Neurosciences Pharmacology

[Sciences/Pharmacology] Death by Benadryl Tik-Tok challenge: making the case on an interesting neurotransmitter

Another day, another “dose makes the poison” day. This time, it is about diphenyhydramine (Benadryl(R)). You surely heard about the recent “Tik-Tok challenge” launched by some folks that is basically overdosing on Benadryl(R) with some report of death as reported here. So far, we have 3 teenagers in Texas that had to be hospitalized following overdose on Benadryl (up to 14 doses at once) and one death on Oklahoma (dose unreported). Diphenyhydramine is usually taken as an anti-allergic due to its anti-histamine activity (which is a major molecule released by basophile white blood cells, responsible for the allergic response). Interestingly, the reason these kids took Benadryl(R) was not for a major allergic reaction to pollen or animals hair. But apparently “to get high”. This raised me some questions as histamine is not a major neurotransmitter as glutamate, or dopamine are.

This raised my curiosity about the role of histamine in the central nervous system (CNS) and how would diphenylhydramine come to play? As usual I love to start with the chemical structures. Histamine is on the left, diphenyhydramine is on the right:

As you can see, histamine is not too far from histidine, an aminoacid. The only thing missing is the carboxyl group (-COOH) on the carbon alpha. Diphenyhydramine that I will call DPH to ease the typing) has not much anything in common with histamine.
Histamine is not a common neurotransmitter, and indeed has a very specific nucleus, according to Haas and Panula (, located in the tuberomammary nucleus, which appears located between the pons and the thalamus, likely part of the hypothalamus. As other nuclei, the histaminergic system is made by projections towards various region of the brain as represented below:

We can see projection into various region including the striatum/substantia nigra (which is involved in movements execution and affected in Parkinson’s disease), cerebellum (involved in the gait posture and coordination in movements like walking), hippocampus (memory formation) or amygdala (which deals with various things including pleasure). What is more interesting is the presence of projection into the medulla, which means it can likely modulate some vegetative functions including breathing or hearbeat regulation.
What is interesting is that such histaminergic system appears well conserved in evolution. We found in mollusk and we found it in mammals, which is interesting. It also has 3 major receptors in the brains (named H1R, H2R and H3R respectively). The biological functions of histamine appears various and include function in the wake/sleep cycle, inhibitor of neural function (which is important as we discuss DPH pharmacology), feeding behavior, fluid intake regulation, thermoregulation and others. But what is interesting is the ability of histamine to act as a hedonist molecules, including impaired reward behavior and altered cognitive functions when volunteers were given H1-antihistamines.

This brings us to the pharmacology of anti-histamines. Interestingly, the first generation of anti-histamines was marked by their persistent side effects on the central nervous system (CNS) and included DPH. These first-generation of drugs side effects were somnolence (a common side effect reported with Benadryl), drowsiness, lack of concentration and attention. The reason why such side effects occur is because these compounds have a very good blood-brain barrier (BBB) permeability, which can exert their central effects easily. To remediate with such issue, a second-generation developed in the aim of reduced BBB permeability was developed such as fexofenadine (Allegra(R)) which is commonly sold as “non-drowsy” anti-histamine.

Now if you look at the Lexicomp (which is a drug database pharmacists commonly access to obtain a detailed drug information), there is an important warning on Benadryl(R): “CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).”. If we dig in further we can see two major adverse effects reported:
Cardiovascular: Chest tightness, extrasystoles, hypotension, palpitations, tachycardia
Central nervous system: Ataxia, chills, confusion, dizziness, drowsiness, euphoria, excitement, fatigue, headache, irritability, nervousness, neuritis, paradoxical excitation, paresthesia, restlessness, sedation, seizure, vertigo

There is a serious risk on the cardiac side, whereas we can see that on the CNS side we have some effects sought as it use for recreation (euphoria, excitement, paradoxical excitation) but also that can be potentially dangerous (ataxia, sedation, seizure). These reactions are anticipated with a normal dosing, now you can imagine if you significantly increase the uptake with a very high dose.

If you are a parent, please discuss with your children about this challenge in a calm and posed manner and explain them why it is more dangerous that it is.

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