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18 impair performance on most performance tasks--in particular, 1991 (FHWA 1991). This was reinforced in the most recent benzodiazepines impair performance on tasks that entail visual Psychiatry Evidence Report (Tragear et al. 2008), and the encoding of information (such as attention, vigilance, visual Medical Expert Panel recommendations (Metzner et al. 2009). search, peak saccadic velocity, and critical flicker fusion) and These documents are advisory in nature, and recommended on a variety of short-term memory tasks. against commercial driver medical certification in drivers tak- ing both benzodiazepine and nonbenzodiazepine hypnotics One study of drivers of commercial vehicles identified and anxiolytics. The bases of these recommendations are increased self-reported crash risk. Self-reported crash data the multiple studies indicating impairment of cognitive were analyzed for Australian truck drivers who regularly or function and driving ability for up to three weeks (DeGier occasionally reported use of a variety of medications, including et al. 1981; O'Hanlon et al. 1995; van Laar and Volkerts benzodiazepines. Drivers reporting the use of benzodiazepines 1998; van Laar et al. 1992), and the increased odds of crash were deemed to be 1.91 times more likely to have had a crash of 1.3 to 2.2 times greater than those individuals who did not in the previous three years. This is compared with those who use benzodiazepines. Crash risk was particularly increased used antihistamines, who were 3.44 times more likely to in individuals of more than 40 years of age, and in the first have crashed; those who used narcotic analgesics, who were week after prescription. The FMCSA noted that it "considers 2.4 times more likely to have crashed; and those with regular evidence, expert recommendations and other data, however consumption of alcohol drinks, who were 1.09 times more all proposed changes to current standards and guidance will likely to crash. Those who consumed mild stimulant drugs be subject to public notice-and-comment" (FMCSA Medical such as caffeine were no more or less likely to have crashed Expert Panel reports web page, accessed May 16, 2010). (Howard et al. 2004). [See also the assessment of various sleep-inducing drugs and the incidence of accident crashes Assessment of benzodiazepines. Use of benzodiazepines by Gustavsen et al. (2008).] for induction of sleep, even for treatment of insomnia, has become less common with the recent entry of the alternative In terms of practical operational use, military forces in nonbenzodiazepines into the pharmaceutical marketplace. several westernized countries have used fast-acting ben- The several research studies examined and cited earlier zodiazepines [e.g., triazolam (Halcion) or temazapam provide sufficient indication that there would be some value (Restoril)] as hypnotics or as sedative sleep aids to help in conducting additional, controlled, medical, and perfor- "put one to sleep quickly" (Nicholson et al. 1980, 1985; mance research to examine the potential of applications of Penetar et al. 1989; Nicholson 1990, 1998, 2009; Wesensten some of the newer short-acting, and short-half-life hypnotics. et al. 1996; Caldwell et al. 2003). In such applications there is Just as they might provide assistance in aviation operations less concern over the immediate effects of the drugs on other (Caldwell et al. 2009; Caldwell 2011), potentially some of forms of performance, because the person in a nap-induced these newer hypnotics could be prescribed in safe sleeping state is "supposed to be sleeping." However, even though the environments when it is anticipated that commercial drivers U.S. Army continues to authorize limited use of triazolam for have plenty of sleep time and recovery time before returning pre-deployment rest or for gaining sleep during continuous to their driving chores. operations, it is now rarely prescribed (Caldwell et al. 2009). The U.S. military had concerns about individuals who upon awakening from benzodiazepine-induced sleep experienced ALTERNATIVE SLEEP-INDUCING COMPOUNDS hangover effects of antegrade short-term memory loss for There are a few additional chemical compounds that are being events/information occurring before going to sleep (Penetar used or could be used to help induce sleep, but that do not fit et al. 1989; IOM 1997). Consequently, the U.S. military has conveniently into the two categories described previously. mostly moved on from employing the quick-acting benzodi- These are outlined here. azepines, switching instead to the use of less risky compounds such as administering synthetic forms of the hormone mela- tonin for use as sleep aids (Caldwell and Caldwell 2003, 2005; AlterialTM Caldwell et al. 2009). More recently, U.S. military forces also have been employing several newer sleep-promoting non- Alterial is an OTC, all-natural sleep inducer, which claims to benzodiazepine compounds such as zolpidem (Ambien) and help people fall asleep fast, stay asleep longer, and improve the zaleplon (Sonata) for quick acting sleep initiation (Cald- quality of sleep all night long. Advertising claims report that well et al. 2009; Gore et al. 2010). Alterial contains natural ingredients (including melatonin, L-tryptophan, and valerian, along with additional ingredients) As DeGier (2005) and the ICADTS Working Group pointed that help calm, relax, and prepare one for a good night's sleep. out, some of the new short-acting hypnotics could possibly The claims are that Alterial does not leave a person feeling serve as viable treatments for insomnia with commercial groggy and irritable the next morning, but rather energized, drivers. The FMCSA has published medical guidance regard- refreshed, and ready to perform. The manufacturer's claim is ing use of hypnotics in drivers of commercial vehicles since that the mix of ingredients helps a person achieve deep, publication of the Psychiatry Medical Conference report in restful sleep without dependency or side effects.

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19 Assessment of Alterial. No research on AlterialTM and nighttime levels of melatonin already in the body quickly human performance measurement was located for this review; dissipate. As the foregoing indicates, it is important to take therefore, it is too early to make any predictive statements melatonin at the correct hour on the circadian physiological about this developmental compound. clock and to limit the amount of ambient light in the sleeping environment. Melatonin users are encouraged to give proper consideration to the timing of the onset of drowsiness and a Melatonin strong urge to sleep. Melatonin, a hormone secreted by the pineal gland in response It has been hypothesized by Mendelson (2005) that mela- to the onset of darkness, is believed to play a role in making us tonin and its agonists might act to affect circadian systems sleepy. Consequently, melatonin frequently has been referred through effects on melatonin receptors in the SCN (the site of to as our body's natural sleeping pill (Reiter and Robinson the so-called circadian timing system). From his studies on 1995). The benefits of both natural secretions of melatonin animals, Mendelson speculated that one possibility is that the and applications of synthetic melatonin (available in pill effects in humans are GABAergic, and the site of melatonin or tablet form in health food stores) elicit interest in this action may be similar to that of benzodiazepines, barbiturates, synthesis because of the role melatonin plays in offering adenosine, and ethanol (Mendelson 2005). [For a review of good potential to help people to feel drowsy, fall asleep, early research on melatonin and sleep see Dawson and Encel deal with insomnia, sleep better, and assist in re-setting (1993), and Cramer et al. (1974), who more than 35 years ago an individual's circadian clocks during work shift changes concluded that "melatonin induced sleep, behaviorally as well (i.e., coping with work shift lag). For more than a decade as by its polygraphic pattern, strikingly resembles natural synthetic melatonin has commonly been used for that purpose sleep."] Subsequent studies repeatedly support this finding. by some commercial drivers (Krueger 19962006). It has also Exogenously administered synthetic melatonin has been shown been widely used in other transportation applications to help to induce a slowing of the electroencephalogram (EEG) to travelers to combat jet lag when making transmeridian flights bring about sleep (Anton-Fay 1971, 1974; Cramer 1980). (Petrie et al. 1989; Lieberman and Mays 1994). Accordingly, the coverage of this compound is more extensive here than Sack et al. (2003a, b) labeled synthetic melatonin as one that provided for other sleep promotion compounds. of a new class of medicinal chemicals called chronobiotics because they are useful in adjusting the timing of circadian The ways in which melatonin might alter sleep still are not rhythms, capable of "resetting the biological clock," and well-understood, and medical researchers do not agree on therefore useful for dealing with jet lag, advanced and delayed exactly how melatonin helps people sleep. The internal core sleep-phase patterns, and for treatment of other forms of body temperature of humans has a distinct circadian rhythm, insomnia. Sack and colleagues (Sack et al. 2003a), as well as rising during the day and falling at night (a swing of only others (Santhi et al. 2008), declared melatonin use to be safe, about a degree Fahrenheit) and having a strong influence and, as a naturally occurring hormone, its administration causes on sleep. In general, it is easier to fall asleep when body fewer problems than many other "synthetic hypnotics." Taking temperature is falling, and it is easier to wake up or maintain synthetic melatonin seemingly has none of the negative side wakefulness when body temperature is on the rise. Melatonin's effects associated with traditional sleep medications. It does effect on body temperature is one of the keys to its ability not significantly disrupt the sleep architecture. Individuals who to enhance sleep. Melatonin is naturally synthesized in the take melatonin report sound nighttime sleep and no resultant pineal gland (a pea-size structure in the center of the brain) grogginess the next day, nor does melatonin interfere with a during the dark phase of the daily light/dark cycle and thus person's memory or performance the next day as some other it is intimately tied into our circadian rhythm physiology sleep aids do (Sack et al. 2003a; Santhi et al. 2008). (Comperatore and Krueger 1990). Researchers studying melatonin have searched for classical As the sun sets each day and darkness begins, our internal problems normally associated with traditional sleeping pills core temperature starts to drop and the pineal gland produces (e.g., suppression of REM sleep, losing the hypnotic impact a surge of a small quantity of melatonin (maintained at about over time with repeated use, and chance for addiction). a 0.3 mg level) that goes to all parts of the body. The nightly Melatonin exhibited no substantial concerns on these topics. fall in body temperature happens to coincide with the steep- After numerous studies administering high doses of synthetic est rise in nightly melatonin levels, which for adults takes melatonin (10 to 100 mg) Wurtman and colleagues at the place somewhere between 9 p.m. and midnight, depending Massachusetts Institute of Technology demonstrated that on one's unique circadian rhythm (Campbell and Broughton 1.0 mg, 0.3 mg, and even as little as 0.1 mg of melatonin can 1994; Reiter and Robinson 1995). Melatonin levels are main- hasten the onset of sleep, whatever the time of day (Lieberman tained in the human body during nighttime sleep (i.e., during et al. 1984; Zhdanova et al. 1995). darkness). The next morning, when sunlight hits the retina of the eyes, neural impulses signal the pineal gland to slow, and Hughes and Badia (1997) conducted a study examining eventually cease melatonin production and, in daylight, the the ability of melatonin in doses ranging from 1 to 40 mg to

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20 induce naps, followed shortly after awakening 4-h post-dose, (G. P. Krueger, personal communications with CMV drivers by administering tests of performance, memory, and fatigue. while teaching a decade of driver fatigue management classes, They found no carry-over fatigue and no negative effects 1996 through 2006). on memory or performance. Even high doses of synthetic melatonin (50 mg) showed no interference with elderly adults Military medical research illustrated that using synthetic (average age 84.5 years, who likely have no naturally occurring melatonin as a sleep aid can be an important contributor to melatonin owing to old age) on memory, concentration, or the repertoire of soldier fatigue countermeasures during mil- motor control (Singer et al. 1994). This is quite different from itary training and operations. O'Neill et al. (1996) addressed what would happen with most, if not all, benzodiazepines. similar applications for use of melatonin, suggesting that it can be of assistance to commercial drivers attempting to Today, researchers generally induce sleep in their lab combat fatigue. They suggested that melatonin would provide studies with considerably lower doses of from 0.1 to 0.3 mg advantages both in terms of assisting drivers to obtain needed of melatonin. It is important to note this because most syn- sleep during arduous work weeks and for use in adjusting to thetic preparations of melatonin sold in health food stores work schedule changes to combat work shift lag when their provide tablets ranging from 1 to 5 mg each, without specifying weekly schedules change (from night shifts to day shifts and how much melatonin is actually in the tablets (quantity and vice versa). Practical applications taught to commercial drivers quality assurance in such formulations is unspecified). included ingesting synthetic melatonin and then attempting to obtain daytime sleep by using completely blacked-out sleeper Benzodiazepines can become less effective after only two berths in Class 8 trucks or in completely blacked-out hotel or three nights of use. By contrast, melatonin does not lose its rooms during the day (Krueger and Brewster 2005). effectiveness over time, and may even become more effective with chronic use as a sleep aid. In a study described by Reiter and Robinson (1995) 2-mg doses of melatonin were given to Availability of Synthetic Melatonin elderly volunteers for two months, and at the end of the treat- ment period, the participants fell asleep even more quickly Synthesized into tablet forms, melatonin has been touted as one than they did after the first week of treatment. of the past decade's natural supplement "miracle compounds" and is sold in health food and grocery stores throughout the At the Walter Reed Army Institute of Research, Wesensten United States. Because melatonin is a synthesized hormone, et al. (2005a) set out to determine whether combining mela- in the United States at least, it is identified as a health food or tonin with low-dose zolpidem might promote daytime sleep dietary supplement and not as a drug. Therefore, synthetically without exacerbating performance impairments seen with high- produced melatonin is not subject to FDA approval. The FDA dose zolpidem alone. This research was initiated out of concern (www.fda.gov) merely states that melatonin is not a regulated that at effective (higher) doses zolpidem not only induces sleep, compound, and that no FDA-sponsored evaluation and testing but also impairs performance. They found no advantages to for safety, effectiveness, or purity has occurred. In some administering melatonin plus zolpidem "cocktails." Unlike European countries, synthetic melatonin is classified as a zolpidem, melatonin alone (5 mg) improved daytime sleep neurohormone and it cannot be sold over the counter. without impairing memory and vigilance (Wesensten et al. 2005a). In the United States, synthetic melatonin is readily avail- able in pill form and is inexpensive (a month's supply costs $12 to $20 at many health food stores). Because synthetic Driver Applications of Melatonin melatonin sold over the counter as a health food supplement is not governed by the FDA, its production is not required Experiments show that bright lights can trigger the response to adhere to "good manufacturing practices." Consumers to cease a person's melatonin production even at night--an are expected to trust what is on the label of the containers of intervention that has been successfully tried to keep individuals melatonin sold in stores. Independent laboratory tests of alert in night-shift factory work (Santhi et al. 2008). Research popular synthetic melatonin products have on occasion found findings are less clear about our body's ability to initiate pro- inconsistency regarding the amount of melatonin actually duction of melatonin simply by going into a darkened envi- found in commercially sold products and what appeared as ronment during daytime. However, a low dose of synthetic the contents on the container's labeling. melatonin can be used to "trick" the body into thinking that dusk (darkness) has arrived earlier, especially if one enters Ongoing medical research on melatonin continues to a darkened room to attempt to sleep (Santhi et al. 2008). explore such questions as: What dosage and use regimen is This has obvious implications for commercial drivers whose safe for administration of synthetic melatonin for specific work and rest schedules are subject to frequent time-of-day purposes? Most sleep research is done with doses of 0.1 and changes (shift workers). Climbing into a darkened truck sleeper 0.3 mg of melatonin, and it would appear that less than a berth after taking synthetic melatonin is a napping strategy 1-mg dose is probably recommended for most operational commonly advocated and used by commercial drivers applications. However, most readily available melatonin pills

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21 or tablets may contain higher doses than the levels of mela- year (National Sleep Foundation 1998). A survey in Detroit, tonin normally secreted into the body by the pineal gland Michigan, reported that in the previous year, 13% had used (0.3 mg at a semi-continuous level until daybreak). Many alcohol to aid sleep, 18% used medication (either prescription or health food stores sell synthetic melatonin in 1 to 5 mg tablets-- over the counter), and 5% had taken both (Johnson et al. 1998). if those tablets were all melatonin, that would amount to a dose more than a 10 times higher than is seemingly required Although drinking alcohol has some sleep-inducing prop- to induce sleep naturally, which may raise concerns about the erties, using it to help one to fall asleep often promotes sleep advisability of repeatedly treating our bodies to this synthetic disturbance as the night progresses (Mendelson 1987, 2005). overdose of a hormone that is so intimately linked to many of Although a "nightcap" drink may help a person fall asleep our important biological processes. Although to date no signi- more quickly, several hours later, as the alcohol oxidizes in ficant hazardous concerns have arisen, in actuality not enough the body, the sedative effect of the alcohol wears off and the scientific data have been collected to identify supplier quality alcohol may cause a rebound effect, making the person rest- assurance issues and any potential long-term effects derived less and agitated. In the second half of the night alcohol may from chronically taking synthetic melatonin supplements. disrupt dreaming (REM) sleep, thus making the period of sleep less restful and restorative of alertness. In that sense, Assessment of melatonin. Synthetic melatonin has been alcohol is not a very effective sleep sedative. demonstrated to be beneficial to some individuals some of the time in assisting them to fall asleep, especially at times of day Drinking a larger amount of alcohol before bedtime may that are not normally conducive to sleeping (e.g., daytime cir- also result in "hangover effects" the next morning, presenting cadian high points). It is essential that with its use additional symptoms of headache, grogginess, sleep inertia, and decreased steps are taken to ensure a darkened sleeping environment. alertness. Frequent consumption of alcohol is known to expose Melatonin offers promise as a sleep-inducing aid for commer- individuals to the risk of ethanol dependence or addiction. cial drivers, especially for their use as an aid to induce naps Alcohol has also been demonstrated to interact significantly during the daytime. Importantly, this topic suggests that some in individuals with obstructive sleep apnea, making the additional research may be needed to work out "sleep and alert- condition worse by increasing the number of apneic episodes ness management protocols and fatigue countermeasures" and causing deeper (worse) oxygen deprivation during sleep for proper and appropriate use of synthetic melatonin in the (Mendelson 2005). particular work settings of commercial drivers. What is needed is to determine "treatment protocols," to develop "guidance" for how and when to use melatonin for help in inducing sleep; Standard restrictions for commercial driving are that BAC for example, for naps. Such protocols might be developed in cannot exceed 0.04%. Since 1995, the FAA also set the lim- conjunction with additional guidance about the use of other its for pilots in the U.S. aviation industry at BAC of less than sleep-promoting compounds that may be suitable for truck, 0.04%, whereas the NTSB requires reporting any ethanol bus, and motorcoach drivers to use both at home and during value exceeding a BAC equal to 0.02%. operations on the road. Researchers could be asked to provide such guidance, perhaps ultimately promulgating it in the form Assessment of alcohol as a sleep aid. Although much of a user-friendly handbook. information about the effects of alcohol on performance and health is known, consuming alcohol as a sleep inducer may Additionally, because synthetic melatonin marketed in result in disrupted and less restorative sleep, as the alcohol health food stores and elsewhere is not governed by the good oxidizes over the several hours a person may be sleeping and manufacturing practices act, some way must be determined to therefore is not widely promulgated as a tenet of sleep main- ensure that those who produce or supply the product provide tenance guidance. The commercial driving community would sufficient quality assurance and indicate appropriate dose benefit from development of user-friendly information and levels for the intended purposes of the commercial driver. guidance documents on numerous chemical substances, including the use of alcohol as a sleep aid. Alcohol Used as a Sleep-Inducing Aid First-Generation Antihistamines Used as Sleep Aids Perhaps the most commonly used technique for inducing sleep or for resolving insomnia is to drink modest amounts of Millions of Americans experience problems with seasonal alcohol (ethanol); perhaps a glass of wine or one or two beers allergies, including sneezing and runny nose associated with before bedtime at night to relax and prepare to fall asleep. the common cold, as well as allergic rhinitis; itchy, watery Reiter and Robinson (1995) estimated that 20% of insomniacs eyes; and itchy throat (i.e., bodily response to pollens in the rely on alcohol to relax their muscles, ease their anxiety, and air). For decades, the most common, effective treatment for help them fall asleep. A telephone survey of approximately such allergies has been to take so-called first-generation 1,000 representative adults in the general population reported antihistamines of the diphenhydraminehydrochloride type that 10% had "self-medicated" with alcohol in the previous (which contain active ingredients of either diphenhydramine

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22 or doxylamine) to block H1 receptors and therefore counter these drugs interact in the body. First generation antihistamines the actions of histamine, a naturally occurring chemical in the are not recommended for chronic use, especially for those body (Kay et al. 1997; Kay 2000). Diphenhydramine is often individuals with glaucoma, peptic ulcer, bronchial asthma, used to treat the common cold, suppress coughs, and treat seizures, or prostate enlargement (Reiter and Robinson 1995). motion sickness (e.g., in Dramamine), and for reactions to insect bites, hives, and rashes. First-generation antihistamines Many other commercially available OTC sleep aids also produce mild to moderate sedative effects that cause (e.g., Compoz, Nytol, Sleep-Exe, and Somnitabs) contain drowsiness and sedation. A large segment of the sleep-deprived antihistamine as the active ingredient--most often as diphen- population occasionally turns to such first-generation anti- hydramine. However, to be truly effective as sleep aids, many histamines (with diphenhydramine) for assistance in falling such antihistamine products would have to contain a higher asleep, and it is this feature that is of principal interest in this dosage of diphenhydramine than what is normally inserted synthesis report. in each antihistamine pill or tablet by the manufacturers. Somnitabs, for example, contain 25 mg of diphenhydramine The concern for transportation safety is two-fold: (1) that per tablet. Some individuals in search of a suitable sleep aid drivers who regularly take first-generation antihistamines take Dramamine, normally used for prevention and treatment for allergy relief may encounter performance impairments of nausea, vomiting, or dizziness associated with motion sick- while driving a vehicle, owing to the drowsiness effects ness, because it contains 50 mg of diphenhydramine, which of maintenance levels of diphenhydramine in the body; may relax them somewhat and help them to fall asleep. and (2) occasionally taking first-generation antihistamines expressly for its sleep-promoting characteristics may leave one The research literature on the use of antihistamines to induce with next-day sleep inertia hangover effects on performance, sleep reports on several aspects related to operator perfor- and these may impact driving safety. mance. Kay et al. (1997) conducted a number of laboratory experiments demonstrating that first-generation histamine-1 The FMCSA has provided advisory guidance on use of receptor antagonists used to treat allergic disorders frequently first-generation antihistamines in the Neurology Medical cause sedation. Most sleep-inducing applications recommend Conference Report (FHWA 1988), and the Pulmonary Med- that a person take first-generation antihistamine tablets at least ical Conference report (Turino et al. 1991), where use of first- 30 min to 1 h before the desired sleep period. Generally, these generation antihistamines is not recommended. A more recent cause drowsiness and bring about reduced sleep onset latencies Pulmonary Evidence review and Medical Expert Panel report (versus placebo) anywhere from 1 to 8 h post-administration had not been published at the time of this writing. (Kay et al. 1997). However, some findings also indicate that first-generation antihistamines often can leave next-day The most widely known, first-generation antihistamine is drowsiness as a side effect (Mendelson 2005). For example, Benadryl--an OTC medication containing diphenhydramine, doxylamine has a half-life of 9 h, which means that if a person and that offers allergy relief. Allergy sufferers also commonly takes a doxylamine tablet at 2300 hours there will still be a sig- take chlorpheniramine, hydroxyzine, brompheniramine, prome- nificant amount in the bloodstream at 8 a.m. the next morning thazine, or doxylamine, along with other first-generation anti- (Carskadon 1993). Tolerance to daytime sleepiness appears histamines under such trade names as Unisom, Sleepgels, to develop rapidly, in approximately 4 days (Richardson et al. Dytuss, and Dramamine. All of them cross the blood 2002). First-generation antihistamine preparations often are brain barrier to block cortical histamine receptors. Antihista- not potent enough to resolve serious sleep difficulties or night- mine products containing diphenhydramine are accompanied time anxiety. The major concern for using antihistamines by caution warnings that they not be used when driving, oper- for sleep management is over their potential for leaving after- ating machinery, or performing other hazardous activities, as effects such as sleep inertia upon awakening. they may cause dizziness or drowsiness. Users also are warned that consuming alcohol while taking diphenhydramine may If a person is using first-generation antihistamines for increase drowsiness and dizziness. allergy relief (that is, he or she uses them not with intentions to aid in falling asleep per se, but rather to lessen allergic Benadryl, in several capsule forms, usually contains discomforts), it is critically important to note that bodily 25 mg of diphenhydramine. Recommended doses of diphen- maintenance levels of all first-generation antihistamines, espe- hydramine (e.g., Benadryl) for treatment of allergies in cially those containing diphenhydramine, have been demon- adults is 25 to 50 mg every 6 to 8 h, not to exceed 50 to 100 mg strated to diminish cognitive and psychomotor performance every 4 to 6 h. If the intended purpose is sedation; that is, for in healthy volunteers (Gengo and Gabos 1987; Gengo et al. treatment of occasional insomnia, then the first-generation 1989; Gengo and Manning 1990; Rice and Snyder 1993; antihistamines such as diphenhydramine may help a person Kay et al. 1997). Performance impairment may be of greater to induce sleep. For example, when it is being used as a sleep significance in patients when the allergic disorder per se aid, 50 mg diphenhydramine should be taken approximately adversely affects CNS function, as suggested in studies in 30 min before bedtime. Taking diphenhydramine while also which a reduction in cognitive functioning in patients was taking other sleep medicines or alcohol is not recommended, as exacerbated by diphenhydramine (Gengo 1996). Laboratory