sleepy person with a pillow over their head, great sleeping pill

Most medications have expected results. And most of the time, people respond in predictable ways. But every so often, someone reacts quite differently.

With respect to diphenydramine (DPH), this paradoxical reaction has been documented and studied. One reader wondered what is known about it.

Q. Products such as Benadryl or Tylenol PM that many people use to help them sleep have the opposite effect on me, causing me to be wide awake.

Why is this? I do struggle with insomnia, but I prefer only natural remedies.

When I take a large dose of melatonin, 6 mg, I still wake up after three hours. Is it safe to double that dose?

A. Most people find that diphenhydramine (DPH), the ingredient in Benadryl and PM pain relievers, makes them drowsy. But some individuals, like you, react paradoxically to DPH and wake up when they take this normally sedating antihistamine.

How Does This Happen?

For decades the mechanism for this unexpected response was unknown. Then scientists discovered that some people process this drug very quickly and convert it to a compound that causes excitation in the brain (CNS Spectrums, Feb. 2008).

Melatonin is also metabolized by the same enzyme system (Pharmacogenetics, Mar. 2003), suggesting that it may not be your best choice as a sleep aid. You might need something that does not rely on these enzymes.

We are sending you our Guide to Getting a Good Night’s Sleep with our suggestions for dos and don’ts as well as herbal helpers, magnesium, acupressure and the timing of light exposure.

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  1. Alice
    Kansas city

    Melatonin at LOW dosage with the time release formula is what works best, and it has worked for me for years. No side effects.
    I have tried diphenhydramine and it kept me on verge of sleeping, and later actually caused me to be awake no matter how sleep deprived I was. I won’t ever touch that stuff. Caused very unpleasant sensations in my legs, too.

  2. Doo J.

    In regards to the question about Melatonin – I researched it a few years back and it seems that upping the dosage can have a reverse affect and that many feel that LOWERING the dosage worked better. Also, you mentioned magnesium. I take a combo Calcium, mag, and zinc with added Vit D and it seems to work well for sleep.

  3. Shubly

    I had a severe reaction to Diphenhydramine, it kept me awake and my body reacted as if I’d had a line of cocaine. Grinding my teeth with my jaw chattering, I felt high but not a good high, very anxious and irritable and literally was awake for a full 24 hours. I’m sticking with Phenergan, that knocks me out and I have no horrible side effects.

  4. Pat

    Since I share so many of these problems and having insomnia for
    as long as I can remember I’d really appreciate to hear replys on
    this topic.

  5. Mona

    Had problems with sleeping and since I have changed my thinking process, I’m beginning to sleep well! Try listening to BK Shivani or Dr. Chopra on You tube!

  6. Susan

    Another adverse reaction to Benadryl and other medications containing diphenydramine is the aggravation of Restless Leg Syndrome (RLS). Don’t take these drugs if you have RLS and don’t want to be walking the floor all night. Other drugs that aggravate RLS are some anti-nausea medicines like phenergan and compazine. A good anti-nausea alternative is Zofran. The Restless Legs Syndrome Foundation has a web site that can probably provide more information.

  7. Cindy M. Black
    Seattle, WA

    It may well be that some element in certain “depressant” compounds is converted by the brain into something that excites vs. relaxes… after all, everything has to have a mechanism of action. But that said, I’ve noticed in my practice — and in myself as well! — that this “paradoxical effect” (“depressants” having the opposite effect, and often vice-versa) occurs far more often in those people who have manic or bipolar tendencies. I’m not saying full-blown syndromes, just tendencies and traits. These more tightly-wound people, of course, would be most likely to experience poor sleep hygeine as well.

    There are very few pain or sleep medications I can take without experiencing at least a degree of unwanted excitation. This most often occurs when the med is at low levels in my bloodstream, and that’s true for most paradoxical med effects. The person who wakes 3 hours after taking a sleep med, unable to get back to sleep, is a perfect example of this.

    Vicodin and many other pain or sleep meds just send me through the roof. However I’ve found that melatonin does seem to work pretty well for sleep. The most effective compound I’ve found is “Knock-Out” by Schiff, which combines 3 mg melatonin with small amounts of magnesium, glycine, B6, GABA, theanine, calcium and valerian. It really is a killer combo and I rely on it. Hope this helps someone. Cheers!

  8. Jan A.

    I can’t use valerian because it keeps me awake. I have a friend who can’t take diphenhydramine because it keeps her awake. I wonder if it is possible that everyone has some medication to which he/she has the opposite reaction. This is a little scary because it is so unpredictable.

  9. Helen M
    Modesto, CA

    Valerian wakes me up, gives me the jitters; however, melatonin helps me to sleep. Many people take higher doses with varying reactions: I take a 3mg dose, that is partially time released. The initial quick action puts me to sleep, the rest keeps me asleep, or enables me to fall quickly back to sleep if I wake up to use the bathroom. I have pain that always disturbs my sleep. Therefore, I believe, that the anti-diuretic action that is part of deep sleep does not occur in me. OTOH, women due tend to wake up during the night for bathroom reasons. My only concern is that I am now dependent on the melatonin for sleep. While it may be natural, I am using it like a drug.

  10. Jan Shelden
    Roanoke, VA

    Both times that I took Tylenol PM for a good night’s sleep, I had Serious laps of memory the next day- very scary. I couldn’t tell what a pin # was, couldn’t figure something else out, so never again. They gave me melatonin at the rehab after an accident- never went to sleep, just drowse. I read something about receptive cells in some people don’t let in that form of melatonin and
    causes light sleeping. My husband said if you’re sleepy, you’ll sleep. Not so!

    • Karen W.
      Albuquerque, NM

      Sleep has always been problematic for me because of two brain conditions. I use an over-the-counter sleep med that contains several natural ingredients and I add about 8 mg of melatonin to that. My sleep doc told me I could go as high as 12 mg IF I gradually increased the dosage from the 3 mg I started with. I don’t need to – the 8 seems to get me to sleep and I usually stay that way. Can’t use benadryl either. Sleep is essential. Go to see a sleep doctor if you just can’t. Sleep apnea, REM sleep disorder – all sorts of things can keep us from sleeping well.

      • Jessica
        Hampton, VA

        I went to a sleep clinic & was told I stopped breathing abt 80 times so I had apnea. I got a CPAP & tried every avail mask & felt claustrophobic with each or couldn’t sleep (no other bouts of claustrophobia any other time or place but I am a very light sleeper & any sounds waken me) so gave it back. Got an old hospital bed & sleep w/head raised. Melatonin is working 75% of the time (have to take antihistamines too because of allergies so adding a sleep aid w/DPH is out as more makes my heart race). I’m open to other suggestions!

  11. MR

    As far as sleep goes, I’ve found that it’s important for me to eat supper on the early side, and to not eat anything else after supper. That includes anything with calories, such as alcoholic or sweetened beverages.
    There is timed-release melatonin, but I prefer to take L-Tryptophan to help me sleep through the night. I take 1 mg before bed, and I also take L-Theanine about a half hour before bed to help me fall asleep. If I foresee problems, such as excitement about the next day, I take 2 mg L-Tryptophan.
    These supplements are not foolproof, but along with some late-afternoon exercise, they’ve very greatly improved my sleep.

  12. Linda
    St. Petersburg, FL

    Any product containing diphenydramine (DPH) gives me severe restless legs.

  13. AA

    Our family has had some success with taking a combination of Valerian, Chamomile and Hops (we buy a product that has the three herbs combined in one pill) as well as the amino acid Glycine.

    Be forewarned that the Valerian smells like old gym socks. Just swallow it quickly. The triple complex mentioned above helps you get to sleep.

    I believe 1-3 g of Glycine before bed is the recommended dose. It supposedly helps lower your core temperature which should help keep you from waking during the night.

    I believe that I messed up my normal sleep pattern and taking these for a while helped me get back in my normal rhythm. Although I have heard that all are safe to take on a continuous basis you have to judge for yourself.

  14. Jean

    I had wondered if the paradoxical response to Benadryl and similar medicines tended to occur in people with ADD or ADHD. Is there any information to suggest that is the case? Thank you for considering this question.

    • Steph

      I definitely don’t have ADD, ADHD or am manic or bipolar and I have a lot of reversed reactions: coffee and tea make me sleepy (especially green tea), some sedatives make me nervous, ashwaghanda makes me jittery, so did the lavender pills my naturopath gave me to try. Strong painkiller from the dentist after wisdom tooth extraction (Vicodin?) had noneffect whatsoever, Tylenol worked so much better for me… I could go on. Came here to see if I am the only one who’s sleep is disturbed by taking glycine. It seems so. If I take 1-2 g at night I don’t sleep deeply all night. Argh. Oh well.

  15. Ginger
    United States

    Antidepressants I have taken Celexa for 2 years.I had to quit taking the drug due to extreme sleepiness. When I tried to quit taking it,I would have terrible side effects.

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