It took me by surprise. The claim was made on TikTok by a very popular dermatologist, Dr. Charles Puza, and was picked up by BuzzFeed. Puza grew concerned when many of his patients confessed to regularly taking Benadryl, an old allergy medication, to help them sleep. Drowsiness is a well-known side effect of the drug, so many people use it precisely because it puts them to sleep.
His worry? The drug has apparently been associated with an increased risk of dementia. The longer you take it, the higher the risk of developing dementia later in life.
This story shows that facts that are commonly discussed in the medical literature about over-the-counter drugs are not always communicated to the public, but this particular claim requires a lot more nuance than a TikTok video is capable of.
Turning anti-allergy lemons into sleep-inducing lemonade
To talk about Benadryl is to talk about antihistamines. Our bodies produce histamine, a type of chemical messenger. When you are stung by a bee, histamine helps create the redness and swelling. It is also a notorious player in allergies. In the 1930s and 40s, the first compounds that blocked the action of histamine—known as antihistamines—were synthesized, including a molecule called diphenhydramine (pronounced deye-fen-HIGH-dra-meen). Doctors could now provide medicated relief from the symptoms of allergies.
The problem with diphenhydramine and other first-generation antihistamines, however, is that they cause drowsiness. So, when hay fever season would begin, you wouldn’t sneeze as much or have to rub your eyes quite as often, but you would be struggling to stay awake, depending on your susceptibility to drowsiness. More recently, second-generation antihistamines were developed—molecules like cetirizine (commercialized here as Zyrtec), fexofenadine (Allegra), and loratadine (Claritin)—and while high doses of these can also make you sleepy, the effect is typically much less than with diphenhydramine.
If you are struggling with insomnia, you can see how an undesirable side effect of diphenhydramine can be turned into an actual solution. The pharmaceutical industry is already selling the molecule as an over-the-counter sleeping aid. Diphenhydramine can be found in a number of commercial products, like ZzzQuil and Benadryl. However, brand names can be deceiving. While the active ingredient of Benadryl in Canada is diphenhydramine, Benadryl sold in the United Kingdom is actually either cetirizine or acrivastine, both second-generation antihistamines that do not cause as much sleepiness as diphenhydramine. This is why looking for the active ingredient listing at the pharmacy is much more important than searching for a particular brand.
The research linking diphenhydramine to dementia, however, does not focus exclusively on this molecule. Rather, it centres on a whole class of chemicals known as anticholinergic drugs.
Low-certainty evidence
Just like Leonardo da Vinci was both an artist and a scientist, drugs can belong to more than one category. Diphenhydramine is not just an antihistamine; it’s also an anticholinergic drug. These types of drugs block the action of a neurotransmitter called acetylcholine. This property can be the primary action of the drug and the reason why it’s prescribed or, as in the case of diphenhydramine, it can be a side effect. Anticholinergic drugs are used to tackle Parkinson’s disease, urinary incontinence, depression, and many other diseases. Because of their effect on the nervous system, they can cause symptoms like memory problems, disorientation, and confusion. What about dementia?
The association between the use of anticholinergic drugs and the risk of developing dementia is not new, though it surprised a lot of people recently (myself included, as I am not a medical doctor). The ways in which these drugs can mess with brain function makes it plausible that their prolonged use could contribute to a state of dementia, i.e. a severe decline in cognition. In fact, a drug for dementia like donepezil (Aricept) can modestly improve cognition because it does the opposite of what an anticholinergic drug does.
There have been quite a few studies investigating whether people who take anticholinergic drugs are more likely than those who do not to develop dementia, but these studies are observational in nature. If we hypothesize that these drugs cause dementia, it would be unethical to give them to people in the context of a randomized clinical trial to prove that they will increase the risk of dementia. Hence, we have to rely on studies where people are prescribed these drugs for valid reasons and compare them to other people who are similar enough but are not prescribed these drugs, a type of study that is less robust than a clinical trial.
In 2021, researchers published a review of this association for the Cochrane Library. Their conclusion from looking at 25 studies in a total of nearly 1 million people? There was low-certainty evidence that older adults who did not have a cognitive impairment and who took anticholinergic drugs may be at an increased risk for some sort of cognitive decline or even dementia. It’s definitely not a sure thing, and these studies cannot prove that the anticholinergic drugs caused, even partially, the dementia that some participants ended up developing later in life. Establishing causation is hard.
That same year, an interesting paper by a British team addressed this exact problem. They wondered if they could prove causation by using the famous Bradford Hill criteria, first formulated by the epidemiologist Sir Austin Bradford Hill in 1965 to help narrow down if cigarette smoking really did cause lung cancer. And in this recent paper, the researchers do a good job of showing that one specific anticholinergic used for bladder symptoms, oxybutynin, does fulfill these criteria: the association with dementia is strong, consistent and specific; taking the drug precedes the disease; there is a dose-response relationship; it is a plausible and coherent link, and there is both experimental evidence for it as well as analogous links with the plaques and tangles seen in Alzheimer’s disease.
Other review articles and meta-analyses have been more generous than the Cochrane paper when rating the quality of the evidence showing an association between anticholinergics and dementia, but the vast majority of these studies are unlikely to include diphenhydramine as they are limited to prescription drugs. (Diphenhydramine can be prescribed but it is more likely to be purchased over the counter.) We are left with a 2015 study out of Seattle, which used records from the pharmacy the participants were using, and these records would often (but not always) include over-the-counter antihistamines, like Benadryl. Researchers saw an increased risk of dementia in the people who were on anticholinergic drugs, including Benadryl.
Deciding what to do with this information is not easy. Not all anticholinergic drugs are created equal: in fact, one review article points out that the anticholinergic drugs used to treat heart problems and digestive issues seem to have a protective role toward dementia, although the number of studies showing this benefit was small. Some have a worse impact on brain function than others, and some do not even cross the blood-brain barrier, which helps isolate the brain from the effects of dangerous chemicals and toxins. If we want to stave off dementia, there are more important modifiable risk factors to consider, like diabetes, high blood pressure, tobacco use, physical inactivity, and social isolation. Then, there are things we cannot control, like age, the biggest risk factor for dementia. In Canada, fewer than 1 in 100 have been diagnosed with dementia between the ages of 65 and 69, but when we look at Canadians aged 85 and above, that fraction goes up to 1 in 4.
For all the talk about doctors overprescribing medication because they’re in the pocket of the pharmaceutical industry, what I saw combing through the literature on this topic was many reminders to deprescribe. While the evidence is not strong enough to show that tapering the number and potency of anticholinergic drugs reduces cognitive decline, many doctors are calling for it or, at the very least, reminding their colleagues to be judicious in their prescription of these drugs, especially in patients who already have dementia. As we age, we become more susceptible to the negative effects these drugs can have on the brain for many reasons that include a slower clearing of drugs from the body and changes to our fat and muscle content.
But if you’re trying to move away from Benadryl out of an abundance of caution and still get a good night sleep, you may be disappointed by the alternatives. When consulting a doctor, they will try to find any specific cause of your insomnia, which could be shift work, restless leg syndrome, or the need to urinate frequently at night caused by an illness or a medication. Solving this problem will indeed improve sleep.
Beyond that, it’s cognitive behavioural therapy with a psychologist; pharmaceuticals other than diphenhydramine that carry their own risks; and sleep hygiene. When Dr. Puza brought up the link between Benadryl and dementia, he suggested as alternatives eye masks, socks, a cold room and a weighted blanket, the kind of common advice that some commenters found “deeply infuriating” and “condescending.” Indeed, people frequently try these tricks before resorting to medication. It’s worth also mentioning melatonin, a hormone supplement available without a prescription, but what little benefit it has to help you fall asleep faster is very disappointing.
In a subsequent video, Dr. Puza added more recommendations on what to do if you’re struggling to fall asleep, suggesting magnesium supplements (for which there is no good scientific evidence), tart cherry juice, and walnuts.
We’re getting dangerously close to recommending walnuts for brain health because they are shaped like little brains. If you’re trying to get a good night sleep, closing TikTok and putting your phone away may be wise.
Take-home message:
- The drug diphenhydramine, marketed in many countries under the brand name Benadryl, is an old allergy medication that some people use to fall asleep
- The evidence linking a large class of drugs which includes diphenhydramine to dementia is of low quality and no cause-and-effect relationship has been established with diphenhydramine yet
