Categories
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 (https://pubmed.ncbi.nlm.nih.gov/12563283/), 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.


Categories
Blood-Brain Barrier Sciences Uncategorized

[Sciences/BBB] Histamine-induced blood-brain barrier disruption in teething children: a “post hoc ergo” on glucocorticoids.

Recently, I have been aware about some parents concerned about the impact of teething on the blood-brain barrier integrity, such claims was wrapped through one of the most bizarre “ergo post hoc” fallacy following that sequence:
1. Teething induces histamine release
2. Histamine is a vascular hyperpermeable vascular factor
3. Blood-brain barrier in babies is leak
4. Therefore Teething induces a blood-brain barrier breakdown in children.

You have to agree that is one of the most bizarre fallacious association, but it has been repeated and spread enough to have parents concerned about the impact of teething on the blood-brain barrier. To dispel that myth and beat that dead horse once for all, I think it is important to demonstrate why this information is fallacious.

 

  1. Teething and histamine release: understanding the mechanism of inflammation.

First, in order to understand the physiological response of teething, you have to understand the mechanism of inflammation. Everyone can provide a clinical presentation of an inflammation: it is red, it is swollen and it is hot.
Inflammation is triggered by lesion or a wound due to internal or external stimuli, in our case teething. Teething involves a mechanical stress (due to teeth growth) and eventually cells and tissue laceration. Such laceration release intracellular contents into the extracellular space that turns on resident immune cells. These cells in turn release what we refer to “pro-inflammatory factors”, a cocktail of different chemicals that triggers the inflammatory bomb on:

We have amino-acids derivatives and peptides (bradykinin, histamine, inflammatory chemokines and cytokines) and arachidonic acid (AA)-derived molecules. The production of AA-derived molecules (also known as prostanoids) are driven by cyclo-oxygenases (COXs). There are two types of COXs: COX1 that is constantly produced at small level and COX2 that is increased during inflammation.  COX1 produce the “good prostanoids” and COX2 the “bad prostanoids”, the latter being the driving force of the inflammation. COXs are the classical targets of the classical NSAIDs found in OTC products including acetaminophen (Tylenol), ibuprofen (Advil) and naproxen (Aleve). All these small molecule target COXs and stop prostanoids production. In the case of teething, inflammation is mostly driven by the release of prostanoids (such as prostaglandin PGE2) and interleukins (IL-1beta) (Blakey, White et al. 1996). Aside of two obscure studies published 40 years ago in obscure medical journals (Cotias, de Medeiros et al. 1968, Soliman, Abdel Wahed et al. 1977) there is no evidence of histamine release following teething. This therefore nullify claim 1.

  1. Histamine and the blood-brain barrier

Histamine is not the major mediator of inflammation, but it is indeed the major mediator in allergic reaction. During an allergic reaction, the immune system respond to the allergen by the production of certain types of antibodies called IgE.

IgE are produced by B-cells that positively responded to the allergen, recognizing it as a foreign body. IgE binds to a certain type of immune cells called mast cells. Mast cells are about less than 1% of the total population of immune cells. These cells are super-loaded with histamine, ready to puff it upon signal. Once IgE binds to its appropriate receptor, mast cells puff and release vast amount of histamine. Histamine in turns triggers the anaphylactic response such as “asthma”, “runny nose” and in the worst case an anaphylactic shock. The main treatment for mild allergic reaction is solved by taking anti-histaminic drugs such as Claritin D or Benadryl.
Because the histamine released in teething is much more negligible than the amount of prostanoids produced, the use of anti-histaminic is worthless because you only address a minor component of the inflammation and omit to block the major component. So the histamine relationship with teething is also refuted at this point. But does histamine can cause the BBB disruption and its leakiness? Yes, but only at high doses and only in very specific cases. Studies that have investigated the biological effects of histamine at the BBB are very old (20+ years) and were achieved with high concentrations (10-100 micromol/L) (Gross, Teasdale et al. 1981, Domer, Boertje et al. 1983, Watanabe and Rosenblum 1987, Butt and Jones 1992, Mayhan 1996). If we consider that histamine is produced during teething, we can conservatively assume that such level would not be over plasma levels found during a severe allergic reaction such as an anaphylactic shock. Reported values for an anaphylactic shock are about 6.35 nmol/L (Laroche, Gomis et al. 2014). Even at that high level, that’s put us about 1000X to 16000X less than values reported to have an activity on the BBB. So claim 2 is also refuted.

  1. Is the BBB leaky in newborns and babies?

TL; DR the short answer is NO. If you want to understand why and what is the science behind my statement, please check my previous post about it: https://scientistabe.wordpress.com/2016/05/21/neurosciencesbbb-thiomersal-and-the-blood-brain-barrier-where-does-the-science-stand/)

 

  1. Conclusions

By now, we should agree that the reason of delaying vaccines in children due to histamine-induced barrier disruption does not stand to science. There is no scientific rationale to support the hypothesis of a massive release of histamine during teething, such release being well below reported values for achieving a BBB disruption and leakage. If you have your baby teething right when he/she is due for immunization, consult with your AAP-accredited pediatrician for what is best for baby.

    5. References

Blakey, G. H., R. P. White, Jr., S. Offenbacher, C. Phillips, E. O. Delano and G. Maynor (1996). “Clinical/biological outcomes of treatment for pericoronitis.” J Oral Maxillofac Surg 54(10): 1150-1160.

Butt, A. M. and H. C. Jones (1992). “Effect of histamine and antagonists on electrical resistance across the blood-brain barrier in rat brain-surface microvessels.” Brain Res 569(1): 100-105.

Cotias, C. T., E. C. de Medeiros, U. V. Lima and C. F. de Santana (1968). “[Determination of histamine release in the blood serum of children during deciduous tooth eruption].” Rev Fac Odontol Pernambuco 1(2): 95-100.

Domer, F. R., S. B. Boertje and S. A. Sweeney (1983). “Blockade of the acetylcholine-and histamine-induced changes in the permeability of the blood-brain barrier of normotensive and spontaneously hypertensive rats by atropine and pyrilamine.” Res Commun Chem Pathol Pharmacol 42(1): 157-160.

Gross, P. M., G. M. Teasdale, W. J. Angerson and A. M. Harper (1981). “H2-Receptors mediate increases in permeability of the blood-brain barrier during arterial histamine infusion.” Brain Res 210(1-2): 396-400.

Laroche, D., P. Gomis, E. Gallimidi, J. M. Malinovsky and P. M. Mertes (2014). “Diagnostic value of histamine and tryptase concentrations in severe anaphylaxis with shock or cardiac arrest during anesthesia.” Anesthesiology 121(2): 272-279.

Mayhan, W. G. (1996). “Role of nitric oxide in histamine-induced increases in permeability of the blood-brain barrier.” Brain Res 743(1-2): 70-76.

Soliman, N. A., S. Abdel Wahed, A. M. Abul Hassan, G. el-Asheiry and A. K. Abdallah (1977). “Systemic disturbances accompanying primary teething: a clinical and pharmacological study.” Egypt Dent J 23(1): 1-8.

Watanabe, M. and W. I. Rosenblum (1987). “In vivo studies of pial vascular permeability to sodium fluorescein: absence of alterations by bradykinin, histamine, serotonin, or arachidonic acid.” Stroke 18(6): 1157-1159.