Among the human senses, smell — or more formally, olfaction — is often considered the most dispensable. In a recent survey, 1 in 6 college students said they would rather lose their sense of smell than their little left toe, and 1 in 4 would forgo their sense of smell to keep their phone.
But for people who’ve found themselves suddenly unable to smell — a more common predicament since the COVID-19 pandemic — the loss can be surprisingly, profoundly devastating.
Zara Patel, MD, a sinus and skull base surgeon and smell specialist at Stanford Medicine, has dedicated her practice to our most underappreciated sense. She sees the effect of its absence in her patients. “People tell me, ‘My life has gone gray. It’s really difficult to find joy in my life anymore,’” she said. “Some might think, why is it that big of a deal?”
Scent permeates our lives so completely — it is literally the air we breathe — that we rarely make conscious note of it. But pay attention and you’ll notice that scents enrich our daily lives, connect us with each other, warn us of danger, and evoke memories and emotions more immediately than any other sense.
More than 1 in 5 Americans has experienced smell loss since the start of the pandemic. The surge has led to a closer look at the underdog sense and its intimate ties to brain health. Smell dysfunction is linked with depression and anxiety. A sudden loss of smell might be the earliest sign of neurodegenerative diseases such as dementia and Parkinson’s, detectable long before any cognitive deficits appear.
Patel believes that smell has more to tell us and that olfactory testing might one day become as routine as mammograms and colonoscopies. But first, someone — why not her? — needs to invent a device that can easily and objectively measure smell ability.
The standard treatments for the loss of smell often take months to work — if they do at all. Her patients’ despair has spurred Patel to develop a faster, more successful solution: injections of a substance derived from the patient’s own blood. She is urging other smell specialists to learn what she says is a simple protocol.
Of the five senses, smell is the most evolutionarily ancient and one we share with the most primitive creatures. Even single-celled bacteria — blind to light and deaf to sound — can sense and react to chemical molecules. That is essentially what smell is — chemosensation. Every pleasing aroma and noxious odor is caused by molecules that have wafted into our noses and been recognized by the specialized neurons deep inside.
Taste is also a type of chemosensation, but if we consider only our tongues, our palate’s palette is limited to sweet, sour, salty, bitter and umami (a savory taste). The myriad complex flavors of food often attributed to taste are largely a result of their smell. Taste alone is like a basic set of crayons next to the nearly limitless shades of oil paint that is smell.
That’s why one of the most noticeable effects of losing one’s sense of smell is strange-tasting food.
Johanna Ta realized something was wrong last summer, several weeks after recovering from COVID-19. She had opened a can of Coke Zero, something she did every day, and thought it tasted funny — like juniper. “Did they change the formula again?” she thought. It was probably just a bad batch, she decided, and went to the grocery store to buy another 12-pack. But those tasted off, too. Later that day, she got into a rental car and realized that the car, too, smelled like the weird Coke Zero.
“It was almost like a switch had been flipped off in my brain,” she said.
Soon she was smelling scents that weren’t there — a variety of smell dysfunction known as phantosmia. Her home smelled like cigarette smoke without anyone lighting up. Actual smells were distorted beyond recognition — a variety known as parosmia. Coffee smelled rancid. Garlic, onions and anything fried or charbroiled reeked of decay.
Nearly half of people with smell loss also experience phantosmia or parosmia.
When Ta, who works in biotech in the San Francisco Bay Area, went on a business trip to Las Vegas, the crowds there smelled like “walking carcasses,” though, funnily enough, she couldn’t smell the cigarette smoke that filled the casinos.
“My family absolutely thought I had lost my marbles,” she said.
Patel can give some patients back a normal sense of smell by excising tumors or polyps blocking their nasal or sinus passages. But these surgeries don’t resolve cases involving damage to the olfactory neurons.
Of all our sensory neurons, the olfactory neurons are the only ones that make direct contact with the environment. The receiving ends of these neurons — 12 million of them — are exposed in a small patch of the mucus-covered lining of the upper nasal passages known as the olfactory epithelium.
Each olfactory neuron recognizes a narrow selection of similar-looking odor molecules. Yet it’s hard to look at a molecule and predict what it smells like or even if it has a smell at all. Chemical structure can hint at smell, but exceptions abound. Molecules that look nothing alike can smell the same, whereas two nearly identical molecules can signal mint and butter to the brain.
Most scents consist of a mix of odor molecules, which activate a combination of olfactory neurons, like a code that the brain then deciphers into bacon, or jasmine, or gasoline.
After recognizing their odor molecules, olfactory neurons carry electrical signals upward — through a thin bony partition called the cribriform plate, which forms the roof of the nasal cavity, about level with the eyes — then straight into the brain.
Sensory neurons responsible for touch, vision and hearing make their first stop in the brain in the thalamus, which relays their messages to other parts of the brain. Olfactory neurons are the only ones that skip the relay station. Instead, they take an express route to the olfactory cortex, which processes smells, as well as to the amygdala, which regulates emotions, and the hippocampus, which encodes memories.
These anatomical connections could explain why smells can trigger memories more intensely than sights and sounds, said Patel, a professor of otolaryngology – head and neck surgery.
There are many ways someone can lose their sense of smell. Sinus inflammation and tumors can block odor molecules from reaching the olfactory epithelium. A type of head trauma, known as a coup-contrecoup injury, in which a hard hit to the back of the head pushes the brain forward in the skull, can shear the neurons at the cribriform plate.
Viral infections were known to cause smell loss long before COVID-19. Most people with post-viral smell loss recover thanks to the ability of olfactory neurons to regenerate, which they do every three to four months. But damaged neurons don’t always regenerate correctly.
By the time patients with long-term smell loss find their way to Patel’s clinic, they’ve tried the conventional therapies: steroid rinses to calm inflammation and months of tedious smell training, in which they practice smelling specific scents while concentrating on their memories of these scents. Yet they still cannot smell.
“You want to be able to help every single person who walks in the door. It was very frustrating for me to not have the answer for that group of patients,” Patel said. “As I looked into the literature, I realized we really didn’t have anything to offer these people.”
But after reading a study showing that platelet-rich plasma injections could treat carpal tunnel syndrome, which is also caused by nerve injury, she developed a protocol to use them for smell loss. Platelet-rich plasma, or PRP, is derived from the patient’s own blood, with blood cells removed, leaving a concentrated serum of platelets and growth factors. The serum is injected directly into the olfactory epithelium to help damaged olfactory neurons regrow.
At Ta’s first visit to Patel, six months after the weird Coke Zero, she realized she was one of many. She’d become used to perplexed reactions to her strange symptoms, but as she described them, “Dr. Patel had this knowing look of ‘Oh yeah, yep, yep,’” she said. “Just having visited her made me feel hopeful.”
Ta decided to try the PRP injections, even though as an experimental treatment they wouldn’t be covered by health insurance.
After the second of the three injections, given two weeks apart, she was overjoyed to find that garlic and onions began to smell normal. Now, a few months after her third injection, she feels she has regained most of her sense of smell, with notable exceptions. She has yet to have a cup of coffee that doesn’t smell like dead rat.
Last year, Patel published the results of a small clinical trial, which found that 57% of patients receiving the PRP injections reported clinically significant improvement in their ability to smell. These days, Patel’s clinic is booked six months out.
Of the effects of COVID-19 Shannon Colon, PsyD, still feels a year and a half after she caught the virus, including fatigue and brain fog, the loss of smell has had the greatest impact on her enjoyment of life, she said. It’s meant missing the new baby smell of her grandniece. Missing the taste of guacamole, one of her favorite foods. Missing the fragrance of honeysuckle that reminded her of growing up in Hawaii and Louisiana. Missing the scents of pine, and leather, and fresh dirt, even the manure from roadside farms along the drive to her mother’s house in California’s Central Valley.
The loss has brought her to some dark places, said Colon, a school psychologist in Reno, Nevada. The pandemic had already taken away the comfort of touch; the loss of yet another sensory pleasure was hard to bear.
“It’s very much like being in prison,” she said. “Other people might appreciate how lonely or devastating that may be, but they’ve never experienced it. It’s just very isolating.”
According to one study, 40% to 76% of patients with smell loss also have depression. The more significant the smell impairment, the more severe the depression.
“Across all of our societies, cultures, in any geographic region in the world, the way we come together as human beings, whether it’s friends, family or strangers, is almost always over food and drink,” Patel said. “If you can imagine not being able to enjoy that, or in some situations feeling repulsed by it, you can imagine why people withdraw and socially isolate.”
After searching for and trying all manner of treatments — from supplements to an injection of anesthetics to nerves in her neck — Colon found Patel’s clinical trial.
Within days after each PRP injection, Colon noticed improvement. Six months after her last one, some smells and flavors have come back. She can taste about 80% of a pickle, by her own estimation, and, when driving through Gilroy, California, she can smell why it’s known as the “garlic capital of the world.” Other scents are still faint or warped echoes. She can barely taste a peanut butter cup, and on some days, guacamole still tastes like soap.
It’s not only the pleasant scents that people miss. Many people develop anxieties around safety or personal hygiene. They might not perceive smoke from a fire or the rancid odor of spoiled food. Scents are such effective warning signals that, since a deadly school explosion in 1937, utility companies have added mercaptan, a chemical that stinks of rotten eggs, to normally odorless natural gas as a safety measure.
Ta still can’t smell her son’s dirty diapers — which isn’t always a good thing. “Sometimes he can go a couple of hours with a soiled diaper, and I wouldn’t know,” she said.
Despite smell’s ancient origins, our understanding of its biology is still catching up to that of the other senses. It wasn’t until 1991 that Columbia University microbiologists Richard Axel, MD, and Linda Buck, PhD, described in detail how the olfactory system works, which earned them the Nobel Prize in 2004.
Studying mice, they found that some 1,000 genes, 3% of the mouse genome, are dedicated to capturing odors. Humans have about a third as many olfactory genes, which still make them the largest family of genes in the human genome.
It’s a myth that humans don’t smell very well. More likely, we’re just out of practice. “We simply don’t exercise our sense of smell as much as we exercise our other senses,” Patel said. “It doesn’t necessarily mean we don’t have the capability.”
Another common misconception is that smell loss is a normal consequence of aging.
Though there’s some decline, it shouldn’t be a huge drop-off, Patel said. A sudden unexplained loss of smell could be a telltale sign of disease brewing in the brain.
“I suspect that the more we investigate these cases longitudinally over time, the more we’re going to realize that many people who we used to put in an idiopathic category — meaning we don’t know why they’ve lost their smell — will eventually end up in the neurodegenerative category,” she said.
Post-mortem studies of brains have found the plaques and tangles tied to dementia appear first in the olfactory system. Numerous studies now suggest that olfactory impairment may be the earliest detectable marker of neurodegenerative diseases.
For smell loss to be a truly useful biomarker, however, we first need a better way to test for smell.
New patients at Patel’s smell clinic are screened with the UPSIT, the University of Pennsylvania Smell Identification Test, a commonly used, 40-item, multiple-choice test with scents ranging from rose to gasoline embedded in the pages of a scratch-and-sniff booklet.
Some are further assessed with the more detailed Sniffin’ Sticks test, in which they’re scored on their ability to detect, identify and discriminate between a series of scent-soaked felt-tipped pens.
In all, there are dozens of such smell tests, but none is considered a universal standard, and results from one test are hard to translate to another. Moreover, they all suffer from an element of subjectivity, such as a person’s past experience with particular scents. How many millennials, for instance, could identify the smell of turpentine?
Sound can be measured in decibels and frequency, light can be gauged by wavelength and brightness, but there’s no analogous way to quantify smells or smell ability.
Patel thinks there should be. With the help of a Stanford Biodesign Faculty Fellowship, she is developing a device that could measure and record the activity of olfactory neurons. The handheld instrument with a malleable probe would be inserted (with local anesthesia) into the nose to reach the olfactory epithelium. The measured electrical activity indicates the severity of smell loss.
“The most important thing is that it’s purely objective. There’s nothing between the electrical signal of these nerves and the answer that we’re looking for,” Patel said.
Patterns of activity might even distinguish between smell loss from neurodegenerative diseases, viral infection or physical trauma. The device also could be used therapeutically to deliver electrical stimulation to the olfactory epithelium to encourage nerve regeneration. It would be a game changer for the study of olfaction.
Patel envisions such a smell-testing device becoming a standard screening tool for early signs of dementia. “What I realized is that not everyone, when you start talking about smell, cares that much,” she said. “But when you start talking about Alzheimer’s disease, people pay more attention.”
If people can accept colonoscopy as a normal screening tool, “they could, hopefully, understand having to put something up their nose,” she said. “They’re numbed up; we place it inside. No big deal.”