemon had scullcap-induced hepatotoxicity.33 Valerian may potentiate balm versus placebo evaluated the effect on cognitive perfor- sedative effects when taken concomitantly with other central ner- mance. The highest dosage of lemon balm (900 mg) was associ- vous system depressants.30 ated with decreased subjective alertness assessed by a visual ana-log scale.40 No studies on its efficacy and safety in the treatment of insomnia were found. The use of Jamaican dogwood has been associated with a sedative St. John's Wort
effect in animals, but, according to Jellin et al,34 there are no scien-tific studies demonstrating this effect in humans. More importantly, Mechanism of Action it is toxic to humans and is no longer available in many areas.34 St. John's wort is a flowering herb used orally for a variety of ail- ments, such as depression, anxiety, and sleep disturbances.
Preparations may include naphthodianthrones (hypericin, pseudohy- Common hops are used orally for insomnia, although no scien- pericin, isohypericin), flavonoids (kaempferol, hyperoside, tific evidence was found to support their efficacy in humans. A quercetin), phloroglucinols (hyperforin, adhyperforin), tannins, pro- sedative effect was shown in rats related to the constituent 2-methyl- cyanidins, essential oils, amino acids, and other components.41, 42 3 butene-2-ol.35 There is no scientific literature evaluating safety. The most active components are thought to be hyperforin and hyper-icin, although other components have bioactivity. Different formu- lations of St. John's wort vary in their levels of these con-stituents,43 although many commercial preparations are standard- The family Papaveraceae includes more than 100 species of ized as to the hypericin content. Hypericin was previously thought poppy. California poppy has been used for sedation but should to be the active ingredient. Early work suggested hypericin acted not be confused with the Oriental poppy (P. somniferum), which via monoamine oxidase inhibition,44 the significance of which is a source of crude opium and alkaloids, including morphine, was discounted by later studies.45-48 More recent attention has heroin, and codeine. No published English literature regarding been focused on the role of hyperforin. Hyperforin inhibits the safety or efficacy of California poppy was found. reuptake of serotonin, norepinephrine, dopamine, GABA, and L-glutamate.49-52 However, the exact mechanism of action of St.
John's wort is unknown. It is possible that other components, Mechanism of Action either in isolation or combination, also contribute to effects.51 There are 2 types of chamomile plants used in herbal prepara- Efficacy and Safety tions, German chamomile (Matricaria recutita) used for restless-ness and insomnia and Roman chamomile (Chamaemelum Most clinical studies of St. John's wort that were reviewed nobile) used orally for a variety of digestive, menstrual, and focused on treatment of depression rather than insomnia. Several nasal-oral mucosal symptoms and topically for eczema, wounds, studies have found St. John's wort to be more effective in short- and inflammation. Sedative effects of German chamomile may term treatment of mild or moderate depression than placebo and be due to the benzodiazepine-like compound in the flowerhead.6 to have similar efficacy as some tricyclic antidepressants53-57 orselective serotonin reuptake inhibitors.58-60 However, these find- Efficacy and Safety ings should be viewed with caution because patient groups wereheterogeneous, extracts varied in their constituents, and the doses Although chamomile tea has a popular reputation as a relaxing of comparison antidepressants were frequently low.
tea that facilitates sleep, clinical studies are lacking. German No published scientific studies of St. John's wort for insomnia chamomile is thought to possess multiple actions, including mild not associated with depression were found. However, limited data sedative properties.36 on the effects of St. John's wort on sleep were located. A double- Chamomile, when used orally as highly concentrated tea, can blind, placebo-controlled, polysomnographic study of 11 young induce vomiting.37 Chamomile can also cause an allergic reaction healthy subjects free of mood or sleep disturbances assessed the in individuals sensitive to the Asteraceae/Compositae family that effect of St. John's wort on sleep (age range 20-44 years). A dose includes ragweed, chrysanthemums, marigolds, daisies, and other of 0.9 mg was found to significantly increase rapid eye movement herbs. Theoretically, German chamomile may interact with antico- (REM) sleep latency versus placebo (84 vs 69 minutes, respective- agulant and antiplatelet drugs, benzodiazepines, or other drugs ly, P = .03).61 A second group of 10 different subjects was studied with sedative properties and may inhibit cytochrome P (CYP) in similar fashion, though using a higher dose of St. John's wort 450.36,38 Therefore, patients taking other drugs metabolized by this (1.8 mg). Mean REM latency in this group was not significantly enzyme system (eg, lovastatin, ketoconazole, itraconazole, fexofe- increased in the active-treatment group versus placebo (104 vs 64 nadine, triazolam, and a number of others) should use caution or minutes, respectively, P = .15).61 No other effect on sleep architec- avoid German chamomile. There are no known interactions with ture, including REM sleep duration, was found, but details were foods, laboratory tests, or specific diseases or conditions.39 not included. Another placebo-controlled, double-blind, random-ized crossover study of 11 older female volunteers (mean age 59.8 Lemon Balm
± 4.8 years) analyzed the effects on sleep electroencephalogram.62There was an increase in slow-wave activity in 10 of 11 subjects Journal of Clinical Sleep Medicine, Vol. 1, No. 2, 2005 CPRC non Rx treatment insomnia.qxp 4/8/2005 4:17 PM Page 177 Oral Nonprescription Treatment for Insomnia taking St. John's wort and 5 of 11 taking placebo. Statistical sig- the FDA issued an advisory for consumers and health-care nificance was not given. Median percentage of slow-wave sleep providers about the potential risk of hepatotoxicity associated increased from 1.5% to 6.0% during active-treatment phase, while with the use of kava-containing products.88 The CDC issued the values decreased during placebo treatment from 4.1% to 2.5%.
results of its investigation in the United States of the cases of Notably, the baseline amount of slow-wave sleep was much lower liver failure associated with kava-containing dietary supplements in the active-treatment group. No other changes were noted in and summarized the European cases.89 Several European coun- sleep duration or architecture, including REM-sleep variables. It is tries have restricted the sale of kava-containing products based unknown if the demonstrated changes in sleep architecture were on the occurrence of adverse hepatic events. Given the potential associated with clinical improvement in insomnia. Moreover, the for severe toxicity, especially in persons with pre-existing liver studies used healthy volunteers, and the results cannot be general- disease or who are at risk for liver injury, recommendation of ized to persons with insomnia symptoms. The studies cited used kava-containing products for insomnia should be avoided.
specially formulated extracts of St. John's wort, and it is unknownwhat effect would occur with commercially available products.
Wild Lettuce
Also, the constituents and method of extraction varied from studyto study, hampering the generalization of results. Wild lettuce has been used orally for insomnia, although its Side effects associated with St. John's wort during clinical trials efficacy has not been established. Caution should be used included gastrointestinal complaints, dizziness, fatigue, anxiety, because a hallucinogenic effect has been reported when the sub- and headaches.41,42,49,56,59,60,63 In an observational study of 3250 stance is inhaled. Jellin et al reported 3 cases who experienced a patients using a commercially available preparation of St. John's febrile reaction associated with headache, nausea, abdominal wort, gastrointestinal symptoms, allergic reactions, tiredness, anx- pain and transaminase elevation after intravenous injection.90 iety, and confusion were most often reported.64 Photosensitivity However, the possibility that the reaction was related to contam- and phototoxicity have been reported.65-67 inates in the injectate could not be excluded.91 St. John's wort has potentially severe drug interactions. In vivo studies have shown that St. John's wort induces CYP450, includ- ing isoenzyme CYP3A4.68-73 Many drugs on the market are metab- Scullcap has been used for insomnia, but efficacy has never olized by CYP3A4; thus, drug interactions are frequent. The com- been shown, based on the literature obtained for this paper. Oral ponent probably most responsible for CYP3A4 induction is hyper- use of scullcap in larger doses may cause seizure activity.90 forin.74 One potential problem in predicting interactions is related Additionally, several cases of hepatotoxicity have been reported, to the fact that most commercially available St. John's wort is stan- though it is not known whether this was due to scullcap or anoth- dardized for hypericin content. St. John's wort also induces intesti- er constituent.33,90 nal P-glycoprotein levels.73,75 The most significant interactionspotentially involve patients with cardiovascular disease, HIV, can- cer, and depression. Serum digoxin levels are reduced by 18% to25%,73,76,77 a mechanism that could account for potential interac- Patrinia Scabiosaefolia Fisch is a member of the Valerianaceae tions with calcium channel blockers, lidocaine, quinidine, war- family, which includes Valerian officinalis L. (Valerian root). An farin, and amiodarone.78 Absorption of indinavir, a nonnucleoside unblinded, uncontrolled observational study of Patrinia root in reverse-transcriptase inhibitor, is reduced.77 Serum cyclosporine patients with neurasthenic syndromes predominated by insomnia levels are reduced, and cases of acute organ rejection have been found statistically significant decreases in insomnia symptoms reported after kidney, heart, and liver transplants.70,72,79-82 Levels of after 10 to 14 days of treatment with various Patrinia formula- amitriptyline and its metabolite nortriptyline are reduced.83 Cases tions.92 Marked improvement was defined as "definite" improve- of serotonin syndrome have been reported in patients taking con- ment or disappearance of symptoms. Improvement was defined as comitant sertraline, nefazodone, or paroxetine.84,85 This may be any reduction in symptoms. The method of symptom rating was related to the serotonin-promoting effects of St. John's wort, and not given. A 20% extract of Patrinia, which contained 10% to 15% St. John's wort should not be used in combination with selective alcohol, reduced insomnia symptoms in 91.9% of 62 patients, with serotonin reuptake inhibitors. Breakthrough menstrual bleeding marked improvement in 30.6%. A tablet containing a dry extract of has occurred in a few women on oral contraceptives, possibly relat- the root reduced insomnia in 80.0% of 284 patients, with marked ed to increased CYP induction and reduced hormone levels.86 improvement in 33.5%. Finally, a capsule containing a volatile oilof Patrinia root reduced symptoms in 81.7% of 60 patients, with Kava Kava
marked improvement in 50.0%. All formulations were associatedwith adverse effects, most frequently nausea. However, the method Kava kava is an herbal product derived from Piper methys- of adverse event documentation was not given. ticum, a shrub indigenous to the South Pacific. In the UnitedStates, kava-containing products are sold as dietary supplements and marketed for the treatment of anxiety, occasional insomnia,premenstrual syndrome, and stress. These supplements are often Mechanism of Action
in the form of raw plant material or concentrated extracts. Since1999, health-care professionals in Europe and the United States The FDA has limited the active ingredients in over-the-counter have reported the occurrence of severe hepatotoxicity (including sleep aids to diphenhydramine hydrochloride, diphenhydramine liver failure requiring liver transplantation) associated with the citrate, and doxylamine succinate,93 which are in the consumption of products containing kava.87 On March 25, 2002, ethanolamine class of H1-receptor antagonists.94 Older prepara- Journal of Clinical Sleep Medicine, Vol. 1, No. 2, 2005 CPRC non Rx treatment insomnia.qxp 4/8/2005 4:17 PM Page 178 AL Meoli, C Rosen, D Kristo et al tions containing methapyrilene alone or in combination with Treatment P (NS) regarded the medication as effective as a sleep scopolamine have been taken off the market due to safety con- aid. Using a visual analog scale of treatment efficacy from 0 ("no cerns. Histamine is a wake-promoting neurotransmitter, and inac- effect") to 5 ("terrific"), mean response scores were 3.12 for tivation or suppression in various animal models has led to seda- Treatment E and 2.00 for Treatment P (P = .001). It is unknown tion and disrupted wakefulness patterns.95 Several reviews have what contribution the analgesic additives played in a potential summarized the sedative effects of first-generation H1-antago- sedative effect. The effect of methapyrilene HCL (50 mg) com- nists in humans.96-100 In a study of 16 healthy volunteers, signifi- bined with scopolamine (0.5 mg) was compared to placebo in five cant increases in daytime sleepiness, measured by Multiple Sleep male subjects (24-25 years of age) undergoing in-laboratory noc- Latency Tests, occurred with the use of diphenhydramine (50 mg turnal sleep monitoring.105 Subjects received placebo (baseline) 3 times daily) versus placebo (6.7 ± 2.6 vs 10.3 ± 3.3; P < .02).101 for three nights followed by active treatment for three nights andtwo placebo (withdrawal) nights. All subjects had a history of Efficacy and Safety
moderate to severe insomnia, characterized by sleep-initiation dif-ficulty in one, sleep-maintenance difficulty in one, and both Observational data from a drug-surveillance program at three symptoms in three. There was little difference in group mean and urban hospitals were used to evaluate the efficacy of the four individual sleep latencies between placebo and drug nights. The most commonly prescribed hypnotics: chloral hydrate, diphenhy- method of statistical analysis and P values were not given.
dramine hydrochloride, secobarbital, and pentobarbital.102 Of Additionally, no significant reduction in wake time was found.
4177 consecutive patients monitored, 2405 (58%) received one The percentage of REM sleep was less during the first active- or more of these drugs during a single hospital admission. The treatment night (20.4%) than baseline placebo night (23.3%). The length of neither individual nor average hospitalization was next 2 drug nights were similar to baseline (23.1% and 22.8%), as given. Diphenhydramine was given to 512 patients, although 213 were the withdrawal nights (24.3% and 24.0%). These results (42%) also received one or more of the other hypnotics. Dosages were not statistically significant.
used were 100 mg (n = 46), 50 mg (n = 440), 25 mg (n = 24) and In one study, no significant difference in total hourly observa- other (n = 2). Physician ratings of efficacy were good in 259 tional wake versus sleep readings were found between placebo (50.6%), fair in 42 (8.2%), poor in 54 (10.5%), and undetermined and diphenhydramine hydrochloride (25 mg) in geriatric insom- in 157 (30.7%). The potential additive effect of other hypnotic niac subjects (mean age 77 years, range 58-92).106 Significant agents was not explored. Subjective reports of sleep quality, sleep improvement occurred with the use of Mandrax (250 mg latency, and sleep duration were significantly better with pento- methaqualone base and 25 mg diphenhydramine); chloral barbital (180 mg) than with 2 doses of diphenhydramine (50 and hydrate, 600 mg; and methaqualone base, 250 mg. Each treat- 150 mg) in male subjects in 2 urban Veterans Administration hos- ment was given for one week without a washout period between.
pitals, although the study was associated with a high rate of pro- Subjects were in either a residential (n = 10) or psychiatric sec- tocol incompletion.103 tion (n = 15) of an elder care facility. All subjects suffered from There are several randomized, placebo-controlled studies of the psychiatric disturbances or "chronic brain syndrome." The fre- hypnotic effects of centrally acting antihistamines. Some of the quent concomitant use of hypnotics, neuroleptics, or antidepres- antihistamines discussed are no longer sold as over-the-counter sants could have also affected study results. sleep aids. Methapyrilene fumarate was used in a randomized, The use of diphenhydramine (50 mg) was studied in a double- double-blind, placebo-controlled trial of postpartum patients.104 blind, placebo-controlled, crossover design in 111 patients, 15 of Interviews conducted the following morning were used in 2 phas- whom were eventually excluded because of protocol violations.107 es of the trial and self-completed questionnaires in a third.
Each treatment leg lasted one week. All patients (mean age 45 ± 13 Interviews were conducted with 142 subjects who received either years) complained of sleep-initiation difficulty. The majority of 50 mg of methapyrilene and 975 mg aspirin (n = 47, Treatment C), patients were women (78%), white (73%), married (58%), and 42 mg methapyrilene and 925 mg acetaminophen (n = 46, high-school graduates (72%). Based on self-completed, daily, Treatment D), or placebo (n = 49, Treatment P). The method of sleep-log responses, diphenhydramine was significantly more dosage selection was not given. Of 9 questions asked regarding effective than placebo in improving all sleep parameters, including pain relief and sleep quality, seven were answered by the patient sleep latency (P < .010), frequency of awakenings (P < .01), wake and two by the treating nurse. Treatment C was significantly more time (P < .001), sleep duration (P < .001), and quality of sleep (P likely than Treatment P (P = .001) and Treatment D (P = .01) to < .001). Physician ratings of efficacy at the end of each treatment be rated as helpful in falling asleep, whereas there was no signif- week were similar to patient responses. Upon study completion, 57 icant difference between Treatments D and P. Nurses' evaluation of the 96 patients preferred diphenhydramine, whereas 21 pre- of hypnotic efficacy was significantly greater with Treatment C (P ferred placebo (P < .001), and 18 had no preference. Doxylamine = .001) and D (P = .02) than with Treatment P, although C was succinate (25 mg) was studied with the same study protocol.108 Of more effective than D (P = .01). A second study phase including 111 insomniacs enrolled, 83 (mean age 46 ± 14 years) completed 111 postpartum subjects similarly assessed the efficacy of 50 mg the study, and 27 did not because of protocol violations or early of methapyrilene fumarate, 390 mg of aspirin, 260 mg of salicy- dropout. Patients also tended to be women (88%), white (88%), lamide, and 325 mg of acetaminophen (n = 55, Treatment E) ver- and high-school graduates (55%). Patient ratings were significant- sus placebo (n = 56, Treatment P). Both subjects and nurses rated ly more positive for doxylamine with regard to sleep latency (P < Treatment E as more effective (P = .001). Treatment E (n = 42) .001), nocturnal awakenings (P < .001), sleep duration (P < .001) was also compared to placebo (n = 31) in a third study phase using sleep quality (P < .001), and morning restfulness (P < .001).
a self-completed questionnaire given to 73 postpartum subjects.
Physician ratings were similar to those of the patients. More Twenty-seven subjects receiving Treatment E and 16 receiving patients preferred doxylamine than placebo (43 vs 15, respective- Journal of Clinical Sleep Medicine, Vol. 1, No. 2, 2005 CPRC non Rx treatment insomnia.qxp 4/8/2005 4:17 PM Page 179 Oral Nonprescription Treatment for Insomnia ly, P < .001), while 24 had no preference. overdose has been associated with rhabdomyolysis and acute A double-blind, placebo-controlled, crossover trial compared renal failure.115, 116 diphenhydramine hydrochloride (1 mg/kg) and placebo in 50 pedi-atric subjects (mean age 5.2 years, range 23.5 months to 12 years), with nine subjects not completing the two-week study period.109There was a significant reduction in subjectively reported sleep Mechanism of Action
latency (P < .05) and frequency of awakenings (P < .01) during 1 Alcohol is a well-known central nervous system depressant.
week of diphenhydramine treatment versus placebo, while there Several effects on sleep architecture have been described after was a statistical trend in increased sleep duration (P = .07).
acute alcohol consumption in nonalcoholic subjects, though In one study, inpatient and outpatient psychiatric patients (n = results are variable. A reduction in sleep latency has been found
144) complaining of insomnia symptoms were randomly by some investigators117-119 but not others,120-122 which is proba- assigned to receive various doses of diphenhydramine (12.5 mg, bly dose dependent.118 Increases in stages 3 and 4 non-REM 25 mg, and 50 mg) or placebo over a two-week period.110 The use (NREM) sleep may occur in the first several hours of sleep118-122 of diphenhydramine was associated with an overall improvement with a reduction in the latter portion of sleep.119,122 The whole- in the severity of insomnia versus placebo (P = .0002), although, night duration of slow-wave sleep is not significantly changed.118,121,122 individually, only the 12.5-mg dose achieved statistical signifi- Changes in slow-wave sleep may also be dose related,118 and one cance (P = .042). study using lower doses of alcohol found a whole-night reduction A randomized, double-blind, crossover trial of temazepam (15 in stages 3 and 4 sleep.120 REM-sleep alterations have been vari- mg), diphenhydramine (50 mg), and placebo given to 17 nursing- ably described. In several studies, higher doses of alcohol (0.9- home patients for five consecutive nights interspersed with 3 1.0 g/kg of body weight) led to a reduction in REM sleep in the wash-out nights found patient reports of sleep latency were short- first half of the night and an increase in the second half.117,123,124 er with the use of diphenhydramine than with placebo (P < .05).
One study using lower doses of alcohol (0.6 g/kg) found no sig- Diphenhydramine was reported to increase sleep duration more nificant change in REM sleep duration either throughout the than temazepam on the fifth night only (P < .05). Three subjects night or in the first two hours.121 In another study, a significant did not complete the study.111 reduction (P < .03) in REM sleep occurred in subjects with and In Shapiro's series, adverse effects were reported in nine sub- without insomnia symptoms after consuming alcohol at a dose of jects (1.8%), and treatment was discontinued in 8.102 Most 0.5 g/kg.122 Stone reported no changes in REM sleep with three patients were given 50 mg of diphenhydramine (n = 7), and two different alcohol doses (0.16, 0.32, and 0.64 g/kg), although there received 100 mg. Side effects included vomiting (n = 1) and was a trend toward increasing REM sleep latency at the 2 high- depression (n = 8). A possible dose-dependent occurrence of side est doses.120 Another study of the dose effects of alcohol on sleep effects was found by Kudo et al.110 No side effects were reported (at 0.00, 0.25, 0.50, 0.75, and 1.00 g/kg) found no significant in 95.8% of the 12.5-mg group, 88% of the 25-mg group, and changes in percentage of REM sleep through either the entire 82.6% of the 50-mg group. The most-reported side effect was night or the first three hours.118 However, REM sleep for both malaise. Doxylamine succinate was rated by patients to have sig- time periods was reduced with increasing alcohol dose, and the nificantly more side effects than placebo (P < .05).108 The most small study size (N = 10) may have led to a Type 1 error. A dose- frequently reported reactions were drowsiness, grogginess, tired- dependent increase (doses of 0.00, 0.50, and 0.75 g/kg) in REM ness, dry mouth, and weakness. Diphenhydramine was associat- sleep percentage (P < .05) was found in 11 young women volun- ed with more drowsiness, dizziness, grogginess, dry mouth, tired- teers.119 Tolerance to these effects occurs after one to three nights ness, and weakness than placebo, although statistical significance of continued alcohol consumption.117,123,124In another study, sig- was not given.107 In a prospective cohort study of 426 hospital- nificant increases in stage 1 sleep were found between hours four ized patients over the age of 70, 114 (27%) received diphenhy- and six of the study night with two doses of alcohol (0.05, 0.75 dramine for sleep, prophylaxis for blood transfusions, or allergic g/kg) relative to placebo (P < .05).119 Further, the amount of reactions. There was a 70% increased risk for impaired cognition wake time was also significantly increased during 6 hours in bed in diphenhydramine-treated patients (42% vs 24%, P < .05), (P < .05) In Stone's series, a significant (P < .05) increase in total which appeared to be dose related.112 Mild drowsiness was sleep time occurred with a low dose of alcohol (446.0 minutes) reported as the only possible adverse reaction associated with the versus placebo (431.1 minutes).120 However, at higher doses use of diphenhydramine hydrochloride in children, occurring in 1 (0.32 and 0.64 g/kg), total sleep time was reduced nonsignifi- out of 41 reported subjects.110 Dimenhydrinate, a preparation cantly (442.0 and 418.3 minutes, respectively). Nonsignificant composed of diphenhydramine and 8-chlorotheophylline, has increases in wake time during the fifth hour of sleep were also been abused due to hallucinogenic and excitatory properties at noted after consumption of 0.75 g/kg (7.5 ± 21.0 minutes) and higher than recommended doses.113 Other central nervous system 1.00 g/kg (17.8 ± 44.8 minutes) of alcohol as compared to place- side effects include sedation, dizziness, stimulation, euphoria, bo (0.6 ± 1.9 minutes) and alcohol doses of 0.25 g/kg (0.6 ± 1.9 nervousness, and extrapyramidal reactions.94 A variety of gas- minutes) and 0.50 g/kg (0.5 ± 1.6 minutes).118 trointestinal complaints, voiding difficulties, impotence, and To appreciate more-subtle changes in sleep, Roehrs et al122 headaches may also occur.94 Antihistamines may increase used fast Fourier transform (FFT) analysis to assess changes in intraocular pressure and should be avoided in patients with nar- electroencephalogram spectra after consumption of a single dose row angle glaucoma.114 Symptoms of overdosage include flush- of alcohol (0.6 g/kg). No significant changes occurred in NREM ing, excitement, and convulsions. Coma may ensue, with death (stages 2, 3, 4) for the whole night, whereas, during REM sleep, usually related to hypotension or cardiac arrest.94 Doxylamine there were significant increases (P < .05) in the 1.25- to 1.5-, Journal of Clinical Sleep Medicine, Vol. 1, No. 2, 2005 CPRC non Rx treatment insomnia.qxp 4/8/2005 4:17 PM Page 180 AL Meoli, C Rosen, D Kristo et al 2.25- to 2.5-, and 4.75- to 8-Hz ranges. Significant changes (P < dependence was a significant risk factor for insomnia (odds ratio .05) were found during NREM sleep when the first two hours 1.75, 95% confidence interval 1.20-2.54). In the previously men- were compared with the remainder of sleep. Augmentation in the tioned study122 of alcohol effects on sleep architecture in subjects 0.25- to 1-Hz range and diminution in the 13.25- to 17-Hz and with and without insomnia, subjects were allowed to select alco- 20.25- to 25-Hz range occurred. Fast Fourier transform analysis hol or placebo in color-coded cups on subsequent study nights after 0.8 g/kg alcohol resulted in an increased mean power densi- based on their preference from previous nights. The insomnia ty during all REM sleep (P < .05) in the 0.0- to 6.0-Hz region group chose alcohol a significantly greater (P < .002) number of (15.3) versus baseline (12.6). During NREM sleep, power densi- nights (2.08 vs 0.67). Furthermore, the insomnia group chose a ty in the 10.0-12.0 Hz band was significantly higher (P < .05) greater (P < .01) total number of ethanol doses (6.69 v. 2.00), or during the test night (3.5 vs 2.4).125 an average of 0.45 g/kg each night.
It appears that alcohol leads to a dose-dependent decrease in The adverse effects of excessive alcohol use on physical and sleep latency. Initial increases in stages 3 and 4 sleep and aug- psychological function are well known. Acute and chronic alco- mentation in slow-wave activity may be dose related, but entire- hol use cause disruption of sleep continuity and exacerbate night changes are not apparent. A reduction of REM sleep in the insomnia symptoms. Alcohol use also worsens sleep-related initial hours of sleep has been found by some investigators, espe- breathing disturbances in a dose-dependent fashion.131 Modest cially at higher doses. All of these studies were performed in reductions in baseline arterial oxygen saturation (3%-4%), healthy, young, nonalcoholic subjects and included small num- increased incidence and duration of obstructive apneas, and bers of subjects (1-20). development of obstructive apneas in chronic snorers has beenfound after alcohol consumption of the subject's maximal social Efficacy and Safety
intake. Other investigators have also found worsening of obstruc-tive sleep apnea after alcohol intake.132-134 As compared to a con- Alcohol use as a sleep aid is an all-too-common and dangerous trol night, inspiratory resistance significantly increased (P = .01) occurrence. The National Sleep Foundation, using a population- during stage 2 NREM sleep after alcohol intake in 7 snoring based survey of adults in 1999, found 14% of respondents used (30.2 ± 4.4 cm H2OzL-1zmin-1 vs 63.7 ± 19.2) and 9 nonsnoring alcohol as a sleep aid.126 In 1996, a random-dial, computer-assist- (16.3 ± 7.0 cm H ed, telephone survey of younger adults (18-45 years) in south- 2OzL-1zmin-1 vs 25.9 ± 16.5) nonobese men.135 The increase in inspiratory resistance was significantly greater (P eastern Michigan (N = 2181) found that 13.3% of respondents (n = .05) in snorers than in nonsnorers. No significant changes in = 290) used alcohol for sleep. The majority used alcohol sporad- minute ventilation, end-tidal CO ically, with 68% reporting regular use of less than one-week 2, or ventilatory response to hypercapnia or isocapnic hypoxia were found in either group.
duration and 84.1% reporting fewer than 30 incidences of use Possible mechanisms for the adverse effect of alcohol on sleep- within the past year.127 A greater number of shift workers used disordered breathing include reduced hypoglossal nerve activity, alcohol than did day workers and those not working. However, altered carotid-body receptor function, depressed arousal regular use of alcohol for longer than four weeks in duration was response, and sleep fragmentation.136 Total growth hormone lev- reported by 32.5% of those who did not work but by only 10.8% els across sleep have been shown to be significantly reduced after of day or shift workers (P < .01). In an interview study of 155 one night (70%, P = .05) and nine successive nights (75%, P < women over the age of 85 years recruited from an urban area, all .05) of alcohol consumption (0.8 g/kg).137 Values returned to participants complained of poor sleep, and most (70%, n = 91) baseline after withdrawal of alcohol. The clinical significance of reported drinking wine or a mixed drink before bedtime to reduce this, if any, is unknown. Alcohol given to infants (1.5-5.6 months insomnia symptoms.128 of age) in breast milk, in concentrations similar to those that Since acute alcohol ingestion may adversely affect sleep archi- occur one hour after maternal consumption of 0.3 g/kg of alco- tecture, especially in the latter portion of sleep, it is possible that hol, resulted in a 25% reduction in the actigraphy-based estimates alcohol may be associated with insomnia symptoms. Most evi- of length of sleep (P = 04).138 This finding was replicated in a dence suggests a reduction in REM sleep and stages 3 and 4 later study, which also found an increase in active sleep during a NREM sleep in the latter portion of a sleep period after acute period of abstinence following alcohol consumption.139 alcohol consumption. Furthermore, an increase in stage 1 sleepand wake time may also occur in the terminal portion of sleep.
Conversely, insomnia symptoms may increase the risk of alcohol VITAMINS AND SUPPLEMENTS
dependence. A population survey using personal interviews con- ducted one year apart in adults over 18 years of age found thatsubjects with insomnia uncomplicated by a psychiatric disorder Relative hypercalcemia has been shown to be associated with were at significantly greater risk (P < .05) for alcohol abuse one insomnia in hemodialysis patients.140 In this study, a reduction of year later than were those without sleep or psychiatric distur- dialysate calcium concentration (1.75-2.00 mmol/L to 1.25 bances (odds ratio 2.3, 95% confidence interval 1.2-4.3).129 In a mmol/L) and subsequent serum calcium level from 9.9mg/dL to longitudinal population study using mailed questionnaire 9.4 mg/dL (P < .0001) led to significant reductions in insomnia.
responses in 1984 (n = 3201) and 1994 (n=2975), insomnia Those patients with constant insomnia dropped from 20.5% (n = prevalence was 10.3% and 12.8%, respectively.130 Only the 1994 15) to 5.9% (n = 4). Occasional insomnia dropped from 37.0% (n survey included lifestyle questions, including alcohol use.
= 27) to 22.1% (n=15). Those without insomnia increased from Subjects reporting insomnia in 1994 had significantly more (P < 42.5% (n = 31) to 72.0% (n = 49). All improvements were statis- .001) symptoms of alcohol dependence than did those without tically significant (P < .005). Notably, of 105 patients initially insomnia (18.9% vs 8.6%). Logistic regression found alcohol assessed, only 76 remained in the study group following inter- Journal of Clinical Sleep Medicine, Vol. 1, No. 2, 2005 CPRC non Rx treatment insomnia.qxp 4/8/2005 4:17 PM Page 181 Oral Nonprescription Treatment for Insomnia vention. Explanation for the dropouts was not given. We found double-blind study showed no effect on delayed sleep-phase syn- no published data regarding the use of calcium supplements for drome with 3.0 mg of B12 daily for four weeks.148,149 An additional insomnia. Similarly, we could find no studies of the incidence of 51 patients, 45 with delayed sleep-phase syndrome and 6 with calcium derangements in primary insomnia.
non–24-hour sleep-wake syndrome were studied in double-blindfashion. No clear benefit was apparent after eight weeks of therapy. Vitamin A
No studies were found that evaluated B12 therapy for insomnia symptoms unassociated with circadian-rhythm disturbances.
Acute poisoning with vitamin A (retinol) leads to drowsiness, sluggishness, irritability, and an irresistible desire to sleep.141 However, we found no data to indicate that clinically used dosesof vitamin A lead to drowsiness, and vitamin A is not routinely used for insomnia therapy. Physiologic Effects. As early as 1974, the use of L-tryptophan was suggested as a natural hypnotic.150,151 Serotonin, an endproduct of L-tryptophan metabolism, is involved in REM Nicotinamide (Niacin) is biosynthesized from dietary trypto- sleep.150 L-tryptophan produces a decrease in REM sleep and phan via the kynurenine pathway and quinolinic acid. In six nor- increase in NREM sleep.150 Partial blockade of L-tryptophan con- mal patients given escalating doses of nicotinamide for two days version to serotonin by parachlorophenylalanine does not alter L- followed by 3 g daily for 21 days, significant (P = .002) increas- tryptophan effects on sleep architecture. Use of a monoamine es in REM sleep were measured (18.4% baseline vs 25.0% at the oxidase inhibitor, which inhibits tryptamine metabolism and end of treatment).142 Using the same protocol, two female increases tryptamine concentrations, in conjunction with L-tryp- patients with insomnia experienced an increase in sleep efficien- tophan resulted in sedation and an apparent drunken state in one cy from 58.5% at baseline to 79.5% after three weeks, with a study. The exact mechanism of action of the sedative effects of L- return to 41.5% after cessation of nicotinamide.142 tryptophan is unknown.
Efficacy and Safety. Sedation associated with the use of L-tryp- tophan has been demonstrated in both normal and insomnia Magnesium is thought to have a role in the promotion of groups.151 Previous literature reviews concluded that L-tryptophan human sleep. The use of magnesium enhances melatonin secre- may be efficacious in shortening sleep-onset latency in patients tion from the pineal gland by stimulating serotonin N-acetyl with insomnia symptoms, though results were not always consis- transferase activity, the key enzyme in melatonin synthesis. In tent.152,153 However, L-tryptophan was taken off the market in the contrast, melatonin may decrease serum magnesium by mela- United States following cases of eosinophilic myalgia syndrome tonin's effects on magnesium distribution.143 However, magne- attributed to contamination linked to bacterial fermentation meth- sium may decrease melatonin production.143 No studies on the ods used in processing L-tryptophan.154 Consequently, L-trypto- efficacy of magnesium in insomnia patients were found. phan is only available by prescription since 1991.
Vitamin B12
Case-report data suggest potential beneficial effects of vitamin 5-hydroxytryptophan (5-HTP) is an intermediate metabolite of B12 in both free-running sleep-wake rhythm (hypernyctohemeral L-tryptophan in the serotonin pathway. Therapeutic doses of 5- syndrome) and in delayed sleep-phase syndrome.144,145 Two report- HTP bypass the conversion of L-tryptophan to 5-HTP by the ed cases of hypernyctohemeral syndrome with normal B12 levels enzyme tryptophan hydroxylase, the rate-limiting step in sero- included a 15-year-old female with a 25-hour sleep-wake period tonin synthesis. Factors such as stress, insulin resistance, vitamin and a 17-year-old male with a 24.6-hour sleep-wake period. Both B6 deficiency, and hypomagnesemia inhibit tryptophan hydroxy- were entrained to a 24-hour sleep-wake rhythm after B12 treatment.
lase. Use of 5-HTP resulted in less REM-sleep fragmentation in The 15-year-old girl was treated with 4.5 mg of vitamin B12 daily alcoholics during short-term abstinence in 1 study.155 In another and experienced symptom recurrence two months after stopping study, the use of 5-HTP in normal subjects was found to augment REM sleep.156 In a group of 3 patients, REM sleep decreased by 12. Two additional patients with delayed sleep-phase syndrome were treated with B the second week of treatment, and rebound occurred following 12.144,146 A 15-year-old girl received 3.0 mg of cessation of therapy.157 Despite the very limited data found sug- 12 daily, with sleep-onset advance by two hours and a gradual decrease in sleep duration from 10 to 7 hours. A 55-year-old man gesting changes in REM sleep, it is unknown what effect, if any, with delayed sleep-phase syndrome since age 18 received 4.5 mg of 5-HTP has on insomnia symptoms. B12 daily with symptom improvement for over six months.
An uncontrolled multicenter trial (N = 106) evaluated B cy in various sleep-wake rhythm disorders. Subjects initially Mechanism of Action
received B12 in 1.5 or 3.0 mg divided daily doses. Non- respondersalso received bright light therapy or hypnotics if necessary.
From clinical and basic science studies, there are reasons to Improvement occurred in patients with non–24-hour sleep disorder believe that diet can be an adjunctive treatment for insomnia. Fat (32%), delayed sleep-phase syndrome (42%), irregular sleep-wake introduced into the gastrointestinal tract of rodents increased total pattern (45%), and long sleepers (67%).147 However, a subsequent sleep and REM time in 1 study.158 Intracarotid delivery of nutri- Journal of Clinical Sleep Medicine, Vol. 1, No. 2, 2005 CPRC non Rx treatment insomnia.qxp 4/8/2005 4:17 PM Page 182 AL Meoli, C Rosen, D Kristo et al ents from digestion can cause hypersynchrony of the electroen- ination diets will improve sleeplessness in all infants. cephalogram and induce sleep.159 Eating can precipitate sleep For dietary treatment of specific sleep disorders associated attacks in narcoleptics.160 Sleep-inducing hormones released with insomnia, the literature is sparse. A randomized prospective from the gut and transport of "hypnotoxins" from digested food study examined a vegetarian diet on feelings of nonrestorative to the central nervous system are proposed mechanisms.158,159,161 sleep, fatigue, and insomnia in 78 patients with fibromyalgia syn- Primary candidates for hypnotoxins are intermediates of sero- drome.175 The diet was designed to increase brain tryptophan, tonin metabolism such as tryptophan. which the authors felt would improve sleep symptoms offibromyalgia syndrome. The patients were randomly assigned to Efficacy and Safety
diet or amitriptyline. After six weeks, there was significantimprovement in the amitriptyline group and no improvement in Single-blinded controlled studies in normal subjects have the diet group. The Argonne diet for the treatment of jet lag alter- shown modest effects on sleep after a small fat and carbohydrate nates "feasting" days (high-protein foods early in the day and meal.162,163 These effects were small statistical declines in move- high-carbohydrate foods at night) with "fasting" days (800 calo- ment time in the last third of monitored sleep periods. Such stud- ries) for 4 days prior to travel.176 This diet improved symptoms of ies have led to the widely accepted notion that a snack before jet lag, including insomnia, in a study of 186 military troops bedtime is part of good sleep practices in the treatment of insom- crossing nine time zones during deployment and nia.164,165 Sleep disturbances, independent of mood, are common return.176Although this unblinded study was prospective, partici- in those with severe weight loss from anorexia nervosa, with pation in the diet was optional, raising the possibility of a signif- reported decreases in total sleep time, slow-wave sleep, and REM icant selection bias.
sleep and associated increases in wake after sleep-onset time.166Refeeding diets in these patients has shown improvements in sleep with a predictable pattern of sleep-stage recovery. The mag-nitude of the recovery effect toward normal sleep has been shown Natrum muriaticum is sodium chloride. Occasionally, it is for- to be a function of recovered weight.166,167 mulated from sea salt. It is a homeopathic remedy used primari- There are relationships between specific diets that directly act on ly for the treatment of various skin conditions but is also used to the known physiology of a disease state, which then have sec- treat a wide range of pathologies.177,178 It is stated to improve ondary effects on sleep. Sleep-related hypoglycemic episodes in sleep by alleviating nightmares in those with depression and diabetics, whether induced by diet or medication, can trigger dis- remorse.179,180 No studies on this compound in the treatment of turbed sleep.161,168 Diets leading to weight gain can exacerbate insomnia were found.
sleep apnea and, therefore, the disturbing effects of apnea on Yoku-kan-san-ka-chimpi-hange (YKCH) is an herbal sleep.169 Weight loss in obesity during controlled, extreme, thera- medicine used for insomnia. A double-blind crossover study peutic diets is associated with an increased use of sedative hyp- compared YKCH to Anchu-san, an herbal drug used for gas- notics.170 Dietary manipulations have been shown to decrease trointestinal complaints, in 20 healthy adult men.181 Using depressive symptoms, including insomnia, in premenstrual tension polysomnography, total sleep time was significantly increased (P syndromes.171 Diets that reduce the intake of substances associated = .04) with YKCH (462 minutes vs 425 minutes). YKCH result- with increased symptoms of attention-deficit/hyperactivity disor- ed in nonsignificant reductions in sleep latency (4.66 minutes vs der improve sleep disturbances in children with attention- 10.4 minutes) and stages 3 and 4 sleep (39 minutes vs 52 min- deficit/hyperactivity disorder.172 Dietary elimination of known psy- utes) and nonsignificant increases in stage 2 sleep (123 minutes chostimulants, caffeine being the most obvious, improves sleep in vs 50.6 minutes) and REM sleep (64.6 minutes vs 48.6 minutes). insomnias of different causes.173 Proponents of specific diets forinsomnia without supporting data on the effectiveness of such diets could make unsubstantiated claims exploiting these known patho-physiologic relationships. For example, milk elimination in milk- As summarized in Tables 2 through 5, most over-the-counter intolerant infants improves many sleep characteristics in such insomnia treatments have very limited evidence supporting safe- infants with milk-induced sleeplessness.174 Based on the literature ty and efficacy. The literature obtained for this paper includes reviewed, there is no evidence to suggest, however, that milk-elim- seven randomized placebo-controlled studies of the short-termhypnotic effects of valerian root. Six used subjects with insomnia Table 2—Adverse Effects: Products with Limited Scientific Evidence of Hypnotic Efficacy
Latin name (or generic name)
V. officinalis L. Restless sleep, gastrointestinal upset, headache, contact allergies,mydriasis, possible carcinogen,possible hepatotoxicity Vomiting, depression, malaise, 94, 102, 107, 108, 110, 112, 113, 114 diphenhydramine citrate, drowsiness, impaired mentation, doxylamine succinate extrapyramidal reactions,rhabdomyolysis, dry mouth,weakness, gastrointestinal upset,headache, impotence, urinary retention,increased intraocular pressure Journal of Clinical Sleep Medicine, Vol. 1, No. 2, 2005 CPRC non Rx treatment insomnia.qxp 4/8/2005 4:17 PM Page 183 Oral Nonprescription Treatment for Insomnia symptoms, and four used some form of objective measurement of eration H1-receptor antagonists exists, the evidence is still pre- sleep variables. Subjects in all three studies located in the search liminary. The studies are frequently flawed by small sample size, that rely on subjectively determined sleep parameters experi- lack of objective outcome measurement, and variable study pop- enced significant improvement, whereas subjects in only one of ulations. Furthermore, studies have only assessed short-term the studies using objectively determined sleep parameters had treatment over a few days or weeks. It is unknown if long-term statistically significant improvement. Most of the studies found habitual use is either safe or effective. There was insufficient evi- had a small number of subjects, which could have masked a pos- dence found to determine the efficacy of hops, chamomile, lemon itive effect. We reviewed eight randomized placebo-controlled balm, St. John's wort, niacin, magnesium, B12, dietary changes, studies of the short-term hypnotic efficacy of first-generation H1- and YKCH for the treatment of primary insomnia. No scientific receptor antagonists in insomnia subjects, only one of which used data were found evaluating the efficacy of passionflower, objective measurements of sleep quality. One subjective study California poppy, wild lettuce, scullcap, calcium, vitamin A, 5- and the only objective study used an antihistamine no longer HTP, or Natrum muriaticum. There is potentially significant approved for over-the-counter use as a sleep aid. Of the five sub- adverse risk associated with the use of Jamaican dogwood, alco- jective studies of diphenhydramine, four demonstrated signifi- hol, L-tryptophan, and kava kava. L-tryptophan is no longer avail- cant efficacy as a hypnotic for less than one or two weeks of able without prescription in the United States. treatment. One subjective study evaluating doxylamine alsoshowed significant improvement. Although a greater amount ofliterature on the hypnotic efficacy of valerian root and first-gen- Table 3—Adverse Effects: Products with Insufficient Scientific Evidence of Hypnotic Efficacy
Latin name
Humulus lupulus Vomiting, allergic reactions Fatigue, gastrointestinal upset, 41, 42, 49, 56, 59, 60, 63, 64, 65, 66, 67 dizziness, anxiety, headache,photosensitivity, phototoxicity Patrinia Scabiosaefolia Fisch Niacin, niacinamide, vitamin B3 None known at recommendeddaily allowances None known at recommendeddaily allowances Vitamin B12, cyanocobalamin, None known at recommended Table 4—Adverse Effects: Products with No Scientific Evidence of Hypnotic Efficacy
Latin or Scientific name
Dizziness, confusion, ataxia, possible prolonged QT Californian poppy Lactuca virosa Possible hallucinogenic Seizures, possible hepatotoxicity None known at recommended daily allowances None known at recommended daily allowances Natrum muriaticum Table 5—Adverse Effects: Products with Significant Safety Concerns
Latin name (or generic name)
Toxicity to humans Dependence, neurotoxicity, cardiotoxicity, 132, 133, 134, 135, 137 myelosuppression, hepatotoxicity,respiratory depression, sedation, depression L-2-amino-3-(indole-3-yl) propionic acid Eosinophilia myalgia syndrome Piper methysticum Journal of Clinical Sleep Medicine, Vol. 1, No. 2, 2005 CPRC non Rx treatment insomnia.qxp 4/8/2005 4:17 PM Page 184 AL Meoli, C Rosen, D Kristo et al man. Pharmacol Biochem Behav. 1982;17:65-71.
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Nano Res. 2011, 4(3): 290–296 Nano Res. 2011, 4(3): 290–296 DOI 10.1007/s12274-010-0081-x CN Research Article Hybrid Silicon-Carbon Nanostructured Composites as Superior Anodes for Lithium Ion Batteries Po-Chiang Chen1, Jing Xu1, Haitian Chen2, and Chongwu Zhou2 () 1 Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA2 Ming-Hsieh Department of Electrical Engineering, University of Southern California, Los Angeles, CA 90089, USA Received: 6 October 2010 / Revised: 13 November 2010 / Accepted: 13 November 2010 © Tsinghua University Press and Springer-Verlag Berlin Heidelberg 2010