Does occasional use of anticholinergic drugs such as Benadryl have serious neurological risks?

It's important to keep in mind the following issues about the recent epidemiological study (1, 2) that examined the connection between cumulative anticholinergic drug use and incident dementia when considering the extent to which its results are generalizable.

• Though interesting, these results need to be confirmed by other independent studies on larger numbers of patients.
• This study was restricted to patients 65 years and older.
• Authors studied cumulative, not occasional, exposure to Anticholinergic drugs. As defined in this study, cumulative anticholinergic exposure was defined 'as the total standardized daily doses (TSDDs) dispensed in the past 10 years' (1, emphasis mine), is quite different from occasional use, which is presumably not daily use.
• The Anticholinergic drug Benadryl is a 1st generation Antihistamine, containing Diphenhydramine, a Histamine H1 receptor antagonist. In the case of diphenhydramine, the daily dose criterion used in this study was 50mg.
• Authors studied whether long-term cumulative intake of all sorts of combinations of antihistamines, antidepressants, antivertigo, antiparkinson, antipsychotics, bladder antimuscarinics, skeletal muscle relaxants, gastrointestinal antispasmodics and antiarrythmics predisposed those 65 years or older to incident dementia, i.e., newly diagnosed dementia. They did not study outcome of prolonged Benadryl intake alone.
• There is currently little biological basis in the scientific literature for linking cumulative anticholinergic use to outcomes like Alzheimer's disease. Even the authors of this study could make a plausible case only for people with Parkinson's disease, i.e., for people with pre-existing brain damage.

This answer therefore discusses the particulars of the question as asked, that is the effects of occasional, i.e., not daily, use of the anticholinergic Benadryl.

'Serious neurological risks' of occasional Benadryl use consist of strong albeit temporary dose-dependent effects on the central nervous system. It can sedate as well as profoundly impair psychomotor function, i.e., tasks, such as driving an automobile, that require both concentration as well as fine motor skills.

Antihistamines are typically used to treat allergy symptoms, specifically those associated with allergic rhinitis such as runny nose, sneezing, itching. A common symptom of allergic reactions, excess histamine is the consequence of Mast cell degranulation caused by their binding to complexes of Allergen bound to Immunoglobulin E, i.e., antigen-antibody complexes (see figure below from 3). When taken during allergy episodes, antihistamines bind histamine receptors, thereby preventing mast cell-derived histamine from doing so. This in turn prevents the full expression of allergy symptoms such as runny nose, sneezing and itching. So far so good.

Problem is action of 1st generation and even some 2nd generation antihistamines isn't limited to just inhibiting the excess histamine that's secreted when large numbers of mast cells degranulate during an allergy episode.

With its own source of histamine, the brain also widely expresses histamine receptors. The tuberomamillary nucleus, a cluster of neurons in the posterior hypothalamus, synthesizes histamine, and these neurons project into various regions of the brain as part of the histaminergic nervous system, and all four types of histamine receptors are abundantly expressed in the brain in distinct patterns (see figures below from 4, 5).

Since most 1st generation and even some 2nd generation antihistamines penetrate the Blood–brain barrier, they can have profound effects on brain function including Anticholinergic effects, sedation and effects on psychomotor function.

Temporary impairment of driving skills is a prominent example of diphenhydramine's effect on the brain. In 2004, the US National Highway Traffic Safety Administration reviewed antihistamine effect on driving-related skills by examining a total of 130 scientific papers published on the subject until 1998 (6). Among other findings, it concluded (6, emphasis mine),

'There is overwhelming evidence from the experimental literature that the 1st-generation antihistamines produce objective signs of skills performance impairment as well as subjective symptoms of sedation'

Obviously, 1st generation antihistamines include diphenhydramine, the one in Benadryl (see figures below from 6).

Bibliography

1. Gray, Shelly L., et al. "Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study." JAMA internal medicine 175.3 (2015): 401-407. https://www.researchgate.net/pro...

2. Harvard Health Publications, Beverly Merz, January 18, 2015. Common anticholinergic drugs like Benadryl linked to increased dementia risk - Harvard Health Blog

3. NIAID Researchers Identify Potential Drug Target for Allergies

4. Thurmond, Robin L., Erwin W. Gelfand, and Paul J. Dunford. "The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines." Nature Reviews Drug Discovery 7.1 (2008): 41-53.

5. Haas, Helmut, and Pertti Panula. "The role of histamine and the tuberomamillary nucleus in the nervous system." Nature Reviews Neuroscience 4.2 (2003): 121-130.

6. Moskowitz, Herbert, and Candace Jeavons Wilkinson. Antihistamines and driving-related behavior: A review of the evidence for impairment. No. HS-809 714,. 2004. http://ntl.bts.gov/lib/26000/260...

https://www.quora.com/Does-occasional-use-of-anticholinergic-drugs-such-as-Benadryl-have-serious-neurological-risks/answer/Tirumalai-Kamala