Paradoxical Excitation from DPH Sleeping Pills

When you think about sleeping pills, you probably imagine medications that make you drowsy. After all, the whole point of sleeping pills is to help you fall asleep easier. In recent years “PM” pain relievers have proliferated. I am talking about drugs like Advil PM, Aleve PM and Tylenol PM. These OTC pain relievers contain the antihistamine diphenhydramine (DPH). It is the antihistamine found in the allergy medicine Benadryl. These DPH sleeping pills and pain relievers are supposed to make you drowsy so you can fall asleep. But some people experience paradoxical excitation. Readers have described a range of problems.

Restlessness from DPH Sleeping Pills

Q. I have a hard time falling asleep without an over-the-counter sleeping pill. Diphenhydramine makes me anxious and restless at the same time the drowsiness hits.

It’s a very uncomfortable experience to be falling asleep at the same time my mind is racing and my body is restless. Is there something safer? Could magnesium be helpful?

Would Magnesium Be Helpful?

A. We have heard from a number of readers that DPH makes them restless. Others agree that a magnesium supplement taken about an hour before bedtime might be beneficial.

One reader shared this experience:

“A sleep doctor recommended oral magnesium. What a relief it has been! I don’t know how I could get along without it.”

Another reader reported:

“My doctor suggested magnesium glycinate. It was life changing. I take a 240 mg capsule about one to two hours before going to bed.”

A review of the scientific literature concluded that there is insufficient evidence to prove magnesium works for insomnia (BMC Complementary Medicine and Therapies, April 17, 2021).

The scientists conclude:

“Given that oral magnesium is very cheap and widely available, the authors found no evidence preventing the recommendation of oral magnesium supplementation for insomnia symptoms in older adults.”

Restless Legs with DPH

Q. I know that many people take the antihistamine diphenhydramine to help them sleep. Unlike them, I feel agitated, not drowsy, when I take it. This drug often gives me restless legs or leg cramps.

A. Researchers call your reaction to diphenhydramine (Benadryl) “paradoxical excitation.” Some have hypothesized that this could be explained by genetic differences in enzyme activity (CNS Spectrums, Feb. 2008).

Other readers have also experienced RLS (restless leg syndrome) after taking diphenhydramine (DPH). We find it disturbing that DPH is a component in most “PM” pain relievers. Using a sleep aid that might cause leg movements or agitation seems potentially counterproductive.

DPH Sleeping Pills Wake Him Up:

Q. Any product like a nighttime pain reliever that contains the antihistamine diphenhydramine (DPH) has the opposite effect on me, keeping me awake all night with jitters and restless-leg type symptoms. This is the opposite of what one would expect or want.

As a result, I have to be very careful about what I take when I can’t sleep. I would really like to understand why I have this reaction to DPH products. Also, what can I can take when I need help with sleep?

Paradoxical Excitation with DPH Sleeping Pills:

A. You are describing “paradoxical excitation on diphenhydramine.” Most people find this medication makes them drowsy. That is why it is included in so many nighttime pain relievers. Here is a partial list:

Acetaminophen PM
Advil PM
Aleve PM
Excedrin PM
Excedrin PM Headache
Ibuprofen PM
Naproxen Sodium PM
Pain Relief PM
Pain Reliever PM
Simply Sleep
Tylenol PM
Unisom PM Pain
ZzzQuil Night Pain

Pharmacologists have known for decades that some people react differently to DPH. Instead of becoming drowsy, they may become agitated or anxious. When I was a graduate student in the Department of Pharmacology at the University of Michigan over 50 years ago I learned about the paradoxical excitation associated with antihistamines like diphenhydramine. It fascinated me then and continues to fascinate me today.

Here is what the pharmacology “bible” (GOODMAN and GILLMAN’s The Pharmacological Basis of Therapeutics) has to say about this effect:

“The H1 [histamine] blockers can both stimulate and depress the CNS [central nervous system]. Stimulation is occasionally encountered in patients given conventional doses, who become restless, nervous, and unable to sleep.”

Why Do DPH Sleeping Pills Wake Some People Up?

One hypothesis is that these individuals metabolize DPH very rapidly to a stimulant compound (CNS Spectrums, Feb. 2008). In reality, though, we do not understand what makes some people super sensitive to diphenhydramine’s stimulant activity.

You would think that the FDA would require some information on the label of PM pain relievers that warns about this paradoxical excitation reaction. Imagine giving someone with a bad cold a liquid cough medicine that paradoxically makes them cough more! Crazy, right?

You would hope that there would be some mention of such a contradictory complication on the label of OTC PM sleeping pills. As far as we can tell, there is no mention of this unusual and unpleasant adverse reaction.

Natural Approaches to Insomnia?

You may find some natural sleep aids less disruptive. Valerian, passionflower, tart cherry juice, lemon balm or melatonin are popular and can sometimes be helpful. People with kidney problems should avoid magnesium supplements to prevent further damage. To learn more about these approaches and many other strategies to deal with insomnia, you may find our eGuide to Getting a Good Night’s Sleep helpful. This online resource can be found under the Health eGuides tab.

Please share your own story of diphenhydramine. Have you tried one of the PM pain relievers? How well did it work? have you ever had a paradoxical reaction to a medication? We would be grateful if you would include your experience in the comment section below.