Does Benadryl Have Serotonergic Effects?

Answer

Diphenhydramine, the active ingredient in Benadryl and Nytol, is a first-generation antihistamine commonly used to treat symptoms of allergies such as itching, sneezing, and runny nose. It is also commonly utilized as a sleep aid.

It works by blocking the action of histamine, a chemical released by the body in response to allergens.

Diphenhydramine is generally not associated with having serotonergic effects, although some studies have noted it may have very mild effects on serotonin, which may be more pronounced in cases of overdose.

Studies on the matter are quite mixed.

What Do The Studies Say?

There have been a few case studies published that suggest that diphenhydramine can be a contributing factor in cases of serotonin syndrome, which is a rare, but serious condition that can occur when there is too much serotonin in the brain. 

One case study published in 2018 documented an individual experiencing 'serotonin syndrome' while taking a combination of tramadol and Benadryl. Tramadol is known to have serotonergic effects, but Benadryl typically is not, although the case study does provide some preliminary evidence of it having mild serotonergic effects.

Other studies have suggested that diphenhydramine has some activity at the serotonin receptor and may inhibit the reuptake of the neurotransmitter. This has been shown more definitively in animal studies versus studies in humans.

Another case study, published in 2011, reported on an individual experiencing well-known signs of serotonin syndrome with an overdose of Benadryl (symptoms like sweating, muscle rigidity, twitching, etc...). The study theorized that diphenhydramine stimulated certain serotonin receptors:

Each symptom of serotonin syndrome is thought to be derived from the overstimulation of different serotonin receptors, including 5-HT 1A, 2A, and 3.7 Overstimulation of 5-HT1A receptors is hypothesized to yield the myoclonus and hyperreflexia in serotonin syndrome. Likewise, overstimulation of 5-HT 2A and 3 receptors is hypothesized to yield hyperthermia and diarrhea, respectively. Therefore, an overdose of diphenhydramine might stimulate 5HT1A and 2A but not 3 receptors as the present case did not show diarrhea.

It should be noted that not all studies show diphenhydramine has any appreciable effect on serotonin. In fact, several have reported it has no effect.

Additional Thoughts From The Pharmacist

Overall, the evidence is a mixed bag.

Some case studies certainly do suggest that Benadryl (diphenhydramine) can have serotonergic effects, but others have found nothing significant.

Diphenhydramine is generally considered safe to take with serotonergic drugs, like SSRI antidepressants, and the risk of developing serotonin syndrome with diphenhydramine appears to be very small.

Nevertheless, it's important to note that while there may be certain individuals who are more at risk of experiencing serotonergic effects from diphenhydramine, the risk appears to be greater in cases of overdose.

Final Words

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