Gastroesophageal Reflux Is Not For The Faint Of Heart

Where Does It Come From?

antacidsIf you’re among the more than sixty million American adults who have heartburn at least once a month, odds are you’ll pick an OTC medication rather than see your doctor. With what you hear on TV and what you see in magazines, you know there’s a slew of remedies to pick from. The one you buy, though, is the one with the most valuable coupon from the Sunday inserts, right?  Right. Heartburn is related to gastroesophageal reflux disease (GERD), but is not exactly the same thing. Heartburn is a sensation of tightness, pain or discomfort that follows an occurrence of acid reflux. Reflux first, heartburn (cardialgia in scientific terms) next. Sometimes there is no discomfort with reflux. Therefore, you can have reflux without heartburn, but you can’t have heartburn without reflux. Reflux is the fire; heartburn is the smoke. The pain is an indication that your esophagus is being damaged by stomach acid. If this happens often, you have GERD.

The exact cause of GERD is not well-defined, but there is awareness that a few factors might be involved, including hiatal hernia (when the stomach pushes up through a hole in the diaphragm), abnormally weak contraction of the lower esophageal sphincter muscle (a ring of muscles where the esophagus meets the stomach to keep food from going backward), and abnormal emptying of the stomach. A welcome announcement is that some of this can be temporary. The management of GERD should be individualized, depending on its seriousness. Mild occasional symptoms can often be controlled with conservative measures, among them diet. Some foods can trigger a GERD episode. Examples include fatty foods, fried foods, alcohol, caffeine, citrus fruits and juices, spicy foods, tomatoes and tomato products, chocolate, carbonated beverages, onions, garlic and dairy. Some foods may be particular to you.

Besides foods, contributors to the agony of reflux include obesity, an epidemic of which is sweeping not only the United States, but also the developed world. Body mass index (BMI) portends the occurrence of GERD (Hajar, 2012), and not just in adults. An increase of a child’s waist circumference, even if normal-weight, elevates risk of reflux disease (Quitadamo, 2012). Some medications can share the blame, too. Calcium channel blockers, theophylline (a bronchial dilator used to treat asthma), nitrates (used to relax blood vessels), and antihistamines are on the list. Smoking, by the way, weakens the lower esophageal sphincter.

How About My Baby?

The causes of infant reflux are easy to understand. The sphincter is insufficiently developed to do its job, so, until it matures, stomach contents creep backward, up and out. It also could be a case of eating too much too fast. Thankfully, this is a self-limiting process that usually resolves by six to twelve months of age (Jung, 2001). In infants, actual GERD is rare, albeit a more serious pathology that warrants medical diagnosis and intervention. Complaints of regurgitation are common during the first year of life, peaking at 4 months (Nelson, 1997).

Here, food intolerance, and especially that of cow’s milk, cannot be discounted, despite what Grandma says about the family history of milk intake. No one can explain why, notwithstanding its use for years, cow’s milk is suddenly a culprit in juvenile gastric complaints of this nature (Semeniuk, 2006). Elimination-challenge studies done in Denmark have demonstrated that cow’s milk hypersensitivity is a real issue (Nielsen, 2004). Inconsolable crying, failure to gain weight, refusing food, bad breath, and burping and hiccups are common symptoms. If the baby vomits, good. Otherwise the pain is doubled as the acid goes back down and multiplies the damage to the esophagus.

What To Do?

If you’ve used all the antacids on the market and have decided to move up to something more potent, the next step is histamine 2 receptor blockers, a.k.a. Pepcid, Tagamet, or Zantac. These drugs can heal the esophagus 50% of the time by blocking the early stages of acid production. No acid, no hurt. But insufficient stomach acid interferes with food digestion, especially of protein. Constipation, dizziness, skin rash, hallucinations, and confusion are side effects. But H2 inhibitors start to work in less than an hour. Yay. Next up the ladder are proton pump inhibitors, the most potent of GERD medications. These include Prilosec, Prevacid and Nexium. They last longer in the body than H2 blockers, but take longer to get started. These have even neater side effects, like tremors, palpitations, muscle spasms, and yellowing eyes. But none of these happen to all people, and some never happen to anybody you know.

How about a natural approach?  Stop eating three hours before bedtime and don’t go supine right after a meal. Elevate the head of your bed six inches to work with gravity. Stop eating when you’re satisfied, not when you’re so filled you can’t get up from the table. Lose that gut.

Is There Something I Can Take?

Mucus is the protective barrier between acid and the gastric lining. The amount of mucus in the esophagus is negligible, but may be just enough to protect against the damage and discomfort caused by refluxed acid (Dixon, 2001). Because it is known to improve the secretion of mucus, licorice extract (deglycyrrhizinated licorice), either singly or as part of an herbal complex, demonstrated capability to attenuate acid reflux symptoms (Larkworthy, 1975) by improving the gastric environment (vanMarle, 1981). Carbenoxolone, a synthesized licorice preparation, exhibited effectiveness comparable to drug therapy (Bickel 1981) at increasing mucus thickness.

A combination product called STW5, containing chamomile, clown’s mustard, angelica root, caraway, milk thistle, celandine and licorice root proved to be as effective as cimetidine (Tagamet) in protecting against acid-induced ulcerations (Khayyal, 2001)
and was identified as a valid therapeutic option for those who prefer phytotherapy to drugs (Melzer, 2004) (Madisch, 2001).

Melatonin is a supplemental hormone produced by the pineal gland that people use to help them sleep. In the gut it’s been identified as an important signaling molecule, where it seems to have a local effect on esophageal mucosa, stimulating the production of prostaglandin E2, which is protective of that mucus layer (Konturek, June, 2007). Additionally, melatonin inhibits gastric acid secretion while enhancing gastrin release, thus stimulating the sphincter to contract and limit esophagus contact with acid (Konturek, Dec, 2007). Even though melatonin trials are limited, results are significant.

Studies that examine alternative approaches to GERD treatment are in the works. While it is such that proton pump inhibitors (PPI’s), often the first line treatment, are effective for non-erosive GERD, their applicability to other GERD patients is under question. An odd thing about PPI’s is they are often used to diagnose GERD based on a person’s response to the drug. A favorable response indicates that GERD has been effectively addressed. That, however, does not necessarily indicate healing of the underlying pathology, which is almost always a problem with the lower esophageal sphincter. A low-carb diet and weight loss might just be the best bet.


Achem SR, Robinson M.
A prokinetic approach to treatment of gastroesophageal reflux disease.
Dig Dis. 1998 Jan-Feb;16(1):38-46.

Altman KW, Stephens RM, Lyttle CS, Weiss KB.
Changing impact of gastroesophageal reflux in medical and otolaryngology practice.
Laryngoscope. 2005 Jul;115(7):1145-53.

Bickel M, Kauffman GL Jr.
Gastric gel mucus thickness: effect of distention, 16,16-dimethyl prostaglandin e2, and carbenoxolone.
Gastroenterology. 1981 Apr;80(4):770-5.

Champion MC.
Prokinetic therapy in gastroesophageal reflux disease.
Can J Gastroenterol. 1997 Sep;11 Suppl B:55B-65B.

J Dixon PhD, V Strugala PhD, S M Griffin MD, P W Dettmar PhD, A Allen DPhil and J P Pearson PhD
Esophageal mucin: an adherent mucus gel barrier is absent in the normal esophagus but present in columnar-lined Barrett’s esophagus
The American Journal of Gastroenterology (2001) 96, 2575–2583

Guslandi M, Cambielli M, Bierti L, Tittobello A.
Effect of carbenoxolone and cimetidine on gastric mucin.
Clin Ther. 1980;3(1):40-2.

Hajar N, Castell DO, Ghomrawi H, Rackett R, Hila A.
Impedance pH Confirms the Relationship Between GERD and BMI.
Dig Dis Sci. 2012 Mar 27. [Epub ahead of print]

Jung AD.
Gastroesophageal reflux in infants and children.
Am Fam Physician. 2001 Dec 1;64(11):1853-60.

Khan M, Santana J, Donnellan C, Preston C, Moayyedi P.
Medical treatments in the short term management of reflux oesophagitis
Cochrane Database Syst Rev. 2007 Apr 18;(2):CD003244.

Khayyal MT, el-Ghazaly MA, Kenawy SA, Seif-el-Nasr M, Mahran LG, Kafafi YA, Okpanyi SN.
Antiulcerogenic effect of some gastrointestinally acting plant extracts and their combination.
Arzneimittelforschung. 2001;51(7):545-53.

Kim DC, Kim SH, Choi BH, Baek NI, Kim D, Kim MJ, Kim KT.
Curcuma longa extract protects against gastric ulcers by blocking H2 histamine receptors.
Biol Pharm Bull. 2005 Dec;28(12):2220-4.

Kolarski V, Petrova-Shopova K, Vasileva E, Petrova D, Nikolov S.
Erosive gastritis and gastroduodenitis–clinical, diagnostic and therapeutic studies.
Vutr Boles. 1987;26(3):56-9.

Konturek SJ, Konturek PC, Brzozowski T, Bubenik GA.
Role of melatonin in upper gastrointestinal tract.
J Physiol Pharmacol. 2007 Dec;58 Suppl 6:23-52.

Konturek SJ, Zayachkivska O, Havryluk XO, Brzozowski T, Sliwowski Z, Pawlik M, Konturek PC, Cześnikiewicz-Guzik M, Gzhegotsky MR, Pawlik WW.
Protective influence of melatonin against acute esophageal lesions involves prostaglandins, nitric oxide and sensory nerves.
J Physiol Pharmacol. 2007 Jun;58(2):361-77.

Larkworthy W, Holgate PF.
Deglycyrrhizinized liquorice in the treatment of chronic duodenal ulcer. A retrospective endoscopic survey of 32 patients.
Practitioner. 1975 Dec;215(1290):787-92.

Lieberman D.
Treatment approaches to reflux oesophagitis.
Drugs. 1990 May;39(5):674-80.

Madisch A, Melderis H, Mayr G, Sassin I, Hotz J.
A plant extract and its modified preparation in functional dyspepsia. Results of a double-blind placebo controlled comparative study.
Z Gastroenterol. 2001 Jul;39(7):511-7.

Madisch A, Holtmann G, Mayr G, Vinson B, Hotz J.
Treatment of functional dyspepsia with a herbal preparation. A double-blind, randomized, placebo-controlled, multicenter trial.
Digestion. 2004;69(1):45-52. Epub 2004 Jan 30.

Maton PN, Burton ME.
Antacids revisited: a review of their clinical pharmacology and recommended therapeutic use.
Drugs. 1999 Jun;57(6):855-70.

 Meletis, Chris D. and Zabriski, Nieski. “Clinical Natural Medicine Handbook.” New Rochelle, NY: Mary Ann Liebert, Inc., 2008. Pp. 208-220

Melzer J, Rösch W, Reichling J, Brignoli R, Saller R.
Meta-analysis: phytotherapy of functional dyspepsia with the herbal drug preparation STW 5 (Iberogast).
Aliment Pharmacol Ther. 2004 Dec;20(11-12):1279-87.

Nelson SP, Chen EH, Syniar GM, Christoffel KK.
Prevalence of symptoms of gastroesophageal reflux during infancy. A pediatric practice-based survey.
Arch Pediatr Adolesc Med. 1997 Jun;151(6):569-72.

Nielsen RG, Bindslev-Jensen C, Kruse-Andersen S, Husby S.
Severe gastroesophageal reflux disease and cow milk hypersensitivity in infants and children: disease association and evaluation of a new challenge procedure.
J Pediatr Gastroenterol Nutr. 2004 Oct;39(4):383-91.

Niemcryk SJ, Joshua-Gotlib S, Levine DS.
Outpatient experience of patients with GERD in the United States: analysis of the 1998-2001 National Ambulatory Medical Care Survey.
Dig Dis Sci. 2005 Oct;50(10):1904-8.

Ness-Jensen E, Lindam A, Lagergren J, Hveem K.
Changes in prevalence, incidence and spontaneous loss of gastro-oesophageal reflux symptoms: a prospective population-based cohort study, the HUNT study.
Gut. 2011 Dec 21. [Epub ahead of print]

NIH Publication No. 07–0882
May 2007
National Digestive Diseases Information Clearinghouse
Heartburn, Gastroesophageal Reflux (GER), and Gastroesophageal Reflux Disease (GERD)

O’Mahony R, Al-Khtheeri H, Weerasekera D, Fernando N, Vaira D, Holton J, Basset C.
Bactericidal and anti-adhesive properties of culinary and medicinal plants against Helicobacter pylori.
World J Gastroenterol. 2005 Dec 21;11(47):7499-507.

Lyn Patrick, ND
Gastroesophageal Reflux Disease (GERD): A Review of Conventional and Alternative

Altern Med Rev 2011;16(2):116-133

Quitadamo P, Buonavolontà R, Miele E, Masi P, Coccorullo P, Staiano A.
Total and Abdominal Obesity are Risk Factors for Gastroesophageal Reflux Symptoms in Children.
J Pediatr Gastroenterol Nutr. 2012 Mar 20. [Epub ahead of print]

Rees WD, Rhodes J, Wright JE, Stamford LF, Bennett A.
Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin.
Scand J Gastroenterol. 1979;14(5):605-7.

Richter JE, Bradley LC.
Psychophysiological interactions in esophageal diseases.
Semin Gastrointest Dis. 1996 Oct;7(4):169-84.

Salim AS.
Sulfhydryl-containing agents in the treatment of gastric bleeding induced by nonsteroidal anti-inflammatory drugs.
Can J Surg. 1993 Feb;36(1):53-8.

Semeniuk J, Kaczmarski M.
Gastroesophageal reflux (GER) in children and adolescents with regard to food intolerance.
Adv Med Sci. 2006;51:321-6.

Sontag SJ.
The medical management of reflux esophagitis. Role of antacids and acid inhibition.
Gastroenterol Clin North Am. 1990 Sep;19(3):683-712.

van der Pol R, Smite M, Benninga MA, van Wijk MP.
Non-pharmacological therapies for GERD in infants and children.
J Pediatr Gastroenterol Nutr. 2011 Dec;53 Suppl 2:S6-8.

van Marle J, Aarsen PN, Lind A, van Weeren-Kramer J.
Deglycyrrhizinised liquorice (DGL) and the renewal of rat stomach epithelium.
Eur J Pharmacol. 1981 Jun 19;72(2-3):219-25.

Vologzhanina LG, Vladimirskiĭ EV.
Efficacy of the drinking magnesium-calcium sulfate mineral water in the combined treatment of duodenal ulcer comorbid with gastroesophageal reflux.      
Vopr Kurortol Fizioter Lech Fiz Kult. 2005 Nov-Dec;(6):17-9.

WebMD Health News. Dec. 22, 2011
Study: Acid Reflux on the Rise
Obesity Increase Likely to Blame, Researchers Say
Salynn Boyles;  Reviewed by Louise Chang, MD

Wiener GJ, Morgan TM, Copper JB, Wu WC, Castell DO, Sinclair JW, Richter JE.
Ambulatory 24-hour esophageal pH monitoring. Reproducibility and variability of pH parameters.
Dig Dis Sci. 1988 Sep;33(9):1127-33.

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

The Sweet Sweep of Sleep

sleepy-womanAhh, the sweet balm that soothes the nerves and restores the soul at the end of the day. Sadly, for some of us it is elusive, and its intangible rewards sporadic. Sleep. It can get interrupted, disrupted and corrupted. Even in its worst state, sleep can be the most desired gift for the time.

There have been thousands of sleep studies over the years, but science still isn’t completely sure why we need it. “Completely” is the key word. One goofy answer is that we sleep to cure sleepiness. It’s agreed that sleep gives the body a chance to rejuvenate. That we know about rapid eye movement sleep (REM) shows that sleep is not a totally static process for the brain. Asleep, it still needs calories. The amount of sleep a person needs is purely singular, and depends on his or her circadian rhythm, which is that twenty-four-hour cycle of biological activities that occur regularly and dependably regardless of illumination. What sleep experts look for are maximum melatonin levels and minimum core body temperature, reporting that one should be asleep at least six hours before lowest temp is achieved. When these occur just after the middle of the sleep cycle, the timing is deemed to be just right (Wyatt, 1999) (Dijk, 2002) (Taillard, 2011).

Too much sleep can be as unhealthy as too little. Where lack of sleep can increase the chance of accidents and CVD issues, a plethora might increase risk of other-cause mortality (Ferrie, 2007). Because animals with brains sleep, we might infer that it’s a needed pastime. Regardless of who and how much, the fact is that we heal better when we sleep, the immune system gets a chance to recoup, memory and cognitive function improve, and a general restoration takes place. And now there’s another reason to cut Z’s…the prevention of Alzheimer’s disease and related cognitive disorders.

Whether it’s more hypothetical than proven, a new study released by the University of Rochester hints that a good night’s sleep can ward off Alzheimer’s disease (Xie, 2013). Lead author, Maiken Nedergaard, notes that sleep serves a vital function, a collective term that includes washing debris out of the brain. The brain produces toxic waste as it works every day. This new study says that while we sleep the brain shrinks in size, allowing the spaces between brain cells to enlarge so that junk can be washed out by the cerebral spinal fluid that is pumped around it (Underwood, 2013).

Researchers in Nedergaard’s lab noticed that mice whose brains were probed while conscious would sometimes fall asleep. When that happened, cerebrospinal fluid would rush into the brain’s interstitial space and wash away cellular debris. Delving into the phenomenon, they observed that the brain’s glial cells, a web of connective tissue that supports neurons, expand during wakefulness to reduce the space between cells and shut off the movement of fluid. During sleep, the interstitial volume changes again.

Interstitial fluid is a solution that bathes the area around cells with a concoction that contains sugars, salts, fatty acids, amino acids, coenzymes, hormones, and neurotransmitters. Different areas of the body have different concentrations of these substances. Little attention was paid to the area between cells before Nedergaard’s investigation because that was considered just space (Herculano-Houzel, 2013).  The brain’s drainage system was termed the glymphatic system, a functional waste management setup that removes extracellular proteins and metabolic waste products from the pathway, but reliant upon the glia instead of a dedicated, albeit absent, lymphatic network.

To double-check their findings, scientists injected the mouse brains with proteins that parallel those implicated in Alzheimer’s disease (AD)—the amyloids. These were washed away faster from the brains of sleeping mice than their awake peers. It is the accumulation of these soluble proteins at the synapses that is believed by some to initiate the disease (Tomiyama, 2010) (Esparza, 2013).

Fragmented sleep is that which does not include much slow-wave sleep and is not refreshing. Total time asleep is less than normal, affecting about a third of all adults. Unfragmented-consolidated sleep is divided into two periods with a gap between. This “bi-phasic” sleep is common and is something people can adjust to. Fragmented sleep is characteristic of Alzheimer’s and Parkinson’s patients, though it is common to the aging process. However, there is debate about whether increased fragmentation is a normal part of aging or indicative of an underlying pathology. Regardless, it is associated with cognitive performance (Lim, 2013). In any case, it’s unpleasant to experience the next day’s sleepiness. There are pharmaceutical sleep aids, but the natural ones, such as valerian and melatonin, are safer.

Melatonin is produced in the brain, but decreases with age and in those with Alzheimer’s disease. There are data from clinical trials demonstrating that melatonin can slow the progression of cognitive impairment in AD patients by protecting neural cells from amyloid-mediated toxicity and by arresting the formation of plaques in the first place (Lin, 2013). As a noted anti-oxidant, melatonin is able to scavenge the free radicals that are likewise implicated in AD etiology (He, 2010), and to improve mitochondrial energy metabolism (Cheng, 2006) (Liu, 2013). Produced in the pineal gland from tryptophan, melatonin, as a sleep aid, lowers body temperature and blood pressure, a condition required for sound sleep.

If sleep can clear the abnormal accumulation of neurotoxins (Rothman, 2012), and if melatonin can help resolve dysfunctional sleep patterns, then this bag of ideas might just hold more than water.


Orfeu M. Buxton, Sean W. Cain, Shawn P. O’Connor, James H. Porter, Jeanne F. Duffy,
Wei Wang, Charles A. Czeisler and Steven A. Shea
Adverse Metabolic Consequences in Humans of Prolonged Sleep Restriction Combined with Circadian Disruption
Sci Transl Med. 11 April 2012; Vol. 4 Issue 129: p. 129ra43

Cheng Y, Feng Z, Zhang QZ, Zhang JT.
Beneficial effects of melatonin in experimental models of Alzheimer disease.
Acta Pharmacol Sin. 2006 Feb;27(2):129-39.

Daniel A. Cohen, Wei Wang, James K. Wyatt, Richard E. Kronauer, Derk-Jan Dijk, Charles A. Czeisler and Elizabeth B. Klerman
Uncovering Residual Effects of Chronic Sleep Loss on Human Performance
Sci Transl Med. 13 January 2010; Vol. 2 Issue 14: p. 14ra3

Dijk DJ, Lockley SW.
Integration of human sleep-wake regulation and circadian rhythmicity.
J Appl Physiol. 2002 Feb;92(2):852-62.

Dragicevic N, Copes N, O’Neal-Moffitt G, Jin J, Buzzeo R, Mamcarz M, Tan J, Cao C, Olcese JM, Arendash GW, Bradshaw PC.
Melatonin treatment restores mitochondrial function in Alzheimer’s mice: a mitochondrial protective role of melatonin membrane receptor signaling.
J Pineal Res. 2011 Aug;51(1):75-86.

Dragicevic N, Smith A, Lin X, Yuan F, Copes N, Delic V, Tan J, Cao C, Shytle RD, Bradshaw PC.
Green tea epigallocatechin-3-gallate (EGCG) and other flavonoids reduce Alzheimer’s amyloid-induced mitochondrial dysfunction.
J Alzheimers Dis. 2011;26(3):507-21.

Dragicevic N, Delic V, Cao C, Copes N, Lin X, Mamcarz M, Wang L, Arendash GW, Bradshaw PC.
Caffeine increases mitochondrial function and blocks melatonin signaling to mitochondria in Alzheimer’s mice and cells.
Neuropharmacology. 2012 Dec;63(8):1368-79.

Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman DM, Brody DL.
Amyloid-β oligomerization in Alzheimer dementia versus high-pathology controls.
Ann Neurol. 2013 Jan;73(1):104-19.

Ferrie JE, Shipley MJ, Cappuccio FP, Brunner E, Miller MA, Kumari M, Marmot MG.
A prospective study of change in sleep duration: associations with mortality in the Whitehall II cohort.
Sleep. 2007 Dec;30(12):1659-66.

He H, Dong W, Huang F.
Anti-amyloidogenic and anti-apoptotic role of melatonin in Alzheimer disease.
Curr Neuropharmacol. 2010 Sep;8(3):211-7.

Suzana Herculano-Houzel
Sleep It Out
Science. 18 October 2013; Vol. 342 no. 6156: pp. 316-317

Huang Y, Potter R, Sigurdson W, Santacruz A, Shih S, Ju YE, Kasten T, Morris JC,
Effects of age and amyloid deposition on Aβ dynamics in the human central nervous system.
Arch Neurol. 2012 Jan;69(1):51-8.

Jáuregui-Barrutia A, Tijero-Merino B, Gómez-Esteban JC, Zarranz JJ.
Sleep disorders in Parkinson’s disease: REM sleep behaviour disorder and restless legs syndrome.
Rev Neurol. 2010 Feb 8;50 Suppl 2:S15-9.

Ju YE, McLeland JS, Toedebusch CD, Xiong C, Fagan AM, Duntley SP, Morris JC, Holtzman DM
Sleep quality and preclinical Alzheimer disease.
JAMA Neurol. 2013 May;70(5):587-93.

Lee JW, Lee YK, Ban JO, Ha TY, Yun YP, Han SB, Oh KW, Hong JT.
Green tea (-)-epigallocatechin-3-gallate inhibits beta-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NF-kappaB pathways in mice.
J Nutr. 2009 Oct;139(10):1987-93.

Lim AS, Kowgier M, Yu L, Buchman AS, Bennett DA.
Sleep Fragmentation and the Risk of Incident Alzheimer’s Disease and Cognitive Decline in Older Persons.
Sleep. 2013 Jul 1;36(7):1027-1032.

Lin L, Huang QX, Yang SS, Chu J, Wang JZ, Tian Q.
Melatonin in Alzheimer’s disease.
Int J Mol Sci. 2013 Jul 12;14(7):14575-93.

Liu XJ, Yuan L, Yang D, Han WN, Li QS, Yang W, Liu QS, Qi JS.
Melatonin protects against amyloid-β-induced impairments of hippocampal LTP and spatial learning in rats.
Synapse. 2013 Sep;67(9):626-36.

Ni C, Tan G, Luo A, Qian M, Tang Y, Zhou Y, Wang J, Li M, Zhang Y, Jia D, Wu C, Guo X.
Melatonin premedication attenuates isoflurane anesthesia-induced β-amyloid generation and cholinergic dysfunction in the hippocampus of aged rats.
Int J Neurosci. 2013 Apr;123(4):213-20.

Rothman SM, Mattson MP.
Sleep disturbances in Alzheimer’s and Parkinson’s diseases.
Neuromolecular Med. 2012 Sep;14(3):194-204.

Taillard J, Philip P, Claustrat B, Capelli A, Coste O, Chaumet G, Sagaspe P.
Time course of neurobehavioral alertness during extended wakefulness in morning- and evening-type healthy sleepers.
Chronobiol Int. 2011 Jul;28(6):520-7.

Tomiyama T.
Involvement of beta-amyloid in the etiology of Alzheimer’s disease
Brain Nerve. 2010 Jul;62(7):691-9.

Emily Underwood
Sleep: The Brain’s Housekeeper?
Science. 18 October 2013; Vol. 342 no. 6156: p. 301

Wyatt JK, Ritz-De Cecco A, Czeisler CA, Dijk DJ.
Circadian temperature and melatonin rhythms, sleep, and neurobehavioral function in humans living on a 20-h day.
Am J Physiol. 1999 Oct;277(4 Pt 2):R1152-63.

Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O’Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M.
Sleep drives metabolite clearance from the adult brain.
Science. 2013 Oct 18;342(6156):373-7.

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.