Key points you should know:
- Nicotine patches have been used, to varying effect, by thousands of people with Long COVID, but their mechanism of action remains unclear.
- Both nicotine’s impacts on the nervous system and Long COVID as a disease are incredibly complex. Combined, researchers have a difficult task teasing out how they work.
- The popular understanding of nicotine’s impact on Long COVID — that it displaces the spike protein from nicotinic receptors in the nervous system — likely does not tell the full story of how it leads to improved symptoms for some people.
- Researchers are trying to identify the exact underlying mechanism and which specific Long COVID subtypes are most susceptible to nicotine in order to identify alternative, targeted therapies.
- Protocols for treating Long COVID with nicotine advise it should be administered in very low doses using a transdermal patch.
After a half century of anti-cigarette advocacy, the chemical substrate nicotine, which makes up about 3% of the tobacco plant, is stepping into its own limelight. Nicotine patches, especially, are having a heyday for their purported health benefits. After 40 years on the market as a cigarette-replacement therapy, the patches have found an unlikely audience among people with chronic illnesses — including those with Long COVID.
Nicotine has had a complicated history with COVID-19 since the early months of the pandemic, when researchers found that smokers might be less likely to get infected with SARS-CoV-2. Real-time hospital data, however, found a higher prevalence of smokers were hospitalized, and that smokers who were hospitalized had worse outcomes. In fact, being a current or former smoker is now recognized by the Centers for Disease Control and Prevention as a risk factor for severe COVID-19.
But some people with Long COVID and the providers who were treating them wondered if nicotine, delivered by a mechanism other than cigarettes, might help with the chronic disease. For the next several years, white papers used anecdotal evidence to expand on that initial hypothesis. Those publications gained traction across Long COVID support groups on Reddit and in hundreds of social media posts, where people have extolled low-dose nicotine patches for treating everything from sinus congestion to lost smell and taste to cognitive dysfunction.
Among the people who have tried nicotine, there have been a wide variety of responses. Some cite it as curative. Some say it has made them sicker.
Researchers do not yet understand how nicotine might help alleviate Long COVID symptoms. To date, there have been no clinical trials formally testing the drug. Pharmacology researchers hope to eventually untangle the interactions between nicotine and SARS-CoV-2 — because if they can, it could lead to a more targeted therapy, without nicotine’s risks.
For now, nicotine has found a crowd of ready advocates among the community of people it has helped. Troy Roach, who developed Long COVID and myalgic encephalomyelitis (ME) in 2020, is among them. Roach began using patches consistently in 2023, and found that it significantly reduced his post-exertional malaise. “I went from 80% to 90% [cognitive capacity],” Roach said. “I didn’t have to count spoons.” After the first few months, his symptom reduction stalled.
That same year, Roach saw a tweet from Tess Falor, founder of the patient-led research collective Renegade Research, inviting new people to participate in their citizen science efforts, and immediately thought of nicotine. With their help, Roach and a few others organized a new patient-led research group. They named it the Nicotine Test.
Now the Facebook group has more than 30,000 members and publishes its own “dosing protocol,” and Roach has coauthored peer-reviewed studies that propose how the treatment may potentially improve Long COVID symptoms, alongside Marco Leitzke. Leitzke, an anesthesiologist by training, was among the first to publish about the theoretical impacts of nicotine on SARS-CoV-2 early in the pandemic. Since then, Leitzke has gained notoriety for his willingness to work with people with Long COVID to develop their own experimental treatment regimens.
Some experts are skeptical of these highly publicized claims, as there is scientific evidence that complicates the key “displacement theory” behind nicotine’s use as a Long COVID treatment. But the lack of any randomized control trials hasn’t significantly stymied the Nicotine Test’s appeal.
To date, Lietzke has fielded thousands of requests for personalized treatment regimens. “I have received around five to 10 emails a day [about administering the patch] over the last four years,” he said.
Nicotine’s mechanisms for treating Long COVID remain unclear
Pharmacologists, researchers who focus on studying how drugs work, have not yet identified exactly how or why nicotine may be a beneficial treatment for some people with Long COVID.
Nicotine has impacts across diverse body systems. Best known as a stimulant, it also affects the cardiovascular system by temporarily constricting blood vessels. Some studies have shown that nicotine can relieve pain. It can also impact inflammation in the brain, and can increase heart rate, blood pressure, respiration, and blood glucose levels.
Some people with Long COVID worry that some of nicotine’s properties could have adverse impacts on those who may try it. Milica, who developed Long COVID in 2022, has avoided nicotine treatments because she’s found through self-experimentation that she’s sensitive to drugs that activate the sympathetic nervous system. (Milica asked to only have her first name used to avoid being “dragged in any personal academic warfare” by the nicotine treatment’s most vocal advocates. )
Her symptoms consist primarily of hyperadrenergic postural orthostatic tachycardia syndrome (a POTS subtype characterized by excess adrenaline) and mast cell activation syndrome, which together influence her endocrine system by causing excessive hormone production. Because these conditions can cause high levels of the hormone norepinephrine, she believes nicotine — which also stimulates norepinephrine — would be detrimental for her and other people with Long COVID with hyperadrenergic POTS.
In 2020, when researchers first observed a potential relationship between nicotine and SARS-CoV-2, some hypothesized that nicotine was displacing a SARS-CoV-2 spike protein from attaching to a specific cell receptor that responds to both the drug and a neurotransmitter, or chemical messenger, called acetylcholine.
This theory, called the “displacement theory,” posits that when the SARS-CoV-2 spike protein attaches to this receptor, it may prevent acetylcholine from binding and disrupt normal cell signaling — making different natural processes in the body go haywire. Because nicotine binds more strongly to these receptors than acetylcholine, proponents of the theory say it could displace the coronavirus protein and restore receptor function.
But the actual underlying biological processes are likely more complicated, said Janna Moen, an immunology postdoctoral fellow at Yale who has Long COVID herself. Moen’s PhD and first postdoctoral research projects both focused on nicotine pharmacology.
In 2023, researchers directly measured the activity of those specific receptors by examining their electrical activity in response to different combinations of spike protein and acetylcholine. They found that the coronavirus spike protein’s effect on the receptor was not straightforward, suggesting that the spike protein does not directly block the action of acetylcholine but instead impacts receptor function by interacting with a different site of the receptor protein — a strike against the displacement theory.
“To me, that was pretty definitive that it is a more complex effect than this common narrative about spike displacement,” Moen said. Two other studies from different groups have reported similar findings.
But nicotine patches are still clearly useful for some people, she added. She’s been using patches intermittently herself since developing Long COVID in 2021.
To me, that was pretty definitive that it is a more complex effect than this common narrative about spike displacement.
Janna Moen, immunology postdoctoral fellow at yale
Researching nicotine could lead to identifying a targeted therapy
Moen and her colleagues at Yale are working to develop a pharmacologically sound explanation for nicotine’s benefits among many people with Long COVID in order to inform future treatments. To do so, they will have to contend with nicotine’s complex interactions in both the nervous and immune systems.
“Nicotinic receptors are one of the most complicated receptor families in the brain,” Moen said. “They’re particularly difficult to study for a lot of logistical reasons.”
There are a wide variety of receptors that bind to nicotine in the body, and nicotine can impact them in many ways. And those responses can change as people use nicotine heavily over time. Plus, Long COVID is a heterogeneous disease, having a range of impacts on multiple body systems, which has made it a challenge for researchers to study.
“First, we have to establish that [nicotine] is having an effect in the animal models,” Moen said. Researchers “don’t always see the same phenotypes, or disease pathways, in animal models because we’re using a mouse to mimic a complex condition that isn’t fully understood,” she said.
If Moen’s group can locate a clear impact, she hopes they could identify existing drugs that target specific types of receptors involved in Long COVID symptoms, and that may come with fewer potential side effects than nicotine. But it’s unclear whether whatever they identify would alleviate symptoms or reverse the underlying causes of disease.
The anecdotal evidence–based protocol for administering nicotine
Until a clearer understanding of the interaction of nicotine and Long COVID emerges, it will be impossible to develop a standardized use model for the nicotine patch, let alone other, more targeted drugs. “The ultimate goal isn’t to just throw nicotine on everything,” Moen said.
But until then, a small number of providers who have heard of the protocol recommend it to their patients.
“It’s super low-risk, inexpensive, doesn’t require testing, and if it’s going to work for someone, it works quickly,” former intensive care unit physician Anna Sattah said. Since 2023, Sattah has run a functional medicine clinic, where she treats people with complex and chronic conditions, including Long COVID and ME.
She first heard about nicotine patches when a colleague’s patient brought in one of Leitzke’s research papers, documenting a group of four participants who reported improvement of their symptoms — although the trial did not have a control group that took a placebo. Since learning about Lietzke’s experimental protocol, it’s “become one of my first-line treatments,” she said. “I like it because it’s nice to have a quick win early while we’re working on other factors that take much longer to have an effect.”
Sattah has seen some adverse reactions in her dozens of Long COVID patients — some have increased fatigue or develop migraines. But she suspects most of these reactions occur due to people’s sensitivity to nicotine if they start at a too-high dose; most patches are designed for people with a heavy smoker’s tolerance.
Moen suspects bad reactions could also be caused by the masking effect of nicotine’s stimulant properties — people might feel so good, they overdo it, and later experience post-exertional malaise. (To this end, Sattah has observed that some of her patients actually do better with other stimulants, like off-label ADHD medicine.)
I like [nicotine patches] because it’s nice to have a quick win early while we’re working on other factors that take much longer to have an effect.
Anna Sattah, physician specializing in complex chronic illness
But these adverse reactions tend to end as soon as patch use has stopped, and so Sattah continues recommending it as a low-risk option. Leitzke said, in an email, that the patches are recommended for all disease phenotypes, but the test group’s protocol advises against nicotine use by people with cardiovascular issues; it may be ill-advised for anyone with a hyperadrenergic condition, too, such as that subtype of POTS.
For patients who are good candidates, Sattah recommends a graduated approach, beginning with small doses of nicotine for only 2 to 4 hours a day, eventually working up to 10 to 12 hours a day for 7 days.
The protocol developed by the Nicotine Test similarly recommends starting with a smaller dose and shorter time period, then gradually increasing both. Nicotine patches, designed for smokers, come in doses that would be intense for someone who is nicotine-naive, and so the test group protocol advises starting with half patches. Sattah recommends that patients avoid cutting the patches, as cuts in the fabric might change the rate of delivery, instead leaving a portion of the patch covered with its sticker paper or a bandage.
Whether or not continuous dosing is ideal is still more or less trial and error. Most studies about long-term nicotine use in humans have focused on smokers, who receive much higher and much more erratic doses of nicotine when compared to a low-dose patch user.
Moen also recommends that the nicotine-curious stay away from other sources of nicotine, including gum, vapes, and cigarettes, which all deliver very high, very short-acting doses of nicotine, increasing the likelihood of addiction — among myriad other potential health risks.
“This is not medical advice,” Moen, who is not a medical doctor, said. “But I cannot emphasize enough that you should not pick up vaping to treat Long COVID.”
Astra Lincoln is a freelance writer who lives in Portland, Oregon. Follow her at @astralincoln.
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