Stalking the Elusive REM: The Biochemistry of OTC Sleep Aids


Confronting insomnia.Many of us have trouble falling asleep or staying asleep. There are several non-prescription options to help with this. This is a review of how those options affect sleep, as well as cautions to observe when choosing a sleep aid.


Anybody who has taken the allergy medicine Benadryl or its associated generic (diphenhydramine) has probably noticed that it can make you really drowsy. In fact, diphenhydramine is a common ingredient in medications with words like “PM” or “Night Time” in their names. Other anticholinergics, such as those found in motion sickness medications, also cause sleepiness.

One might be tempted to use diphenhydramine as a bedtime sleep aid. However, recent research (2015) indicates that this is not a good idea. The Adult Changes in Thought (ACT) study followed about 3,500 seniors over time. It found that those who had taken anticholinergics such as diphenhydramine regularly for three years or more had a 52% higher risk of dementia (especially Alzheimer’s disease) than did those who had taken these medications for a short period (a month or less).

How could anticholinergics be related to dementia and memory loss? As their name suggests, they work by antagonizing, or reducing the uptake of, acetylcholine. There is extensive research showing that acetylcholine plays a key role in the normal functioning of memory, particularly in the formation of memories. One of the ways acetylcholine contributes to memory formation is by increasing the activity of NMDA (N-methyl-D-aspartate) receptors in the brain. Therefore, it makes perfect sense that drugs that suppress the action of acetylcholine would be associated with disorders involving memory, such as Alzheimer’s.

Acetylcholine is an important neurotransmitter. In addition to its role in memory formation, it activates muscles and regulates excitatory responses in the peripheral nervous system. In the central nervous system, it helps sustain attention while we are awake. While we are asleep, it promotes REM (rapid eye movement) during sleep.

This means that diphenhydramine, which suppresses acetylcholine, in turn inhibits REM sleep. Since REM sleep is essential to awakening mentally refreshed from a night of sleep, diphenhydramine is not a particularly good sleep aid. Although it helps people drop off to sleep, it does not produce a good quality of sleep.

What if you have been taking anticholinergics, and would like to increase the amount of acetylcholine in your body to help repair memory deficits? Acetylcholine is not available in food sources, but it is built from choline, in which particular foods are rich. These include eggs, various kinds of liver, salmon, low-fat dairy, Brussels sprouts, peanuts, and wheat germ.


Valerian root, which comes from a flowering herb, is known for its efficacy in relaxation and sedative effects. By increasing the amount of the neurotransmitter gamma aminobutryic acid (GABA), valerian helps calm the nerve cells in the brain, reducing anxiety. GABA counterbalances the action of the excitatory neurotransmitter glutamate, helping to keep the brain from being, literally, overexcited. For people whose insomnia is caused or compounded by anxiety or a “racing mind,” valerian can be especially helpful.

Valerian has been clinically proven to significantly improve sleep quality, including rapidity in entering slow-wave sleep (a restful, deep sleep), reduced sleep disturbances, and an increase in the percentage of REM sleep.

Valerian may slow down how quickly the liver metabolizes certain common prescription drugs (such as statins and tricyclic antidepressants), as well as alcohol. If you are taking prescription medications, be sure to check with your pharmacist or physician about drug interactions. Caution should also be taken in combining it with black cohosh, another herbal remedy. The NIH warns against taking it if you have liver disease, although none of the compounds in it are known to be hepatotoxic.


Melatonin is a naturally occurring hormone (produced by the pineal gland, in response to darkness) that can be taken as a supplement. It has been clinically demonstrated to improve perceived sleep quality and to reduce awakenings, even in settings in which noise and light are present.

There are anecdotal reports that melatonin is associated with increased vividness and, to some degree, bizarreness, in dreams. However, the experimental evidence for this is weak, and it appears to vary from individual to individual. Most people tolerate it well.

Melatonin is considered quite safe, especially in the short term (up to two years of regular use); long-term effects have not been studied. Melatonin can interact with some prescription drugs (such as anticoagulants, diabetes medications, and birth control pills), so one should consult a pharmacist or physician before using it.

Tryptophan and Serotonin:

Tryptophan is an amino acid that serves as a precursor for both serotonin and melatonin.

Serotonin is a compound that promotes feelings of safety and relaxation, which are conducive to sleep. However, while it helps people get to sleep and reduces sleep disturbances, it also counteracts acetylcholine and is a suppressor of REM sleep. A serotonin deficiency can result in sleep disturbance, as well as anxiety, depression, and overeating.

You can obtain tryptophan, which helps the brain produce serotonin, from eating carbohydrates, especially whole grain oats, brown rice, corn and quinoa. Turkey, nuts, and seeds are also good sources of tryptophan. Serotonin itself can be obtained from some dietary sources, such as walnuts, pineapples, bananas, kiwis, plums, and tomatoes.


In summary, there are several nonprescription sleep aids available, through over-the-counter supplements and through food sources. Anticholinergics are probably not a good choice due to recently discovered risks, whereas supplements such as melatonin and valerian have some promise, depending on what other medications a person is taking.

For Further Reading:

Bauer, B. (2016). Is melatonin a helpful sleep aid — and what should I know about melatonin side effects? Published online by the Mayo Clinic on November 11, 2014. Retrieved online August 2, 2016 at:

Biala, D. (2015). Food sources of acetylcholine. Published online by Livestrong, January 18, 2015. Retrieved online August 2, 2016 from:

Buchanan, K., M. Petrovic, S. Chamberlain, N. Marrion, and J. Mellor. (2010). Facilitation of long-term potentiation by muscarinic M(1) receptors is mediated by inhibition of SK channels. Neuron. 2010 Dec 9;68(5):948-63.  doi: 10.1016/j.neuron.2010.11.018.

Gray, S., M. Anderson, S. Dublin, J. Hanlon, R. Hubbard, R. Walker, O. Yu, P. Crane, and E. Larson. (2015). Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study. JAMA Intern Med. 175(3):401-407. doi:10.1001/jamainternmed.2014.7663.

Hall, R. (1998). Neurotransmitters and Sleep. Published online by Missouri University of Science & Technology. Retrieved online July 31, 2016, at:

Hasselmo, M. (2006). The Role of Acetylcholine in Learning and Memory. Curr Opin Neurobiol. 2006 Dec; 16(6): 710–715. doi: 10.1016/j.conb.2006.09.002

Huang, H-W, B-L Zheng, L. Jiang, Z-T Lin, G-B Zhang, L. Shen, and X-M Xi. (2015). Effect of oral melatonin and wearing earplugs and eye masks on nocturnal sleep in healthy subjects in a simulated intensive care unit environment: which might be a more promising strategy for ICU sleep deprivation? Critical Care 2015 19:124 doi: 10.1186/s13054-015-0842-8

O’Mahony, S., G. Clarke, Y. Borrea, T. Dinan, and J. Cryan. (2015). Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behavioural Brain Research 277 (2015) 32–48.

Vazquez, J., and H. Badhdoyan. (2001). Basal forebrain acetylcholine release during REM sleep is significantly greater than during waking. Am J Physiol Regul Integr Comp Physiol. 2001 Feb; 280(2):R598-601.

Winkler, J., S. Suhr, F. Gage, L. Thal, and L. Fisher. (1995). Essential role of neocortical acetylcholine in spatial memory. Nature. 1995 Jun 8;375(6531):484-7.

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