Review Article Updates on Nutraceutical Sleep Therapeutics and Investigational Research

Michael Yurcheshen,1 Martin Seehuus,1,2 and Wilfred Pigeon1,3

! University of Rochester School of Medicine and Dentistry, "#!Elmwood Avenue, Rochester, NY !$"$%,USA %Middlebury College, !$Old Chapel Road, Burlington, VT #&'&(, USA (Veterans Administration, $## Fort Hill Avenue, Canandaigua, NY !$$%$, USA

Correspondence should be addressed to Michael Yurcheshen; michael [email protected]

Received !" May!#$% ; Accepted $July!#$%

Academic Editor: Karen Nieber

Copyright © !#$% Michael Yurcheshen et al. &is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Approximately %#% of the population will su'er from a sleep disorder over the course of their lifetime. &ere is increasing interest in nutraceuticals for these conditions. &e quality of the evidence for the safety and e'ectiveness of using these supplements to treat sleep disorders varies substantially. In this review, we discuss the data about the e'ectiveness and safety of six commonly used plant-based sleep therapeutics: ca'eine, chamomile, cherries, kava kava, L-tryptophan, marijuana, and valerian. We explore both historical uses of each substance and the current state of the literature.

1. Introduction sources. Second, a number of general and systematic reviews of melatonin are already published in the literature. Overall, it is estimated that over %#% of the US population &e inclusion of any of the agents in this review does will su'er from a sleep disorder at some point in their life not imply endorsement; the agents were selected on the basis [$].&ese conditions include disorders of sleep initiation and of common use in the general population in conjunction maintenance (i.e., insomnia), hypersomnolence, and others. with public interest in their research and development. &is As a therapeutic group, there is an abundance of interest in review will summarize both the historic use and state of the nutraceuticals for these disorders. Many naturally occurring literature for these agents and provide an assessment of the products are manufactured and marketed for a variety of )eld’s understanding of their sleep/wake e'ects. sleep symptoms. Comprehensive research on these natural products for 2. Caffeine sleep-related indications is in its adolescence, and there is a spectrum of evidence supporting the e(cacy of these agents. Ca'eine is among the most widely consumed plant-based &e agents range from ca'eine, with signi)cant evidence to drugs worldwide. With the exception of cannabinoid extracts, support its potential in several sleep conditions, to marijuana, it is the only agent discussed in this review that has FDA with virtually no evidence, and many in between. recognized formulations. As such, ca'eineisbothanutraceu- Here, we focus on six commonly recognized plant-based tical and a pharmaceutical product. It is also singular in nutraceuticals with hypothesized impact on sleep disorders: this discussion of plant-based sleep therapeutics, in that it is ca'eine, chamomile, cherries, L-tryptophan, marijuana, and used for conditions of excessive sleepiness, rather than the valerian. &e exclusion of melatonin from this focus is based disorders of sleep initiation and maintenance. upon two factors. First, although melatonin may be obtained &ere is a wide array of sources for naturally occurring from a variety of plant sources or from chemical synthesis, ca'eine [!, *]. A typical +oz cup of co'ee brewed from formulations have traditionally been derived from animal roasted beans contains roughly $##mg of ca'eine. Teas !Evidence-BasedComplementaryandAlternativeMedicine range from being completely unca'einated/deca'einated to role in precipitating more serious arrhythmias is speculative over $##mg, depending on the type and brewing method. [$#]. More recently, an association between ca'eine intake Chocolate and chocolate products contain ca'eine, about and hemorrhagic stroke was established in a population $# mg for a $oz serving of milk chocolate. Some sources are based study, although the study examined ca'eine ingested less well known in the United States. &ese include guarana, a in processed form and not from ca'einated beverages [$$]. A plantnativetoSouthAmericawhereitisformulatedintofood link between )brocystic breast diseases has been suggested, consumables and ingested for its natural stimulating e'ects but some studies cast doubt on this relationship [$!]. In [,].Ca'eine (usually obtained from deca'eination processes) general, most of the side e'ects of ca'eine are minor and self- can also be added to arti)cial sources such as soda and energy limited. drinks. Ca'eine ($,*,--trimethylpurine-!,"-dione) has a number 3. Chamomile of biochemical actions. Its principal action is adenosine antagonism, and there are a number of ca'eine analogs with Chamomile compound is derived from several plants in the variable a(nities for A$and A!receptors [!]. Adenosin- Asteraceae family, native to southern and Eastern Europe. ergic pathways upregulate non-REM sleep, and it is the Chamomile has been traditionally served as an infusion, but antagonistic e'ect at these receptors that primarily accounts a number of formulations are available, including tablets, for ca'eine’s stimulant properties. It also acts as a cyclic powders, and gelcaps. As with virtually all nutraceuticals, AMP phosphodiesterase inhibitor, perhaps contributing to chamomile is considered a dietary supplement and is not its alertness and mood elevating e'ects [*]. Ca'eine has a FDA regulated. Chamomile has a reputation as a natural aid number of other proposed bioactive mechanisms, including for insomnia and has been used for millennia in this capacity. acetylcholinesterase antagonism that may account for its In common use, the supplement is generally considered to be memory-enhancing properties [%]. In addition to ca'eine, sopori)c, rather than hypnotic, and is easy to )nd in brick co'ee and tea contain a number of antioxidants, but it is and mortar and online retail outlets throughout the United unclear if these have any particular bene)cial action from a States. sleep or circadian standpoint ["]. Chamomile contains several compounds that might have On a macrolevel, these actions all contribute to ca'eine’s therapeutic e'ects [$*]. In laboratory studies, Apigenin stimulant e'ects. In a rigorous Cochrane meta-analysis, caf- demonstrates anxiolytic properties and appears to be a feine was found to be e'ective in controlling errors secondary candidate for chamomile’s e'ectiveness as sopori)c [$,–$"]. to shi.work and is perhaps as e'ective as other (potentially Apigenin is a 0avonoid and acts as an antagonist at $ $ !S more expensive and di(cult to obtain prescription) therapies GABAA receptors and at $GABAC receptors. GABA modu- for this purpose [-]. It can also be e'ective in treating lation is a common mechanism for many hypnotics, although! " # sleepiness in other types of circadian rhythm disorders, such these putative receptors$ are not those modulated by ben- as jet lag [+]. Although several FDA approved stimulants have zodiazepines or benzodiazepine agonists [$-]. Apigenin has been studied for residual sleepiness in treated sleep apnea, also been recently studied for additional properties, including ca'eine has not been studied for this malady. At one time, anti-in0ammatory e'ects, although the relationship between ca'eine was suggested as a therapy for central sleep apnea, but these and possible sleep inducing e'ects is still speculative. it is no longer routinely used for treatment of this condition. &e literature is sparse in terms of controlled trials Ca'eine has been demonstrated to improve performance examining chamomile and its sleep inducing properties. In with a number of psychomotor tasks. &is quality can be arecentstudy,*,subjectswererandomizedtoplaceboor useful both individually and from a public safety standpoint. !-# mg of chamomile extract [$+].&is dosage is much higher For instance, ca'eine may help to reduce the likelihood of than could be prepared and ingested as a tea. Chamomile did motor vehicle accidents in commercial drivers. In one case- not demonstrate a statistically signi)cant bene)t over placebo control study, Australian researchers polled %*# commercial in the predetermined primary sleep endpoints, speci)cally, drivers who had been involved in a recent motor vehicle sleep diary metrics. Similarly, there was no statistically sig- accident and compared them to %$- control drivers. [/]. ni)cant impact on daytime functioning. &is is the only high A.er adjustment for confounding factors, drivers who had quality clinical trial published to date regarding clinical e(- consumed ca'eine (speci)cally for the purpose of staying cacy of chamomile, and the authors highlight its limitations, awake) had a "*% reduced chance of a crash (odds ratio including small sample size and challenges in developing #.*-,/%% con)dence interval #.!-to #.%#).&is study had e'ective dosing. All other clinical studies do not meet class $A anumberofpotentialmethodological0aws,includingrecall evidence and are generally limited to case reports and series. bias,butsuggeststhatca'einecouldreducethelikelihoodofa According to Clinicaltrials.gov, there are no other trials that commercial vehicle crash and therefore promote public safety are recruiting or recently completed examining the e'ect of when used in this manner. chamomile on sleep [$/]. &e side e'ects of ca'eine are well recognized. Recently, Like the record on e'ectiveness, the published literature there has been signi)cant interest in establishing the safety examining the tolerability of chamomile is generally limited. of energy drinks, many of which contain signi)cant amounts &e only randomized, controlled trial of chamomile did not of ca'eine. Agitation, insomnia, and appetite suppression demonstrate any adverse e'ects, but the sample size was lim- are some of the more common side e'ects. Palpitations can ited [$+]. In other reports, chamomile was linked to contact be common with excessive ca'eine ingestion; however, its dermatitis, but only while used topically [!#, !$]. Although Evidence-BasedComplementaryandAlternativeMedicine * several population based studies have examined the impact of between-group e'ects was small to moderate in favor of of supplements on premature labor and gestational weight, the tart cherry juice, far less robust than observed from estab- the largest of these did not )nd any association between lished pharmaceuticals. Nonetheless, the observed e'ects of chamomile and these outcomes [!!]. With limited literature, tart cherry juice do also compare favorably with the use of de)nitive conclusions about chamomile’s side e'ects are exogenous melatonin for insomnia [*-]. lacking. &e amount of melatonin intake from the two tart cherry studies (#.#+ mg) is less than the lowest doses of exogenous 4. Cherries and Cherry Juice melatonin (#.*mg) found to have an impact on sleep [*+]. Moreover, the relatively rapid elimination half-life of mela- Of many varieties of cherry, tart cherries in particular are tonin ( $hour)castsomedoubtontheimprovementsseen purported to have a number of bene)cial health e'ects in wake a.er sleep onset. It is possible that other mechanisms with some evidence supporting decreases in oxidative stress or pathways< to improved sleep underlie the positive signal levels of in0ammatory markers and muscle damage following that remains with respect to cherries and sleep [*/]. At exercise while enhancing muscle recovery [!*–!+]. this stage, the questions of if and how cherries promote or Montmorency tart cherries (Prunus cerasus)contain improve sleep in clinical samples remain unanswered, as does several phytonutrients including the phenolic acids with the mechanism of action by which such improvements may anthocyanins chief among them [!/]. Anthocyanin levels in occur. tart cherries exceed those found in sweet cherries and other fruits and a positive linear relationship between anthocyanin 5. Kava Kava levels in cherries and oxidative stress protection in neuronal cells has been reported [*#, *$]. Tart cherries also contain high Kava kava (Piper methysticum)isaplantnativetoseveral levels of anti-in0ammatory substances and melatonin [!/, ecosystems of the Western Paci)c, including Hawaii. &e *$, *!].&is suggests two putative sleep-promoting pathways sedative and anxiolytic e'ects of the root from the various for tart cherries (and perhaps some sweet cherries as well). substrains of this plant have been known for millennia. First, the presence of anti-in0ammatory cytokines in tart Peoples of French Polynesia, for instance, have been using cherries suggests one potential pathway to sleep enhance- preparations of the plant for a variety of maladies, including ment, given that a number of in0ammatory cytokines are symptoms of anxiety and depression. Most raw kava kava intricately related to the modulation of sleep [**]. Second, is produced and harvested outside of Western nations and the relatively high content of melatonin in some cherries may imported into European and North American markets for serve as a source of exogenous melatonin, a substance with processing. Kavalactones appear to be the primary psychoac- proven sleep-regulating properties. Only very limited clinical tive constituents contained in the plant, of which several have research, however, has been conducted to assess the impact of been identi)ed. &e putative receptors of these compounds cherries on sleep. include GABA, serotonin, and dopamine, among others [,#]. In separate studies, sweet and tart cherries were associ- By reputation, kava has a host of therapeutic e'ects, ated with very modest sleep improvements in already good including anxiolytic, euphoric, and sedative properties. Of sleepers. In a crossover study ( )ofmontmorencytart these, the anxiolytic bene)ts of the nutraceutical are probably cherry juice blend, nonsigni)cant reductions in sleep latency the best characterized. A !##* Cochrane report, republished (approximately %minutes) and% $=20minute in wake a.er sleep in !#$#, analyzed a total of $!randomized, controlled studies onset (WASO) were measured from sleep diary data [*,]. In with a total of -## participants [,$]. Several additional an uncontrolled study ( ), seven varieties of Jerte Valley studies were excluded from the analysis, as they did not sweet cherries (Prunus avium)wereconsumedaswholefruits meet inclusion criteria. A.er rigorous analysis, the authors over seven, separate -!%-hour=12 periods. Actigraphy measured concluded kava is superior to placebo in controlling anxiety, improved sleep outcomes compared to baseline [*%]. Notably, but the e'ect size seemed small due to small numbers of both studies measured urinary melatonin levels and found subjects included in the trials. increases over basal levels following cherry supplementation In animal models, one kavalactone, kavain, appeared (and compared to placebo in the crossover study). Together, to change sleep micro- and macroarchitecture compared to these two studies suggest that tart cherry juice and whole other sedatives [,!]. An analogous trial has not been con- sweet cherries each increase melatonin levels in healthy ducted in humans. In fact, almost no randomized, controlled sleepers, making more plausible the possibility that melatonin trials have explored the e(cacy of kava kava in treatment for supplementation may improve sleep in a sleep disordered insomnia and the few published trials have generally included sample. sleep metrics as a secondary outcome measure. A poorly Only one study to date has investigated the e'ect of conducted trial published in !##,examined the impact of a cherries in a clinical sample. In a small crossover study kava extract on sleep scores on a validated sleep questionnaire ( )amontmorencytartcherryjuicewasassociated in subjects with baseline anxiety [,*]. A.er excluding a with statistically signi)cant improvements in self-reported number of potential subjects, the authors compared *, sleep%=15 among older adults with insomnia [*"]. Compared to subjects taking kava extract to !-subjects taking placebo. placebo, subjects drinking tart cherry juice for two weeks &ey saw a statistically signi)cant bene)t to kava compared reported less severe insomnia and a reduction in time awake to baseline in their predetermined metrics, but both groups following sleep onset compared to placebo. &e magnitude saw signi)cant improvements. In the absence of high quality, ,Evidence-BasedComplementaryandAlternativeMedicine randomized controlled trials, there is clear opportunity to three-arm RCT ( ) compared one-week administration explore the e(cacy of kava in primary insomnia. of a food sourced tryptophan (butternut squash seed) to Kava has been subject to a number of safety concerns, pharmaceutical grade%=49 tryptophan and a carbohydrate alone and this itself is a matter of controversy [,,].&e primary (placebo), all prepared in food bars. In this study, both forms one amongst these is the possibility of hepatotoxicity. Due of L-tryptophan resulted in signi)cant improvement on sleep to concerns about this speci)c side e'ect as well as other diary measures of insomnia, but similar improvements were regulatory matters, kava has been highly restricted, particu- noted in the placebo condition such that no signi)cant group larly in the European Union where it had been banned from time interactions were observed [%*].&e largest improve- import for a number of years. Several authors have suggested ment was in total sleep time with a $/- minute increase in that the mode of preparation of the kava extract, including ×the squash seed condition and a ,!-minute increase in the what portion of the plant is used, can play a role in this tryptophan supplement condition, although there was also toxicity. &ere is suggestion that preparations made from the a$--minuteincreaseintheplacebocondition.Inaddition, root of the plant are generally safe, whereas other portions of some of the gains were maintained at one-week follow-up. At the plant, such as the stems or leaves, might be more toxic this time point, placebo was associated with a further increase [,%]. Likewise, there is some speculation that the method of of additional !, minutes of total sleep time. Taken together, extraction, speci)cally the solvents used in the process rather these trials do not provide convincing support for the e(cacy than the plant-based compounds themselves, might be the of L-tryptophan for insomnia. true o'ending concern [,"]. With respect to safety, the sale of tryptophan was banned in the USA from $//$ to !##$ following a large tryptophan- 6. L-Tryptophan related outbreak of eosinophilia-myalgia syndrome (EMS) leading to *- deaths. Sales resumed in !##$, but cautions &ee'ectsoftheaminoacidL-tryptophanonsleephavebeen relatedtoworseningofliverandkidneydiseaseremaindueto investigated since the $/-#s with varying support for its role in the link to EMS [%,, %%]. It is also listed as “likely unsafe” for treating sleep disorders [,-]. L-Tryptophan is a precursor to pregnant or breastfeeding women. On its own, tryptophan is serotonin from its metabolite, %-HTP.Tryptophan is available generally safe with mild side e'ects that include gastrointesti- in a variety of plant and animal products including eggs, nal side e'ects as well as headache, lightheadedness, drowsi- cheese, chocolate, oats, )sh, poultry, spirulina, sesame, and ness, dry mouth, visual blurring, muscle weakness, and sexual sun0ower seeds, among many others. Tryptophan is available problems. In addition, there may be major interaction with as an over-the-counter dietary supplement; it is also available serotonergic agents such as many antidepressants, leading to in prescription form in Europe, typically as an antidepressant. serious side e'ects such as serotonin syndrome. It might act Nocturnal administration has been shown to increase synergistically with sedative-hypnotic medications to cause concentrations of both serotonin and melatonin; thus its oversedation; caution should be used when considering with putative mechanism of action may be through either mela- central nervous system depressants as to avoid excessive tonin enhancement or serotonergic e'ects. Signi)cantly sleepiness and sedation. reduced sleep latency and increased subjective ratings of In sum, there is evidence supporting a sleep moderating sleepiness in healthy adults during the day have been reported e'ect of L-tryptophan. Some safety concerns remain from the in a number of uncontrolled and controlled studies [,+]. EMS outbreak and from the possible severe interaction e'ects Varying doses have been shown to signi)cantly reduce (especially with serotonergic agents), but L-tryptophan is sleep latency and increase subjective ratings of sleepiness in generally well-tolerated with limited side e'ects. Controlled subjects with insomnia [,-]. Interestingly, in an experimental trials in samples of insomnia patients, however, are quite tryptophan depletion study in $% insomnia subjects, trypto- limited and their combined )ndings are mixed at best. phan depletion had a negative impact on sleep continuity, increasing stage $sleep and decreasing stage !sleep [,/]. A 7. Marijuana systematic review of sixty-four randomized controlled trials exploring the use of alternative modalities to treat insomnia In recent years, there has been signi)cant interest in medical found mixed evidence for L-tryptophan, although this was marijuana as a treatment for a variety of medical conditions, based on only three studies [%#]. In a four-arm RCT ( especially for, but not exclusive to, palliation. Cannabinoids ), Hartmann et al. compared one-week administration of are thought to exert their e'ects primarily through a variety tryptophan, 0urazepam, secobarbitol, and placebo [%$]. Only%= of G-couples cannabinoid receptors in the central nervous 960urazepam was associated with subjective sleep improve- system and in peripheral tissues. &e marijuana plant can ments relative to placebo. Tryptophan did not improve sleep contain over "#cannabinoids, some of which appear to be during the --day treatment phase, but in the week following more bioactive than others [%"]. treatment discontinuation, sleep latency did improve relative Leaving aside the recreational history of marijuana, the to placebo. In a blinded crossover trial of high (!g) versus plant has generated signi)cant interest over millennia for low/placebo dose (#.#,g) L-tryptophan ( ), Demisch et its purported medicinal properties. In the United States, the al. reported a signi)cant di'erence between full L-TRP dose cultivation of the plant was referenced as early as the $-th and the placebo dose, but only if the placebo%=39 was given )rst. century. In general, there was a permissive attitude towards &erewasnogroupdi'erencewhenthefulldosewasreceived the drug, both recreationally and medicinally, until the early )rst, suggesting a signi)cant placebo e'ect [%!]. Finally, a !#th century. Marijuana was included in e'orts to control Evidence-BasedComplementaryandAlternativeMedicine % more socially dangerous drugs, such as opiates and cocaine Cannabis has been demonstrated in several clinical trials to throughout the $/##s. It came under increasing regulation, improve chronic pain in a variety of patient populations ["%]. either by taxation or direct restriction, until the $/%#s, when Many of these trials did not include a sleep outcome and any both the Boggs Act and the Marijuana Control Act mandated bene)t to cannabis on sleep, even in patients with chronic sentences for drug o'enders. pain, is still speculative. Both before and during this time, marijuana has been &e list of potential side e'ects of marijuana is long, described for relief of a variety of conditions, including politically charged, and beyond the scope of this review. Like pain, spasticity, emesis, and anorexia. &e medicinal use any drug, marijuana, with multiple bioactive agents, could of marijuana has included synthetic cannabinoids in tablet certainly be harmful depending on a number of factors. &ere form, as well as the delivery of more “natural” forms of the is evidence for psychological dependency. &e inhalation of drug such as smoking or alimentary ingestion. &e FDA marijuana smoke has also been implicated in periodontal and released a policy statement in !##"that there was no sound pulmonary diseases ["", "-].&ese potential drawbacks do medical evidence supporting the use of marijuana for medical need to be considered for a general patient population. purposes; since that time, $#states have approved medical At this time, there is insu(cient evidence to prove de)ni- marijuana bills into law, and the controversy shows no signs tively the impact of THC on sleep architecture or to support of abating [%-]. the use of marijuana in the management of sleep disorders, With this background, there is interest in considering this but the topic has been subject to almost no scienti)c scrutiny. plant-based drug for the management of sleep disorders. It Future research should consider these questions, as well as bears noting that there are signi)cant legal and quality control indications for the drug, potential side e'ects, and the still hurdles in conducting medical research on cannabis [%+]. signi)cant legal hurdles in many states. With these limitations, it is important to highlight that the absence of evidence does not necessarily imply evidence of 8. Valerian absence. &e literature is sparse with observational studies regard- Valerian is a perennial herb that has long been held to ing the e'ects of cannabinoids on sleep. Many of these reports have sedative properties. &e Greek physician Galen recom- were published over ,#years ago and are limited by small mended valerian for insomnia. &e most common species sample size. Regarding sleep architecture, the evidence about from which valerian is derived is Valeriana o)cinalis.Vale- cannabinoid’s impact is con0icting.& e reports varied in rian is extracted from the dried root and rhizomes of regard to dosage and chronicity of THC administration, this plant by soaking in one of several solutions (water, leading to a great deal of methodological inconsistency. In ethanol and water, or methanol and water) and then either general, the case series are consistent in that acute THC centrifuging or drying the mixture to concentrate the primary administration reduced REM sleep in study subjects [%/, active plant compounds including valerenic acids and amino "#], although at least one report was not supportive of this acids ["+]. )nding ["$].&ere was no agreement as to THC’s impact An e(cacious dose is considered to be one which has the on slow wave sleep, with some studies suggesting increase equivalent of !to *grams of dried root material. Although in this stage and others suggesting decrement or no change commercially available preparations of valerian are most ["#, "!, "*].&ere was no described trend for metrics of common in tablets ranging in dose from *##to "##mg/day insomnia, such as number of awakenings or sleep onset andtoalesserextentin!–,mL tinctures ["/], it is impossible latency (SOL). A few of the papers did describe increased to determine their valerian equivalent when extraction ratios sleep onset latency or wake a.er sleep onset in the withdrawal are not provided. One pharmacokinetic study in healthy state ["#, "!, ",].&ese observations provide little insight subjects taking a "##mg dose of valerian extract, with an into the mechanisms of sleep regulation of THC. It also bears undisclosed extraction ratio, observed peak concentrations at noting that change in sleep architecture, particularly in regard *#–$!# minutes with a mean elimination half-life of $.$hours to total percentages of sleep stages, does not necessarily and its marker, valerenic acid, was observed in serum for up confer therapeutic advantage. For instance, most commonly to %hours [-#]. prescribed antidepressant medications suppress REM sleep, &e precise mechanism of action for valerian is unknown, but this has no known direct detrimental or salutatory sleep as is what compound or combination of compounds is e'ect on the individual patient. Similarly, changes in sleep responsible for any sedating e'ect. &e main putative path- architecture mediated by THC do not necessarily imply a way is thought to occur through inhibition of sympa- therapeutic e'ect. thetic activity by action upon the neurotransmitter gamma- &ere is no published evidence that demonstrates bene)t aminobutyric acid (GABA), although it may also be via of marijuana in the management of primary sleep disor- binding with adenosine (A$) and/or serotonin (%-HT-%a) ders. Speci)cally, PubMed searches for cannabis and sleep, receptors [-$, -!]. Importantly, like with kava kava, the cannabis and insomnia, and cannabis and sleepiness did solution used in the extraction method (the water to alcohol not produce any studies that have explored the impact ratio) can dramatically impact the concentration of con- of cannabinoids on disordered sleep. Likewise, there are stituent compounds extracted [-*]. Moreover, since valerian no published data that demonstrate an impact of cannabis is not FDA regulated, the content and concentrations can in treatment for posttraumatic stress disorder, a complex vary from the listed amount on labels in the United States condition with sleep disturbances as an essential feature. [-,]. Under the auspices of the European Pharmacopoeia, "Evidence-BasedComplementaryandAlternativeMedicine preparation/dosage control in Europe is stricter. In addition, In one, $## postmenopausal women aged %#–"#who had valerian can be prepared in combination with other herbs insomnia were randomly assigned to receive twice a day for such as hops (Humulus lupulus)orlemon-balm(Melissa four weeks %*# mg of a valerian root extract or %#mg starch o)cinalis), further complicating the assessment of valerian’s as placebo in capsules (although the extraction ratio was e'ect on sleep. not provided, so the valerian dose equivalent is unknown). With respect to safety, valerian is on the FDA’s GRAS Nonetheless, in this study, valerian was associated with a (generally recognized as safe) list and is approved for use greater reduction in PSQI scores over the treatment period as a food. &e main secondary e'ects of valerian include (from /.+to ".#) than placebo (from $$.$to/ .,) and a greater gastrointestinal e'ects such as diarrhea, abdominal pain, proportion of participants achieving a %-point reduction in nausea, and pyrosis and central nervous system e'ects their PSQI score (*#% versus ,%) [+*]. In another, /$ patients such as headache, nervousness, and drowsiness, although diagnosed with primary insomnia, perceived total sleep time these e'ects are generally mild and self-limited. With the of "hours,andanInsomniaSeverityIndexscore - exception of diarrhea, none have been elevated when com- were randomized to receive a $# mg zolpidem tablet or one pared to placebo in clinical trials [-%, -"].&ere are no tablet< containing *##mg of a valerian extract (standardized> notable interactions between valerian and pharmaceuticals, to #.+% valerenic acid), hops, and passion 0ower (Passi*ora but caution might suggest avoiding it in combination with incarnata) extracts at bedtime for two weeks [+,].&irty- benzodiazepines. nine subjects in each group completed the study, which &e empirical evidence for valerian on sleep remains found signi)cant improvements on sleep diary-measured inconclusive due to contradictory )ndings. Several studies sleep latency, total sleep time, and nocturnal awakenings as have found no e'ect of a single dose of valerian [--–-/]. A well as signi)cant improvements on the ISI in each group. systematic review of !/controlled and eight open label trials &ere were no time by group di'erences on any of these concluded that, despite some positive studies, the majority of measures, suggesting equivalency between zolpidem and this )ndings were negative and, therefore, that there is no overall particular formulation of valerian, hops, and passion 0ower. e'ect of valerian, regardless of preparation type or whether In sum, the evidence to support the use of valerian or not it was combined with other nutraceuticals [-%]. A as a sleep aid for patients with insomnia remains rather subsequent review of sixteen studies exploring the treatment mixed, with more negative than positive studies overall. A few of insomnia using valerian with or without hops concluded high quality studies now report modest bene)ts of valerian that twelve studies showed some sleep bene)t of valerian for insomnia patients. &e safety of valerian is now well- [+#].&is review included *uncontrolled trials. Furthermore, established. there were signi)cant methodological di'erences among the thirteen RCTs. Among the RCTs, positive e'ects of valerian 9. Summary were observed in $of $# assessing total sleep time; %of $$ assessing sleep latency; *of" assessing slow wave sleep; !of From even this basic review of a few of the nutraceutical $# assessing nocturnal awakenings; and, of $* assessing sleep supplements available for sleep disorders, it is clear that there quality. is a spectrum of evidence to support their use. With few Ameta-analysisfoundastatisticallygreatere'ectof exceptions, a general theme with these agents is that there valerian on sleep quality compared to placebo, but it found are historical and anecdotal reports of sleep bene)t, but the that there were no other di'erences [+$]. A subsequent meta- science falls signi)cantly short of class IA evidence. In fact, analysis of $+RCTs, which included three newer randomized some of the agents have essentially no published data at trials, found a di'erence in e'ect favoring valerian when a all to support their use, even as case reports. &e National sleep quality variable was dichotomized but no di'erence Institutes of Health has National Center for Complementary in sleep quality measured by visual analog scale and no and Integrative Health (NCCIH), with a !#$% budget of di'erence in sleep latency [-"].&e authors further conclude $!,.$million dollars, about two one-hundredths that of the the most recent clinical trials were of high methodological National Cancer Institute [+%]. For those who have an interest quality and su(cient sample size, but their combined results in these plant-based products for use in sleep disorders, the were not conclusive. hope is that some of this modest budget along with other In the largest trial included in the meta-analysis, Oxman support will be granted for these types of research. and colleagues (!##-) conducted a multicentre trial com- paring the equivalent of approximately *."grams of valerian from commercially available valerian tablets to placebo Conflict of Interests taken for two weeks in ,#%adult participants with $- month insomnia and a score %onthePittsburghSleep &e authors declare that there is no con0ict of interests regarding the publication of this paper. Quality Index (PSQI) [+!].&ere were very few signi)cant> di'erences between groups on> the primary and secondary sleep outcomes; the authors conclude that valerian may have References a small e'ect on sleep quality but is unlikely to reduce the time it takes to fall asleep or increase daytime energy level. [$] B. M. Altevogt and H. R. Colten, Sleep Disorders and Two high quality studies have been published since this Sleep Deprivation: An Unmet Public Health Problem,National large meta-analysis exploring valerian’s impact on sleep. Academies Press, Washington, DC, USA, !##". Evidence-BasedComplementaryandAlternativeMedicine -

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