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ADHD Adults

Unusual observation with Benedryl

I was diagnosed with ADHD about three years ago. My diagnosis is ADHD combination type noted as with severe inattention and hyperactive. I live in Texas and allergy season has kicked in. Today I bought generic benedryl for my allergy symptoms and noticed something I thought was maybe unique and I am wondering if anyone else has had the same experience. I have often wondered and asked my former doc if a med existed that would slow me down and not put me to sleep. Each day my mind is working 24/7, some days it is so bad I literally feel like I’m going insane! It is absolutely frustrating and all I want is peace and quiet within myself. My former doc said there is no such meds. I currently take Dextroamphetimine and Xanax. After taking the benedryl I did become a little drowsy but not to where I wanted to sleep like when I take the Xanax. But something else happened. For the remainder of the day I found my peace and quiet. It was great!


I am not surprised that your doctor prescribing your ADD meds did not think about this.  He reads up on psych meds…

I have ben using a generic Benadryl for years now as a sleep aid.  It has a short life in the system and there are no after effects in the morning.  I wake up ready to start my day.  The generic name for this is Dyphenhydramine HCl.  I can buy them at CVS in a bottle of 365 tablets.  I have allergies and nothing else I have tried really deals with the symptoms except Benadryl in any form.  The cost for the bottle is less than $20, so it is also economical.

Make a note of your observation for your next doctor’s visit.  I use a single tablet dose during the day because it does make me sleepy, but the single tablet dose handles my allergy symptoms.

Note:  I do not take any ADD meds.  The Benadryl does slow down my brain so I can actually get things done.  After more than three years using Benadryl for both allergy symptoms and as a sleep aid, I have notice no ill effects at all.  My PMD suggested doing this.

Hope that helps!

Posted by Dianne in the Desert on Apr 12, 2014 at 9:12pm

DIPHENHYDRAMINE: The published average plasma half-life is 8.5±3.2 hours (5.3 to 11.7).  There is, however, a tremendous amount of variability in how different people metabolize it.  Poor metabolizers can have a half-life of 45 hours!  As people age there is a general decrease in the ability to metabolize it properly.

Just as importantly, there is an incredible amount of variability in how people react to it in the usual lowest dosage form supplied (25 mg).  For some it has no major CNS effect, for some it is so sedating that they are incapacitated, and for some it creates what is known as paradoxical hyper-excitability. 

How it effects someone is also very dependent on what other medications they are concurrently taking.  It is among the list of drugs that is metabolized by the cytochrome P450 enzyme system (D26 in particular) so it can have serious interactions with other drugs. 

For those people who do experience sedation with diphenhydramine (and who do not metabolize it slowly) it can be a helpful sleep-aid.  For those who experience paradoxical hyper-excitability it is obviously not helpful in that regard.  For those who metabolize it slowly, the sedation it causes the next morning and into the next day makes it so that decreasing sleep latency (time it takes to fall asleep) makes no appreciable difference in their quality of life (they’re still dragging-ass just the same as if they had not slept well). 

For example, I fall into the group of people who under “normal” circumstances, do not get drowsy from it.  So it was never a good sleep aid for me.  In fact, I ended up being able to take a “safe” drug for hives (head to toe) when I was breast feeding, prescribed by the dermatologist that was consulted while I was still in the hospital post C-section, and took 75mg three times a day.  However, later on down the road a few years I decided to take it (thinking it would have no appreciable effect on my level of consciousness & I had something going on for which I could NOT be sedated) but found out that when mixed with a drug I was taking at the time it now caused me to be unable think and unable to stay awake.  I begged out of that really important thing which I needed to be fully alert for…no big deal—whatever it was or whoever it was who I reported to was understanding of my stupidly thinking I could still take it without any bad effects (they were similarly “medically educated” after all).

My best friend, on the other hand, had an allergic reaction to a topical ingredient found in anti-itch creams (the local anesthetic) so she took only 25mg of Benadryl to try to stop the itching and called me up so incredibly “sped-up” mentally that she feared she was going crazy, yet she was so physically “sped-down” that her speech was slurred and she would periodically start to doze off as she was talking to me.  When she would wake up from these short episodes she’d start freaking out again thinking she was going crazy (and she declared that she was convinced she needed to go to the emergency room & she was adamant that she was perfectly fine to drive herself to the ER).  I talked her down from that idea the whole time I was driving 30-minutes to her apartment.  I tried to also talk her down from thinking she needed to go to the ER (I’m a physician assistant—I told her she would be fine & just needed to wait this out—and not incur the ER charges).  She did not listen to me.  I had known her for 20 years, but had never seen her so agitated (and quite frankly psychotic).  So I drove her to the ER where they did nothing at all, but allowed her (and I) to wait it out a few more hours (then charged her $1000 for their time).  I should add that at this time she was taking no other medications; this is her “normal” reaction to Benadryl.  She had never taken it before.

Back to those drug interactions.  Diphenhydramine is an inhibitor of the CYP 2D6 iso-enzyme.  This means it will increase the blood levels of any drugs that are substrates of the 2D6 iso-enzyme.  Among dozens of other drugs that are listed as being 2D6 substrates (most of which are the SSRI’s) another category is all of the amphetamine class of drugs (Adderall, Vyvanse, Dexedrine, etc).  Depending on your particular genetic make-up, when you combine diphenhydramine with dextro-amphetamine it will increase your plasma levels of dextro-amphetamine anywhere from 1.5-8 times it’s usual level (only a conservative estimate based on the effects some inhibitors have on substrates as there is no published data I have found which determines the precise effect these two drugs have on each other)—some inhibitors have been shown to increase the level of the substrate by 20 times it’s normal level (when not combined with an inhibitor). 

The HUGE problem with these types of drug interactions (and clinicians being able to spot them when/if they do occur) is that the effects are generally fairly small initially and will only increase over time.  By the time a person ends up having a truly toxic level of amphetamines in their blood stream (and now climbing the walls or hostile—or having dangerously high blood pressure or worse, a heart attack) is that the concurrent usage of the inhibitor (diphenhydramine) started several months prior to the onset of any symptoms which would point to amphetamine toxicity being to blame for any of this.  How much and how fast the amphetamine plasma levels will build up will be determined only by your particular genetic make-up. 

Now I will add an interesting post-script to my own personal experience with diphenhydramine several years ago.  Once I found out that when combined with the meds I was already taking, that diphenhydramine now caused sedation I started taking it occasionally to help me sleep (the non-prescription way of treating ADHD induced insomnia in a patient who has not been properly diagnosed yet and is being treated for non-existent bipolar disorder).  Over time (after daylight savings time—Spring Forward) I started taking it most nights.  Eventually it was determined (by me) that what felt like depression was only daytime sedation—I must be one of those people who do not clear it in the “usual” amount of time (the “SHORT HALF LIFE” that is only true on average and in most people…the crap that people ASSUME only because if it is over the counter then surely that means it’s “safe”).  I only realized this once I stopped taking diphenhydramine for sleep and noted that PARADOXICALLY, not getting enough sleep felt far better than when I was taking diphenhydramine…

I’ll spare you the long lecture on what the anticholinergic effects of diphenhydramine create when taking drugs that also are anticholinergic.  I’ll spare you the lecture about how the vast majority of physicians (which includes psychiatrists who must first go to medical school and be trained just like any other physician to obtain that “MD” but who then go on to completing a residency in psychiatry) would like for diphenhydramine to not be sold over the counter because it can cause things like cholinergic crisis when combined with other psych meds & those used in Parkinson’s disease…and it can profoundly complicate the diagnosis of insomnia…

The fact that your psychiatrist did not recommend diphenhydramine for you or anybody else to “treat” ADHD just means he/she is probably a good doctor.  The fact that he/she did not answer “diphenhydramine” when asked if there was a drug that would make YOU calm down but not be sedated means he/she does not consider him/herself to be able to psychically predict how YOU would respond to diphenhydramine when you are concurrently taking an amphetamine (or when you are not concurrently taking one) has no bearing whatsoever on their actual knowledge of pharmacology.

Posted by BC on Apr 13, 2014 at 1:38am

Thank you so much for the great info! I will definitely be talking to my doc about this at my next appointment.

Posted by wesleyutwood on Apr 13, 2014 at 5:10am

The chances of amphetamine toxicity are not high because diphenhydramine isn’t listed as one of the “potent” inhibitors of 2D6.  The ones considered “potent” are Prozac, Paxil, cinacalet ( ), goldenseal, and quinine/quinidine.  In the vast majority of people those are the ones of major concern because they can/will cause problems for everyone.

Only for that subset of the population that are slow metabolizers (have some inherent defect in the enzymes necessary to properly metabolize these drugs at a “normal” rate to begin with) will the rest of the less potent inhibitors start to become a problem.  What we now know (so far) based on current genetic research is that slow 2D6 metabolizers constitute 1% of the Asian population, 6-8% of the African American population, and 7-10% of the Caucasian population.

All the metabolism stuff aside, the sedative effects of diphenhydramine (for those who do experience sedation from it) are often completely or partially offset by the concurrent administration of any drugs that are “stimulating” whereas the sedative effects are exacerbated to some degree by the concurrent administration of any drugs that are CNS depressants.  This is what happened in my case; only when diphenhydramine was combined with another CNS depressant (a fairly potent one) did I experience the sedative effects at all (and could also now tell how long the diphenhydramine was staying around in my system—as the sedation lasted well into the next day and mimicked the symptoms of depression, no energy, lethargic, disinterested). 

There’s another interesting fact about metabolism however that I should point out.  Diphenhydramine (as well as Paxil & Prozac) are not only inhibitors of 2D6 but they are also substrates. So this means that they slow down 2D6 metabolism of themselves—can theoretically cause increasing plasma levels of themselves when taken alone (usually only when taken in high doses), not in combination with anything else.  Since the build up of substrate levels by an inhibitor of that enzyme tends to be a slow process and cumulative over a long period of time, perhaps it was only the daily or almost daily dosages of diphenhydramine that eventually created more than just night-time sedation for me, but also a lingering sedation well into the daytime hours. 

I really just hope that all of this information on the pharmacodynamics of diphenhydramine helps everyone to better appreciate how much there is to consider when it comes to prescribing drugs (even those which are considered “safe” and “over the counter”), and how much of an unknown there is when prescribing any drug due to genetic variability.  What works for one person can be a total nightmare for someone else and there’s usually no way to tell in advance who will have a real nightmare of an experience from simply taking one dose of something. 

I’ve seen many cases of paradoxical hyper-excitability before but they’ve all looked more like someone who just goes from “normal” to “hyperactive ADHD.”  I’ve only seen one case of what looked like a bizarre illicit drug overdose with psychotic features once—and it was probably a good thing it was in my best friend whom I’d known so well and for so long (and probably a good thing I went with her to the ER because they had a hard time believing she had really only taken one little Benadryl pill).  They might have run up her ER bill even higher with drug screens, pumped her stomach just in case, who knows, if she had gone by herself.

Posted by BC on Apr 13, 2014 at 7:37am

BC - awesome info! Thanks so much for it. I have been telling doctors for years that I am allergic to Benadryl - and usually getting disbelief as a result.

Every time I have taken it, I get so anxious that I want to peel my skin off. I remember my mother being furious that I was bouncing off the walls after she dosed us kids for some “peace and quiet.” Only as an adult did I realize that she was likely using Benadryl, so this always seems to have been my reaction.

This has happened whether I was on or off of benzodiazepines, and literally nobody believes me, or insists that I am wrong about the drug causing this. My psychiatrist believes me, mostly because he has seen my anxiety and fear of making it worse.

I seem to have a tendency to react “atypically” to more than a few drugs. I have sometimes wondered if this is more common in the ADHD population.

Anyway, I just say no to Benadryl and related drugs for precaution more than anything else. Nice to know I’m not insane and this is in the info.

Posted by EllaMc on Apr 15, 2014 at 1:23am

EllaMc:  In the future don’t use the word “allergic” when referring to how you react to Benadryl (and NEVER list it as something you are allergic to in medical records or forms you fill out at doctor’s offices). 

A true allergy to a medication is a response by your immune system thinking the medication is a “threat.”  The symptoms of allergy are hives, other skin rashes (or “fixed drug eruption”), asthma possibly progressing to anaphylaxis, etc.

Just use the terminology that doctors use (and is included in all the literature—“hyper-excitability”).  I more general terms, how you respond to benadryl could also be termed a “hyper-sensitivity reaction”—but never an allergic reaction.

Posted by BC on Apr 15, 2014 at 1:37am

I have been taking hydroxyzine , generic for Visteril, for 5 years now.  I started on it to help with sxs after a car accident and did not want to take a benzodiazepine.  At first I was taking 50 mg, but I have dropped down to 25 as needed.

Posted by CIGRACE on Apr 15, 2014 at 7:29am

Histamine is a neurotransmitter that can ‘spark’ other NT’s into action. Excess brain histamine can lead to racing thoughts, anxiety and conversely a black depression.
Antihistamines such as benadryl do not remove histamine only block the uptake in some manner. When it clears the body, there may be a rebound effect. Tolerance can also occur as the body gets used to the dose and that can make rebound worse.
If it helps though, it may be worth checking into low histamine diet and some foods and herbs that help the body clear histamine.

Posted by Gadfly on Apr 15, 2014 at 7:54pm

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