The link was found in a wide range of anticholinergics, from tricyclic antidepressants like doxepin (Sinequan), to first-generation antihistamines like chlorpheniramine (Chlor-Trimeton), Benadryl, and antimuscarinics for bladder control like oxybutynin (Ditropan).There is a strong and possibly irreversible link between Alzheimer’s disease and many commonly used medications for insomnia, allergies, and depression, according to a large recent JAMA Internal Medicine study.

Three years of taking either daily Benadryl, Advil PM, Tylenol PM, or Motrin PM, for example, is associated with about a ten percentage point increase in the probability of experiencing dementia or Alzheimer's compared to no use. This risk association is "significant," Malaz Boustani, M.D., M.P.H., told Drug Discovery & Development.

Boustani, director of the Aging Brain Care Program at Eskenazi Health in Indianapolis, Indiana, was not involved in the study. But he has done smaller scale work making similar findings. This was the largest study ever, and utilized the most rigorous standards ever, he said. “Methodologically, this is the best you can get; it doesn’t get better than this. This has established a significant link between anticholinergic drugs and Alzheimer’s." Very few other phenomena have been found to possess such a strong potential link. “It’s rare,” he said.

The new study

Many groups have suggested such links. But for the current study, the team of senior author Eric Larson, M.D., M.P.H., of the University of Washington (UW), engaged in longer follow up (over seven years), and utilized a tighter assessment of use. The study followed some 3,500 Group Health participants, average age 73, with the Adult Changes in Thought (ACT) study, which is a Group Health/UW project funded by the National Institute on Aging.

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The group showed for the first time a dose response; that is, that Alzheimer’s risk may grow with higher use. For instance, it found people taking a minimum of 25 mg of an anticholinergic called diphenhydramine (or one Advil PM, Tylenol PM, Motrin PM, or Benadryl pill) a day for three to 12 months increased their relative risk for dementia by 19 percent; one to three years, 23 percent; three to seven years, 54 percent compared to no use (if the statistically significant increase occurred among the latter group).

Furthermore, this was the first study to find that dementias associated with anticholinergics may not be reversible even years after drug use stops. Wrote Boustani and the Indiana University Center for Aging Research’s Noll Campbell, Pharm.D., in a JAMA editorial: “The risk for dementia was consistent when comparing participants with recent and past heavy use of such medications with nonusers, suggesting that the adverse cognitive effects are permanent. Other studies have consistently shown similar results.”


Lead author Shelly Gray, who is director of the geriatric pharmacy program at the UW School of Pharmacy, found the link in a wide range of anticholinergics, from tricyclic antidepressants like doxepin (Sinequan), to above-mentioned "PM" products with diphenhydramine, to first-generation antihistamines like chlorpheniramine (Chlor-Trimeton) and Benadryl, and antimuscarinics for bladder control like oxybutynin (Ditropan). The team came to the conclusion, for example, that people taking at least 10 mg/day of doxepin, 4 mg/day of chlorpheniramine, or 5 mg/day of oxybutynin for more than three years are at greater risk for developing dementia.

Gray herself was surprised by the findings. “There was one prior study that examined this study question, but we thought we might not find these medications were related to dementia because we had a better study design, and were able to better adjust for some health conditions that might be confounders through use of statistical methods,” she told Drug Discovery & Development. “We know that anticholinergics are related to impaired cognition acutely when people take these medicines. They feel a little groggy, less attentive, etc. But these are reversible changes. This study suggests these medicines are also related to dementia, or irreversible cognitive changes.”

Substitutes are available for some of the problems addressed by anticholinergics. Those suffering from depression can take a selective serotonin re-uptake inhibitor (SSRI) like citalopram (Celexa) or fluoxitene (Prozac). Those with allergies can take a second-generation antihistamine like loratadine (Claritin). Behavioral changes can help urinary incontinence.

Boustani, who is also a professor of medicine at Indiana University, told Drug Discovery & Development that, when it comes to insomnia medications, “basically any cold medications that make you sleepy might contain anticholinergics, so stay away from drugs that make you sleepy.” NyQuil is an exception, he said. It makes people sleepy, but does not contain an anti-cholinergic. Still, “if your solution for a sleep problem is a pill, a quick fix, do you want that?” Any drug taken for a long time could come with problems. “I tell people, if they have to take any such drug for more than 30 days, they should think about alternatives. Maybe you should just take it easy. Maybe you should adopt Grandma’s Remedy of hot milk, hot tea, and rest. Physical fitness is always good. Mindfulness, reflection, physical fitness, tea.”

The cause

The cause of this potential link is unknown. Anticholinergics can block the neurotransmitter acetylcholine. “But there are many hypotheses” as to why anticholinergics can lead to Alzheimer’s, Boustani told Drug Discovery & Development. “The current medication for Alzheimer’s, Aricept, does the opposite of what Benadryl does, for example. We think that same pathway is involved. So anticholinergics may reduce the function of acetyl receptors, and may end up killing the brain cells.”

Gray told Drug Discovery & Development she agreed that “we do not yet know the mechanism by which anticholinergics may increase risk for dementia. It is possible that long term use of these medications leads to changes in the brain similar to those seen with Alzheimer’s disease, such as neuritic plaques and neurofibrillary tangles. In animal models, procedures that blocked transmission through these kinds of pathways increased the concentration of beta-amyloid, a main ingredient in the plaques found in the brains of patients with Alzheimer’s disease.”

Nothing is likely to be fully nailed down anytime soon as it would be unethical to do a gold standard clinical trial. Clinical trials can be done to prove benefit. But to prove a deficit would mean doctors would have to assign patients to take say, Advil PM, every night for three years to assess damage.

The recent trial also did not factor in two other classes of common drugs tapped by the American Geriatrics Society as associated with cognitive problems: benzodiazapines (recently found to hamper rodent neurogenesis) and histamine receptor antagonists.

But even given these limitations, this trial, with its seven years of data, was “very, very good,” Boustani said.  Via computerized dispensing, doses and uses were well established. Potential confounding variables—like people taking anticholinergics for depression or insomnia precisely because they were in the grips of an undiagnosed dementia already—were weeded out.

Boustani’s crew is working on a mobile application to help people figure out what drugs to avoid. In the meantime, he directs clinicians and patients to a chart by the Aging Brain Care website that lists drugs containing anticholinergics.

Gray’s group is in the process of “examining whether these medications are related to changes in the brain of a subsample of this study cohort that has been autopsied after death,” she told Drug Discovery & Development. “We will be examining whether those who used anticholinergics had higher plaques, tangles and other markers of cerebrovascular disease than those who did not use these medications.”