Ask people who have lost a family member to dementia if they would like to avoid a similar fate and you will get an unequivocal answer: YES! Although the FDA recently approved two new drugs, aducanumab (Aduhelm) and lecanemab (Leqembi) to treat Alzheimer’s disease, there is no evidence such medications will reverse memory loss or reduce the likelihood of requiring nursing home care. What if we told you that a shocking number of drugs appear capable of raising your risk for dementia?
They could include some over-the-counter pain relievers, certain OTC allergy drugs and popular nonprescription heartburn medicines. We suspect you will be surprised at the number of potential problem meds we all take for granted. Can avoiding such medications lower the risk of developing dementia?
Contradictory Studies Create Confusion!
Health professionals and patients love clarity. Elevated blood sugar levels lead to diabetes and that is bad news. A high fever usually indicates an infection that can be dangerous. Aspirin can be irritating to the stomach. These observations are not controversial.
Many of the topics we cover here on The People’s Pharmacy are confusing, contradictory and even contentious. That is especially true when it comes to things that may be raising your risk for dementia. What are doctors and patients supposed to do when studies disagree?
Heartburn Drugs and Dementia? The Headlines Are Worrisome:
A study published in a highly respected journal (Neurology, Aug. 9, 2023) created scary headlines:
“Long-Term Use of Some Acid Reflux Drugs Linked to 33% Higher Dementia Risk” (Psychiatrist.com)
“Long-term use of certain reflux medications is associated with a higher risk of dementia, study suggests” (CNN)
“Popular heartburn medicine may increase dementia risk by 33%” (USA Today, Aug. 9, 2023)
“Long-term use of acid reflux medications linked to higher dementia risk” (Washington Post)
What Did the Researchers Discover about PPIs Raising Your Risk for Dementia?
The investigators recruited more than 5,700 people who did not have dementia at the start of the study. Those who used a PPI for more than 4.4 years:
“…were at a 38% higher risk of developing dementia in later life.”
In the spirit of transparency we must point out that this is an association, not proof of causation. Let’s drill a bit deeper, though.
Here is the authors’ introduction to this research:
“Proton pump inhibitors (PPIs), available via prescription and over-the-counter, are currently the first-line therapy for the short-term treatment (4 to 8 weeks) of gastroesophageal reflux disease (GERD) and peptic ulcers. In a study based on U.S. emergency department visits, PPI use increased from 4% to 9% from 2002 to 2009. PPIs were dispensed over 115 million times in 2016. Additionally, up to 63% of PPI prescriptions did not have a documented gastrointestinal diagnosis and may have been inappropriately prescribed. Long-term use of PPIs has not been approved; nevertheless, chronic PPI use is common.
“Chronic PPI use has been linked to numerous health conditions such as stroke, cardiovascular disease, chronic kidney disease, and dementia. Previous studies on the relationship between PPI use and dementia report mixed results.”
Conflicting Results Regarding PPIs Raising Your Risk for Dementia:
When South Korean scientists analyzed nationwide records over the decade between 2002 and 2013, they concluded that older heartburn drugs such as famotidine were just as likely to be linked to dementia as PPIs (Drug Safety, June 2018).
“The risk of PPIs being associated with dementia may be overestimated.”
Even more confusing, a few meta-analyses have looked at the results from several trials and found no significant association between PPI use and dementia (Diseases of the Esophagus, Oct. 2020). A meta-analysis of observational studies found that the risk of dementia increased by 16 percent, a nonsignificant amount, for PPI users (British Journal of Clinical Pharmacology, Feb. 2023). According to the authors, their study does not provide clear evidence for an association between PPI use and dementia.
Why Don’t We Know if PPIs Could Be Raising Your Risk for Dementia?
Researchers have been worried about the possibility of PPIs raising your risk of dementia since 2010. (Journal of Clinical Pharmacology and Therapeutics, April 2010). From where we sit, it feels a bit like a seesaw going up and down or a pendulum swinging back and forth. Some systematic reviews of clinical trials say don’t worry.
But then along come other studies that reinforce the risk. For example, scientists analyzed the medical records of more than 73,000 older Germans over seven years (JAMA Neurology, April 2016). Those who took PPIs long term were 44 percent more likely to get a new dementia diagnosis by the end of the study.
The authors concluded:
“The avoidance of PPI medication may prevent the development of dementia. This finding is supported by recent pharmacoepidemiological analyses on primary data and is in line with mouse models in which the use of PPIs increased the levels of β-amyloid in the brains of mice. Randomized, prospective clinical trials are needed to examine this connection in more detail.”
Now you understand why this issue is so confusing. The very first PPI, Prilosec, was approved by the FDA in 1989. Even after 30 years, we do not have a comprehensive understanding of the risks of this powerful class of medications taken by millions of people on a daily basis.
Instructions for over-the-counter PPIs like Nexium and Prilosec are quite clear:
“Do not use for more than 14 days unless directed by your doctor. You may repeat a 14-day course every 4 months. Do not take for more than 14 days or more often than every 4 months unless directed by a doctor.”
We think that is very good advice!
What About Painkillers? Are NSAIDs Raising Your Risk for Dementia?
If you think proton pump inhibitors are popular, check out nonsteroidal anti-inflammatory drugs (NSAIDs).
According to U.S.Pharmacist (March 17, 2016):
“Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used drug classes in the world. It is estimated that more than 30 million people use these medications on a daily basis, and they account for 60% of the analgesic market in the United States. There are approximately 20 different OTC and prescription NSAIDs available in the U.S. NSAIDs are used for the treatment of fever, acute or chronic pain, and inflammation caused by a variety of conditions.”
We suspect that the question about NSAIDs raising your risk of dementia has been flying well below the radar for decades. That’s because drug companies probably do not want to pay for the kind of long-term research that would be needed to resolve this controversial issue.
There are studies that suggest NSAIDs may actually reduce the risk of developing dementia.
The authors of a study published in the journal Neurology, Sept. 28, 2010 note:
“…not all studies have found an apparent protective effect of nonselective NSAIDs. In particular, the Adult Changes in Thought (ACT) study observed increased incidence of all-cause dementia and AD [Alzheimer disease] dementia in individuals with heavy nonselective NSAID use.”
The authors of the study referred to above published their results in Neurology, June 2, 2009 and concluded:
“In a large cohort study of an elderly population-based sample, we observed no reduction in risk of dementia or AD among users of NSAIDs. Instead, we found that prior sustained NSAID exposure was associated with increased incidence of dementia and AD.”
NSAIDs and Nasty Brain Plaque:
The authors of the 2010 article in Neurology performed autopsies on 257 people who died in the Adult Changes in Thought (ACT) study. The researchers were looking for brain pathology.
“Our results indicate that heavy use of NSAIDs by ACT participants was associated with increased NP [neuritic plaque] score, a hallmark feature of AD that contains amyloid β peptides, abnormal neurites, and reactive glia.”
Trust us when we say that amyloid β (beta) peptides are not what you want forming in your brain. We would like to see more robust and long-term research to resolve the question of whether NSAIDs may be raising your risk for dementia!
What About Anticholinergic Drugs Raising Your Risk for Dementia?
Here we go again, with headlines that sound like they could be hype:
“Hay-fever drugs linked to Alzheimer’s” (Irish Independent)
“Over-the-counter pills could raise risk of Alzheimer’s: study” (New York Post)
“Common allergy, depression meds may increase odds of dementia” (CBS NEWS)
“Dementia ‘linked’ to common over-the-counter drugs” (BBC News Health)
These headlines are scary. Should you be concerned? In a word, yes!
Researchers studied participants in the Adult Changes in Thought (ACT) study conducted in the Seattle area (JAMA Internal Medicine, online, Jan. 26, 2015). These were older people enrolled in an integrated health care delivery system called Group Health. Over 3,000 individuals were included in the research, and none had dementia when they entered the study starting in 1994.
Scientists tracked their drug use and cognitive function over the next two decades. The higher the dose of anticholinergic drugs and the longer such medications were taken, the greater the risk of dementia. In this study, the most common anticholinergic drugs were antihistamines found in over-the-counter allergy drugs and nighttime pain relievers, antidepressants that are also prescribed for nerve pain and medications prescribed to treat incontinence or symptoms of overactive bladder.
The authors conclude:
“Higher cumulative anticholinergic use is associated with an increased risk for dementia. Efforts to increase awareness among health care professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time.”
The Evidence Keeps Accumulating:
The authors concluded:
“Many people use anticholinergic drugs at some point in their lives, and many are prescribed to manage chronic conditions leading to potentially long exposures. There are robust associations between levels of anticholinergic antidepressants, antiparkinsons, and urologicals and the risk of a diagnosis of dementia up to 20 years after exposure.”
What Are Anticholinergic Medications?
We have been writing about this category of drugs for a very long time because of a clearly established link to cognitive impairment. These medicines are known as anticholinergics because they interfere with the ability of a crucial brain chemical called acetylcholine (ACh) to attach to nerve cells. ACh is essential for muscle contraction. Without adequate amounts of this neurotransmitter you could not breathe, blink your eyes or tie your shoelaces. Body movement can only happen when ACh triggers a muscular contraction.
Acetylcholine is also critical for proper brain function. Without ACh doing its job transmitting messages between brain cells, you would become forgetful and confused.
Twilight Sleep for “Painless Childbirth”
One of the most potent anticholinergic medications, scopolamine, was used for decades with a narcotic like morphine to induce “twilight sleep.” Starting about a century ago, women were given this combo during labor and delivery so they wouldn’t remember the pain or anything else about the experience.
The German researchers who developed this approach in the early 20th century said that it produced:
“clouded consciousness with complete forgetfulness.”
Are Modern-Day Anticholinergics Raising Your Risk for Dementia?
Most physicians are offered a few hours of training about anticholinergic drugs (at best). They are taught about belladonna, aka deadly nightshade. (The drugs atropine, hyoscyamine and scopolamine were derived from the plant Atropa belladonna.) Such medications have been used to treat diarrhea and what was once called “spastic colon.” The combination of atropine and diphenoxylate (Lomotil) remains popular for diarrhea.
Scopolamine (Transderm Scop) is still prescribed for motion sickness, and ophthalmologists and optometrists may use atropine drops to dilate the pupils during an eye exam. Doctors also employ other anticholinergic drugs such as ipratropium (Atrovent) and tiotropium (Spiriva) for asthma. Anticholinergics such as fesoterodine (Toviaz), oxybutynin (Ditropan) and tolteradine (Detrol) are frequently utilized to control the symptoms of overactive bladder.
Popular Antihistamines & Sleep Aids:
What most modern-day physicians have not learned, however, is that many other drugs also have anticholinergic activity. As mentioned in the ACT study, first-generation antihistamines were linked to dementia. We are talking about drugs like chlorpheniramine and diphenhydramine (DPH).
You may be surprised where DPH shows up. It is the primary ingredient in many allergy and hay fever meds ,including the popular brand name Benadryl. But DPH is also found in a huge number of nighttime pain relievers and sleeping pills. Look at the label of Advil PM, Aleve PM, Bayer PM, Excedrin PM, Nytol, Simply Sleep, Sominex, Tylenol PM or Unisom and you will may find diphenhydramine as a key ingredient.
We do not worry very much about the occasional use of such drugs. But chronic use, day in and day out for both pain and insomnia, begins to add up to substantial anticholinergic exposure. That is especially true if these drugs are used year in and year out.
The researchers noted that an older class of antidepressants called “tricyclics” was also linked with dementia. Drugs such as amitriptyline or doxepin are not prescribed as much for depression as they once were. That’s because of newer antidepressants such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac) and sertraline (Zoloft). But some physicians prescribe amitriptyline for nerve pain and doxepin for insomnia. These drugs can produce classic anticholinergic side effects: dry mouth, constipation, blurred vision, rapid heart rate, difficult urination, confusion, cognitive impairment and drowsiness.
Bladder Drugs (Urinary Incontinence)
In the ACT study the most common anticholinergic drug in the class of meds for overactive bladder was oxybutynin (Ditropan). Other medicines in this category include fesoterodine (Toviaz), and tolterodine (Detrol). By the way, an over-the-counter form of oxybutynin is now available for women under the brand name Oxytrol.
Here’s the Real Problem:
What concerns us far more than any individual anticholinergic medication is the combination of several drugs with anticholinergic activity. Physicians may not realize that the anti-anxiety agent alprazolam (Xanax) has anticholinergic activity. So does the ulcer drug cimetidine (Tagamet). The dizziness drug meclizine (Antivert, Bonine) also has this activity.
We could go on and on, but by now you get the picture. There are dozens of medications that have this property. Someone taking Tylenol PM to get to sleep who is also taking amitriptyline to ease nerve pain along with oxybutynin to control an overactive bladder could end up disoriented and forgetful. But don’t take our word for it. Here are stories from visitors to this website:
“Many years ago my urologist prescribed Ditropan and I took the drug for about four years. I had an hour’s drive to work each day and I began to realize that many days I could not remember the drive and would arrive at work with my mind in a somewhat “fuzzy” state. I happened to pick up a new prescription for Ditropan at the pharmacy and started reading the side effects of the drug.
“I saw that my symptoms could be connected to the drug. I stopped taking the drug immediately and decided that I would try to control my bladder some other way (exercises, etc). My symptoms went away and I have not had any problems since. I still cope with bladder issues but I would rather be clear-headed.”
“I was prescribed amitriptyline for headaches and couldn’t stop sleeping! I also felt sluggish mentally and pretty much dead overall. It was an awful feeling.”
This comment comes from Abigail:
“I appreciate your warning about anticholinergics. I only took Lomotil for IBS [irritable bowel syndrome] when I went out for an event, so I thought my episodes of brain confusion were caused by senior moments. After your warning I realized I was taking an anticholinergic. I stopped taking Lomotil and have regained my mental clarity. Thank you!
Who Takes an Anticholinergic Drug?
You might wonder how many older people are on anticholinergic medications. According to the Seattle team of researchers, 8% to 37% are taking such drugs, despite warnings to health professionals that risks might outweigh benefits. In other words, as many as one-third of people over 65 could be taking an anticholinergic drug without even knowing it.
The authors of the study point out that this may not be reversible:
“The general view is that anticholinergic-induced cognitive impairment is reversible on discontinuation of medication therapy. However, several investigators have reported that anticholinergics may be associated with an increased risk for sustained cognitive deficits, such as mild cognitive impairment or dementia. One biologically plausible mechanism for these findings is that cumulative use of these agents results in pathologic changes in the brain similar to those observed with Alzheimer disease (AD).”
Most Doctors Don’t Know Which Drugs Are Anticholinergic:
As mentioned earlier, medical students get an hour or two training about anticholinergic medicines. They learn about atropine, hyoscyamine and scopolamine, classic drugs in this category.
What they don’t always learn is how many other medications also have anticholinergic activity. If you ask your doctor whether cimetidine (Tagamet), furosemide (Lasix) or alprazolam (Xanax) could have anticholinergic action, the chances are pretty good that you would be told no. But the list of such drugs is surprisingly long.
Here is a link to a list that we have prepared. We must emphasize that no one should EVER discontinue any drug without first checking with the prescriber!
That said, the Seattle team of researchers suggests that:
“Prescribers should be aware of this potential association [the increased risk for dementia in people with higher-use of anticholinergic drugs] when considering anticholinergics for their older patients and should consider alternatives when possible. For conditions with no therapeutic alternatives, prescribers should use the lowest effective dose and discontinue therapy if ineffective.”
Would you like to know more about how medications can affect brain function? We have much more information in our chapter, “The Screwing of Senior Citizens.” In addition to a list of anticholinergic drugs, there is a long list of medications that older people should generally avoid (The Beers List). This information can be found in our book, Top Screwups Doctors Make and How to Avoid Them.
We would be derelict if we didn’t point out that this is not the first study linking anticholinergic drugs to dementia. In our book we describe the “Three-City Study” from France.
These investigators concluded that
“elderly people taking anticholinergic drugs were at increased risk for cognitive decline and dementia. Discontinuing anticholinergic treatments was associated with a decreased risk.”
In addition to the long list of anticholinergic drugs, researchers have also discovered that benzodiazepine drugs frequently used to calm anxiety or aid sleep are also associated with a greater risk of dementia (BMJ, online Sept. 10, 2014). A problem became apparent in older people who had taken such medicines for at least three months, but the longer they had been on the drugs, the higher their risk of an Alzheimer disease diagnosis. If you would like to read more about that study, we have written about it.
Are Your Drugs Raising Your Risk for Dementia?
Lest you think this is only an older person’s problem, we hasten to point out that middle-aged and younger people can also experience anticholinergic side effects. Just because you are 57 does not mean you are immune to these complications.
Health professionals need to be far better educated about anticholinergic pharmacology and its consequences on the brain. And patients need to ask their physicians, nurse practitioners and pharmacists whether any of their medicines have anticholinergic activity. And let’s not forget the controversy swirling around proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs (NSAIDs).
You may find this article of additional interest:
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