Most Americans have probably consumed or have been prescribed an anticholinergic drug in the past. Medications with anticholinergic activity like Benadryl are drugs that, on the pharmacodynamics level, block the effect of the neurotransmitter acetylcholine at muscarinic receptors in neurons. Such drugs are highly prevalent and are commonly used as therapeutics for conditions including but not limited to depression, gastrointestinal disorders and overactive bladder, and respiratory disorders. Benadryl, for example, is a common household medication that is used to treat allergic reactions and contains the psychoactive compound Diphenhydramine (DPH). Psychoactive compounds are substances that, when administered, chemically alter the nervous system and result in neurological and behavioral effects. Immediate side effects of DPH, in particular, may include delirium and sedation. However, a recent publication by Dr. Shelly Gray and colleagues in JAMA Internal Medicine presented compelling evidence that such acetylcholine antagonists may also have a startling long-term effect: significantly increased risk for dementia.

 

Medications with anticholinergic activity like Benadryl are drugs that, on the pharmacodynamics level, block the effect of the neurotransmitter acetylcholine at muscarinic receptors in neurons.

Approximately 35,000 men and women that were 65 years and older and with no signs of cognitive impairment participated in a longitudinal study in Seattle titled “Adult Changes in Thought.” Group Health pharmacy records of the individuals were used to identify all prescription and over-the-counter drugs that the participants took up to ten years before the study began. Participants were tracked for ten years since enrolling in the study and were required to check-in with the experimenters every two years during that time.

An experimentally designed variable called total standardized daily dose (TSDD) was calculated for each subject in order to determine exposure to anticholinergic drugs by the conclusion of the study. Statistical analysis was applied to eliminate confounding variables such as comorbidities and health status, as well as to determine correlation between TSDD of anticholinergic drugs and incident dementia. Incident dementia was measured using the diagnostic criteria for Alzheimer disease.

Interestingly, subjects who had high TSDDs in the past were at similar risk for dementia compared to those with recently high TSDDs. This data suggests that dementia risk may persist even in patients who discontinue their anticholinergic medication. Additionally, a dose response relationship, graphically depicted as a sigmoidal curve, was found for dementia and TSDDs. Such a relationship suggests that potency and efficacy is most effective at intermediate dosages and less effective at small or high threshold doses.

While Gray’s experimental design did adjust for many potentially confounding variables such as baseline incident dementia scores, other potentially confounding variables might have existed in this study.

While Gray’s experimental design did adjust for many potentially confounding variables such as baseline incident dementia scores, other potentially confounding variables might have existed in this study. For example, the number of years of education of an individual has been shown to correlate strongly with higher cognitive functioning and decreased risk of cognitive impairment in numerous dementia-related studies. Other potentially confounding variables that were not adjusted for include but are not limited to socioeconomic and cultural factors such as social status, economic status and financial stability, and access to healthcare. Adjusting for these additional variables may strengthen the validity of the statistical results of this experiment, and would confirm whether dementia risk was strictly and significantly associated with anticholinergic exposure.

The lack of diversity among subjects of this study’s sample suggests that these results may not be completely generalizable to the greater population of 65-year olds. This experiment restricted participation to healthy subjects who were without medical comorbidities upon enrolling in the study. This qualification would not, in reality, be met by many people at this age and thus would not be inferential to such a population. Having a subject group that includes individuals with comorbidities in addition to a control group of health individuals may further confirm the influence of anticholinergic medications on cognitive impairment. Lastly, future experiments should conduct this same experimental procedure in other parts of the country outside of Seattle to ensure that these results are generalizable to other communities.

While the suggested improvements would strengthen the results of this study, Gray and colleagues’ work still provides powerful evidence to suggest that long-term use of anticholinergic drugs could lead to elevated risk of cognitive impairment and dementia.

While the suggested improvements would strengthen the results of this study, Gray and colleagues’ work still provides powerful evidence to suggest that long-term use of anticholinergic drugs could lead to elevated risk of cognitive impairment and dementia. The findings of this experiment should be especially relevant considering the prominence of anticholinergic compounds like DPH and how often they are consumed. Dementia-related clinical research studies that hope to analyze longitudinal cognitive impairment should consider calculating TSDD doses of all participants and adjusting any related statistical analysis accordingly. Additionally, while Benadryl and other medications containing such anticholinergic compounds have numerous medical benefits, users should exercise caution when consuming such compounds.

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