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Misc Does Diphenhydramine reduce GABA?

The Holy Quadruplty

The Holy Quadruplty

Bluelighter
Joined
Feb 9, 2022
Messages
704
Does Diphenhydramine reduce GABA levels, or even increase them?
This was asked on Google...

Question:
"Does Diphenhydramine effect GABA receptors"

Answer:
"The total GABA content was markedly decreased in cortex and hippocampus by both 10 and 20 mg/kg previous treatment of diphenhydramine; however, the total glutamate content was unaffected.

I also clicked on it, and read a short article. I'll try to copy, and paste it soon. I also looked up one of Diphenhydramine's metabolites on Swiss, and it had probability for multiple GABAa receptors so I wonder if it affects them in anyway at all.

What do you guys think/know about this?

Update
Here's the article I was talking about, and it actually also seems contradicting since they're saying that diphenhydramine withdrawal may lead to seizures. Anyway here's most of the article.

Seizure susceptibility significantly increased in amygdaloid kindling and pentylenetetrazol model 10 days after drug withdrawal from a 2-week treatment with H1-antihistamines. Meanwhile, GS activity and expression in the cortex or hippocampus decreased simultaneously with a marked decline of glutamine and GABA content. Comparable inhibition of GS activity by methionine sulfoximine was also sufficient to increase the susceptibility, while supplementation with glutamine reversed the high susceptibility 10 days after diphenhydramine withdrawal. Moreover, the seizure susceptibility increased 10 days after diphenhydramine withdrawal in wild-type mice but not in histidine decarboxylase knockout mice, which lack histamine.

Conclusions​

Chronic H1-antihistamine treatment produces long-lasting increase in seizure susceptibility in nonepileptic rodents after drug withdrawal and its mechanism involves impairment of GS through blocking the action of histamine.
 
The article doesn't contradict itself.

H1 histamines like diphenhydramine, in repeated administration, inhibit glutamate synthase (GS), which is the endogenous precursor to GABA.

So yeah, antihistamines appear to lower GABA levels, and thus also lower seizure threshold.
 
Snafu in the Void said:
The article doesn't contradict itself.

H1 histamines like diphenhydramine, in repeated administration, inhibit glutamate synthase (GS), which is the endogenous precursor to GABA.

So yeah, antihistamines appear to lower GABA levels, and thus also lower seizure threshold.
Click to expand...
Wouldn't more glutamate make more GABA, and how would effects drugs like Xanax if so? Would Diphenhydramine decrease the effects of Xanax? They also say seizures from Diphenhydramine withdrawal, but wouldn't you think they'd increase GABA if they have a chance of seizures when withdrawling from it?

...oh wait you said inhibits glutamate not release it?
 
Last edited:
Snafu in the Void said:
Glutamate synthase -> glutamate/glutamine -> GABA

By inhibiting glutamate synthase less GABA would be created and available.


Theoretically maybe, but probably not by a significant amount.
Click to expand...
But if Diphenhydramine decreased GABA then wouldn't you have more GABA during Diphenhydramine withdrawal thus preventing seizures? That's what's confusing me since less GABA is usually what causes seizures, and it seems like Diphenhydramine makes my Xanax stronger plus more anxiolytic!
 
How much diphenhydramine are you taking with the Xanax?

I think dph at
Low doses block histamine receptors causing drowsiness
Moderate doses block muscarinic acetylcholine receptors causing confusion memory issues and other delirious effects possibly making you feel more intoxicated or in a stupor

Additionally at sodium channels and potassium channels I think at high doses or in certain people could contribute to a possible seizure.
 
I think at 100 mg it may start to have muscarinic antagonism effects.

I think the main confusion here is likely most of the sedative drugs youve probably seen act on mainly gaba and tend to be antiseizure or cause seizures when you stop them.

But, diphenhydramine acts at h1 and mACh receptors which can cause similar subjective effects (how you feel) without hitting the same buttons in your head because your brain has tons of buttons.

Also not all sedatives are anticonvulsants.

Like I take valproic acid and it is a anticonvulsant but not really a sedative.

And no dph is a sodium and potassium channel blocker and they can cause you to have a seizure alot of meds do.

So I think the simplest way to help you is what helped me and keep it as simple as possible:

H1 receptor
MACh receptor
Na channel blocker
Potassium channels

First two being major and bottom two being minor targets (mainly related to possible seizures or heart)

Just type em in wiki and you'll have a rabbit hole of info when I don't understand a word I just click it

Hope this helps
 
The Holy Quadruplty said:
Btw can you get norepinephrine effects from Benadryl?
Click to expand...
I doubt it, in the infinite wisdom of youth I once took 500mg benadryl and nothing to mention besides a weird gummi-like body feeling* and sedation.

* Got the same on one occasion where I, also very wisely, took a dose of clozapine from a buddy because I forgot my sleep aid and she told me it would do the same. Result was same gummi like body feeling so I think it is the result of anticholinergic activity because clozapine, too, is an anticholinergic (besides being a dopamine antagonist etc).
 
plumbus-nine said:
I doubt it, in the infinite wisdom of youth I once took 500mg benadryl and nothing to mention besides a weird gummi-like body feeling* and sedation.

* Got the same on one occasion where I, also very wisely, took a dose of clozapine from a buddy because I forgot my sleep aid and she told me it would do the same. Result was same gummi like body feeling so I think it is the result of anticholinergic activity because clozapine, too, is an anticholinergic (besides being a dopamine antagonist etc).
Click to expand...
Yea it has anticholinergic effects, but I know it blocks the re-up take of norepinephrine which increases it. I know it doesn't do it very strongly, but just trying to get more info. Same with Chlorpheniramine, and they both do the same on dopamine. Chlorpheniramine actually has strong serotonergic effects.
 
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