In short
We rank diphenhydramine C tier for sleep: it is very anticholinergic, which is part of why it works and exactly what we do not like for patients. The exception is when we want anticholinergic effect alongside an antipsychotic.
Our take
They are very anticholinergic, which is part of why they work, and we do not like that for patients, so they go in the C tier.
“They're very anticholinergic as well, which is also part of why they work, and I don't like that for patients, so they go into the C tier”
44:46Sleep Medications Treatment Tier List: Best Insomnia Medications RankedAug 2026
When we use it
In our opinion it is just too anticholinergic for sleep. We do not like to use it unless we are looking for anticholinergic effect alongside an antipsychotic.
“there's Benadryl, which is just way too anticholinergic in my opinion. So I don't like to use that unless I'm looking for anticholinergic in conjunction with a antipsychotic”
33:38Insomnia and Sleep Medications in PsychiatryDec 2024
It also comes up on
- AnticholinergicsMany TCAs, paroxetine, anti-parkinsonian medications and bladder relaxants for overactive bladder are anticholinergic, and diphenhydramine is a big one.
- ClozapineMinimize other anti-muscarinic drugs: many TCAs, paroxetine, anti-parkinsonian medications, bladder relaxants for overactive bladder, and diphenhydramine is a big one.
- GabapentinFor sleep, give a medication, usually trazodone or gabapentin. Hydroxyzine is fine too. Avoid anticholinergics like Benadryl if you can.
- PTSDFor sleep, usually trazodone or gabapentin; hydroxyzine is fine too. Avoid anticholinergics like diphenhydramine if you can.
- TrazodoneOn day one, the first-line sleepers are the non-habit-forming ones that support deep, healthy sleep: trazodone and gabapentin, with hydroxyzine a fair choice too. These are broadly applicable for sleep in most to all disorders. Avoid anticholinergics like Benadryl if you can.
From these episodes
- Sleep Medications Treatment Tier List: Best Insomnia Medications RankedAug 2026 · 1 point
- Insomnia and Sleep Medications in PsychiatryDec 2024 · 1 point
Every point above is something said on the Psychofarm podcast, with the words as spoken and a link to the moment in the episode. It is education, not medical advice, and an episode reflects what we thought when we recorded it.