Early in the pandemic, a puzzling pattern emerged from Chinese hospital data: smokers appeared to be dramatically underrepresented among COVID-19 patients, leading some researchers to wonder whether nicotine might somehow protect against the virus. That observation launched years of study into nicotine’s relationship with SARS-CoV-2, producing results that pull in opposite directions depending on which biological pathway you examine. The short version is that nicotine does not appear to be protective, and smoking clearly worsens COVID outcomes, but the underlying biology turned out to be genuinely complicated.
The Smoker’s Paradox
The idea that nicotine might help against COVID-19 did not come from nowhere. A pooled analysis of hospitalized COVID-19 patients in China found that only about 6.5% were current smokers, roughly a quarter of what you would expect based on how many people in China smoke.1PubMed Central. Systematic review of the prevalence of current smoking among hospitalized COVID-19 patients in China: could nicotine be a therapeutic option? Similar patterns showed up in French hospital data and a few other countries. The gap was large enough that researchers started floating a “nicotinic hypothesis,” suggesting nicotine might interfere with the virus in some beneficial way.
The finding attracted enormous attention, not all of it healthy. Social media lit up with claims that vaping or using nicotine patches could prevent infection. Some researchers began planning clinical trials. Others urged caution, pointing out that hospital admission data is a terrible way to measure who gets infected in the first place.
Why the Numbers Were Misleading
The low rates of smokers among hospitalized COVID patients had several mundane explanations that took time to sort out. The biggest was a problem with who was missing from the data. A study based on the Stockholm Public Health Cohort found that smokers were more likely to not respond to COVID-19 survey questions, and these non-responders were more likely to have other risk factors for infection.2PubMed Central. New insights into the paradox between smoking and the risk of SARS-CoV-2 infection (COVID-19): Insufficient evidence for a causal association When the people most likely to smoke are also the ones least likely to show up in your dataset, the remaining smokers look artificially scarce.
Another issue was the way smoking history gets recorded at hospital admission. Many studies lumped former smokers in with people who had never smoked, which inflated the “non-smoker” category. Researchers in Stockholm tried to correct for this misclassification and found it explained part of the gap, though not all of it.3PubMed Central. Does misclassification of former tobacco smokers explain the ‘smoker’s paradox’ in the risk of COVID-19? Insights from the Stockholm Public Health Cohort There were also confounders like age: smokers in some populations tend to be younger, and younger people were less likely to be hospitalized with COVID in the first place. None of these issues proved the paradox was entirely an artifact, but together they made the raw numbers far less convincing than they first appeared.
What Smoking Actually Does to COVID Outcomes
While the infection-rate question remained murky, the evidence on what happens once a smoker catches COVID was more straightforward and far less encouraging. A meta-analysis found that about a third of people with a smoking history experienced disease progression, compared to roughly a fifth of non-smokers. Across pooled data, ever having smoked was linked to about 60% higher odds of COVID-19 disease progression and about 19% higher odds of dying from the disease.4PubMed Central. Smoking is associated with worse outcomes of COVID-19 particularly among younger adults: a systematic review and meta-analysis The association held even after adjusting for other factors, suggesting smoking itself was driving worse outcomes rather than just being a marker for other unhealthy behaviors.
A large real-world study from New York City added some nuance. Among nearly 10,000 COVID-19 patients, current smoking was not significantly associated with higher rates of hospitalization, in-hospital death, ICU admission, or intubation after adjusting for other variables.5PubMed. Controversy over smoking in COVID-19-A real world experience in New York city The same was true for former smokers. This single-center finding stood somewhat at odds with the broader meta-analytic picture, which pooled many more studies and generally found worse outcomes for smokers. The tension between these results reflects the messiness of observational data during a pandemic, where different populations, different waves of the virus, and different hospital systems could all shift the numbers.
The weight of the evidence, though, lands on the harmful side. Multiple systematic reviews concluded that smoking worsens COVID-19, with younger adults appearing to be hit particularly hard relative to their non-smoking peers.4PubMed Central. Smoking is associated with worse outcomes of COVID-19 particularly among younger adults: a systematic review and meta-analysis
The ACE2 Problem
To understand why nicotine’s role in COVID-19 is so contested, you need to know about ACE2, the protein on cell surfaces that SARS-CoV-2 uses as its main entry point. Nicotine increases ACE2 levels in lung tissue. In human lung cells, nicotine exposure ramped up ACE2 and made the cells more susceptible to viral replication.6PubMed Central. Nicotine upregulates ACE2 expression and increases competence for SARS-CoV-2 in human pneumocytes In mice, nicotine vapor raised ACE2 levels in male lungs, though interestingly not in females.7PubMed Central. E-cigarette vape and lung ACE2 expression: Implications for coronavirus vulnerability
More recent work has added detail to this picture. Nicotine and its major breakdown product, cotinine, appear to enhance viral entry through different but complementary routes. Nicotine increases ACE2 and another protein called TMPRSS2 that the virus also uses to get inside cells, while cotinine boosts a different enzyme that helps cleave the virus’s spike protein. Together, they made cells more vulnerable to infection in lab experiments.8PubMed Central. Nicotine and cotinine enhance SARS-CoV-2 entry through distinct but complementary mechanisms in human respiratory epithelial cells This is all cell-level and animal-model work, so it cannot tell us exactly what happens in a living person, but the direction is consistent: more nicotine, more doorways for the virus.
The Nicotinic Receptor Hypothesis and Its Failure
The more speculative idea was that SARS-CoV-2’s spike protein might bind directly to nicotinic acetylcholine receptors, the same receptors that nicotine activates. If that were true, nicotine could theoretically compete with the virus for those receptors and block infection. Molecular simulations initially suggested the spike protein could interact with these receptors in a stable way.9Biophysical Journal. Molecular Dynamics Simulations Support a Direct Interaction between SARS-CoV-2 Spike Protein and Nicotinic Acetylcholine Receptors
But computer simulations predict what could happen, not what does happen. When researchers at the National Institutes of Health actually tested this in the lab, they found that none of the spike protein fragments they tested could meaningfully compete with a known receptor-binding molecule at the nicotinic receptor’s main binding site. Electrical recordings of receptor activity showed no clear effect of the spike protein on receptor function. The researchers concluded that competition between the spike protein and nicotine at these receptors is “unlikely to be a relevant aspect of this complex disease.”10PubMed Central. An experimental test of the nicotinic hypothesis of COVID-19 This was a significant blow to the nicotinic hypothesis, though proponents noted that the virus might still interact with these receptors in ways the assay did not capture.
Separately, lab tests found that nicotine had no ability to protect cells from SARS-CoV-2 infection at any concentration tested.11PLOS ONE. Nicotine has no significant cytoprotective activity against SARS-CoV-2 infection If nicotine were blocking viral entry through any mechanism, you would expect to see some protective effect in cell cultures, and none appeared.
The Nicotine Patch Trial
The most direct test of whether nicotine could help COVID patients was a randomized, double-blind trial in France. Researchers gave nicotine patches or placebo patches to patients on mechanical ventilation for severe COVID-19. The results were unambiguous: 28-day mortality was 28% in both groups. Ventilator-free days were essentially identical. Nicotine patches made no measurable difference for critically ill COVID patients.12PubMed Central. Nicotine patches in patients on mechanical ventilation for severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial
This trial is particularly valuable because it tested nicotine directly, divorced from the act of smoking, in a rigorous clinical setting. Whatever the cell-level findings might suggest about nicotine’s anti-inflammatory properties, they did not translate into a survival benefit for people critically ill with COVID. A separate meta-analysis of nicotine replacement therapy in critically ill smokers (not COVID-specific) did find shorter ICU stays for the nicotine group, but no significant difference in time on mechanical ventilation, and the analysis involved very few patients.13Tobacco Induced Diseases. Evaluating the effectiveness of nicotine replacement therapy in critically ill smokers: A meta-analysis of randomized controlled trials
Nicotine’s Anti-Inflammatory Side
The reason nicotine kept surfacing as a possible therapeutic was not entirely without biological basis. Nicotine activates a pathway called the cholinergic anti-inflammatory pathway by binding to a specific receptor type. This pathway dampens the release of inflammatory molecules, and it has been exploited clinically in conditions like ulcerative colitis.14PubMed Central. Cytokine Release Syndrome (CRS) and Nicotine in COVID-19 Patients: Trying to Calm the Storm Since severe COVID-19 is driven in large part by runaway inflammation, the idea of calming that response with nicotine had a certain logic.
But nicotine’s effects on the immune system are not simply anti-inflammatory. It broadly suppresses both innate and adaptive immune function.15PubMed Central. Effect of Nicotine on Immune System Function Nicotine impairs T-cell signaling and inhibits antibody responses.16PubMed. Effect of nicotine on the immune system: possible regulation of immune responses by central and peripheral mechanisms In animal studies, nicotine-treated mice infected with influenza actually survived longer because the dampened inflammation caused less tissue damage, but they carried much higher viral loads because inflammation is also how the body clears the virus.17PubMed. Nicotine-induced modulation of T Cell function. Implications for inflammation and infection
This dual nature is the crux of why the nicotine-COVID question is so unsatisfying. Nicotine simultaneously does things that could theoretically help (suppress the inflammatory storm) and things that would clearly hurt (increase viral entry points, suppress immune clearance). Which effect dominates probably depends on timing, dose, the patient’s immune status, and the stage of infection. The French patch trial suggests that in critically ill patients, the effects roughly cancel out or the harmful ones win.
Smokeless Tobacco and E-Cigarettes
One way to separate nicotine’s effects from the lung damage caused by smoking is to look at people who use nicotine without combustion. Scandinavian snus, a smokeless tobacco product, provides a natural experiment. Finnish data found that current snus users had about 68% higher risk of confirmed COVID-19 compared to never-users.18PubMed Central. Tobacco use and risk of COVID-19 infection in the Finnish general population The researchers noted their findings suggest nicotine does not play a protective role. A Swedish population study found a similar pattern, with snus users of both sexes showing modestly higher infection rates.19PubMed Central. The Association Between Tobacco Use and Risk of COVID-19 Infection and Clinical Outcomes in Sweden: A Population-Based Study
The e-cigarette data is harder to interpret. A study of young adults who had never smoked conventional cigarettes found no significant increase in COVID-19 risk among current e-cigarette users.20PubMed Central. Electronic cigarette use and risk of COVID-19 among young adults without a history of cigarette smoking But a different survey-based study of young people found that ever-users of e-cigarettes were about five times more likely to be diagnosed with COVID-19, and dual users of cigarettes and e-cigarettes were about seven times more likely.21PubMed Central. Association Between Youth Smoking, Electronic Cigarette Use, and COVID-19 That second study’s enormous effect sizes should be taken with caution: it relied on self-reported data, and testing rates were far higher among e-cigarette users, meaning they may simply have been diagnosed more often rather than infected more often.
Taken together, the smokeless nicotine data does not support a protective effect and, if anything, leans toward slightly higher infection risk. The snus findings are particularly telling because snus delivers nicotine without any of the lung irritation caused by inhaling smoke or vapor.
Long COVID and Nicotine Receptors
One area where nicotine research took an unexpected turn was long COVID. A group of researchers proposed that SARS-CoV-2 might disrupt signaling through nicotinic acetylcholine receptors in ways that contribute to the lingering fatigue, cognitive fog, and autonomic dysfunction many patients experience after infection. Because nicotine binds to these receptors with much higher affinity than the body’s own acetylcholine, the reasoning went, it might restore normal signaling. In a small, uncontrolled case series, the researchers reported that nicotine patches led to improvements ranging from substantial to complete remission in some individuals with post-COVID syndrome.22PubMed Central. Is the post-COVID-19 syndrome a severe impairment of acetylcholine-orchestrated neuromodulation that responds to nicotine administration?
This hypothesis remains highly preliminary. The case series involved only a handful of people with no control group, making it impossible to separate the nicotine’s effect from placebo response or natural recovery. Still, the idea has generated interest in long-COVID patient communities, and some patients have experimented with nicotine patches on their own. Rigorous trials would be needed before this could be considered anything more than an intriguing lead. The broader point from the nicotinic cholinergic literature is that these receptors are deeply involved in mood, cognition, and inflammation control, which makes them plausible targets for post-viral syndromes even if the acute infection story did not pan out.23PubMed Central. Nicotine and the nicotinic cholinergic system in COVID-19
Nicotine Withdrawal in Hospitalized Smokers
A practical concern that often gets lost in the therapeutic debate is what happens to regular smokers who are suddenly hospitalized and cut off from nicotine. Nicotine withdrawal can cause agitation, anxiety, difficulty concentrating, and cardiovascular stress, all of which can complicate intensive care. This problem predates COVID but became more visible during the pandemic as hospitals filled with patients who could not leave their beds. Nicotine replacement in this context is not about treating COVID; it is about managing withdrawal in a patient who happens to have COVID, which is a well-established clinical consideration that some hospitals still handle inconsistently.
The Tobacco Industry Factor
Any discussion of nicotine research during COVID-19 should acknowledge the industry backdrop. The tobacco industry has a long and well-documented history of funding research that shapes scientific narratives around its products. A review of tobacco industry activity in research found that conflicts of interest between researchers and tobacco companies are a recurring problem, and that science and the public should approach industry-supported research with skepticism.24PubMed Central. Activity of the Tobacco Industry in Research and Scientific Literature
This does not mean every paper suggesting nicotine might have beneficial properties was industry-funded or compromised. Many were conducted by independent academic researchers asking legitimate questions. But the pattern matters. When a finding aligns with what the nicotine industry would like the public to believe, extra scrutiny is warranted. Some early papers promoting the nicotinic hypothesis were co-authored by researchers with ties to tobacco or e-cigarette companies, and the rapid amplification of “smoking protects against COVID” claims on social media served nicotine-product marketing whether or not that was anyone’s intention.
The underlying science is messy enough without adding commercial interests to the mix. Nicotine genuinely does activate anti-inflammatory pathways, and it genuinely does upregulate ACE2. Those findings are real. The question of whether either matters clinically for COVID-19 patients has been largely answered by the patch trial, which found no benefit. What remains is the more nuanced work of understanding how nicotine interacts with different stages of viral infection and whether any of those interactions could be harnessed in a controlled medical setting, separated from the addictive and cardiovascular harms of the molecule itself.
Nicotine’s Cardiovascular Risks During Acute Infection
One dimension that often gets overlooked in the nicotine-as-therapeutic conversation is cardiovascular safety. COVID-19 itself increases the risk of blood clots, heart inflammation, and damage to the lining of blood vessels. Nicotine, through any delivery method, constricts blood vessels, raises heart rate and blood pressure, and promotes a prothrombotic state. Researchers have warned that prior nicotine exposure may “prime” the cardiopulmonary system for worse outcomes by affecting ACE2 signaling in lung cells in ways that go beyond just viral entry.25PubMed Central. Is nicotine exposure linked to cardiopulmonary vulnerability to COVID-19 in the general population? Giving nicotine to an acutely ill patient whose cardiovascular system is already under viral assault introduces risks that go well beyond the virus itself. The French patch trial did not report major cardiovascular side effects, but it was designed to detect mortality differences, not subtle vascular harm.
For anyone considering self-treating with nicotine patches based on headlines or social media claims, the cardiovascular dimension alone should give pause. Nicotine is not a benign molecule, and the absence of proven benefit against COVID makes the known risks of nicotine exposure especially hard to justify outside of a supervised clinical trial.