Nicotine – what a strange thing! Nicotine patches are perhaps the most surprising entrant yet in the treatment sweepstakes for long COVID, chronic fatigue syndrome (ME/CFS), fibromyalgia, and related diseases.
Nicotine, of course, is the substance in the tobacco in cigarettes which makes them so addicting – and nicotine withdrawal, we know, is no joke. Cigarettes could be viewed as profoundly efficient ways of delivering nicotine to the brain. It’s the quick hit that tobacco smoke provides, though, that makes nicotine so addicting.
Slow-release low-dose nicotine patches, gummies, lozenges, inhalers, etc., on the other hand, are used to wean cigarette smokers off their addiction. It’s the slow release that does it; when nicotine is released slowly, its addictive power apparently either completely disappears or almost disappears – allowing its beneficial properties to emerge. It certainly has some.
Indeed, a close look at what nicotine patches do brings up the question of why they didn’t show up on the radar of ME/CFS/FM patients long before the coronavirus pandemic hit…
“It’s fascinating to me frankly that one molecule found in nature can be so potent. It’s hard to imagine you could engineer a drug to do this.” Peter Attia MD
It’s no surprise that we know a lot about nicotine. The tobacco plant – our main source of nicotine – comes from the Solanaceae family – which includes, alongside tomatoes, potatoes, eggplant, and peppers, psychoactive plants such as henbane (Hyoscyamus albus), belladonna or deadly nightshade (Atropa belladonna), jimson weed (Datura stramonium), and mandrake (Mandragora autumnalis). (Because tobacco can cause mild euphoria in some, it is also classified as a “psychoactive” plant.)
(It should be noted that nicotine does not cause the cancers caused by smoking or chewing tobacco – other parts of the plant do that.)
The fact that nicotine might make people feel better is no surprise given how many people smoked cigarettes/pipes before their dangers became apparent. By enhancing the activity of the nicotinic acetylcholine receptors (nAChRs) in the brain, nicotine increases several feel-good chemicals (mostly dopamine but also serotonin, GABA, endogenous opioids, and endorphins) that may be lacking in the brains of people with ME/CFS, FM and long COVID. Nicotine also triggers the release of acetylcholine and activates the sympathetic nervous system causing the release of epinephrine (and norepinephrine) – a stimulating neurotransmitter.
Immune enhancement is a total surprise, though. Nicotine also plays a key role in the cholinergic system – a system that presents fascinating possibilities for diseases like ME/CFS and fibromyalgia (FM) which feature an underactive parasympathetic nervous, or “rest and digest”, system.
The cholinergic system involves neurotransmitters (acetylcholine), receptors (AcHRs), and enzymes that activate the “cholinergic anti-inflammatory pathway“. With its direct link between the central nervous and immune systems, a dysregulated cholinergic system is believed to lead to inflammatory and autoimmune diseases. It turns out that nicotine enhances the productivity of this beaten-down system in ME/CFS/FM.
Nicotine may also help with some aspects of brain fog. A recent paper, “Nicotine’s effect on cognition, a friend or foe?”, reported that nicotine can enhance attention, and short-term and long-term memory – and nicotine has been used as a performance-enhancing drug. While warning of the dangers of smoking and high-dose nicotine use, the authors conclude that “nicotine-derived compounds could be a promising strategy to alleviate neurological disease-associated cognitive deficit“.
Indeed, an older meta-analysis of 41 double-blind, placebo-controlled studies found that nicotine or smoking “had significant positive effects on aspects of fine motor abilities, alerting and orienting attention, and episodic and working memory”. A more recent meta-analysis of 33 studies featuring nicotine patches found that they “had statistically significant positive effects on attention” but non-significant effects on memory, in healthy non-smoking adults.
Studies suggest that the nicotinic receptors involved in the cholinergic immune response play a key role in neuroinflammatory diseases such as multiple sclerosis, Alzheimer’s, and Parkinson’s disease and nicotine has produced a variety of positive effects in a multiple sclerosis mouse model.
If you follow Peter Attia, MD. in his longevity podcast, he uses nicotine at times to enhance his mental clarity.
Nicotine has even received some study as an exercise enhancer. While noting that more study was needed, a 2017 meta-analysis reported that about 2/3rds of studies found that nicotine significantly increased heart rate compared to placebo or control. Given the chronotropic incompetence that appears to be happening in ME/CFS, the ability to raise the heart rate during exercise might be a help. Increased blood pressure and blood flows were also reported to be significantly increased in multiple studies. Another 2017 study found that nicotine improved anaerobic performance but a recent study did not.
Nicotine Clinical Trials
Most nicotine clinical trials are focused on smoking, but nicotine is also currently being assessed in depression, chronic pain, multiple sclerosis, improving hearing in the elderly, and improving cognition.
The COVID-19 Nicotine Saga Begins
Smoking, Nicotine and COVID-19
The COVID-19 nicotine saga began on a false note. Studies suggesting that smokers were at less risk from COVID-19 prompted an early 2020 paper proposing the use of nicotine as a treatment. While the limitations were noted in the first paper, the idea that smoking and/or nicotine might be protective against COVID-19 caught on in some circles. (Several years and studies later, the idea that smoking is protective has been decidedly squashed.)
Also in 2020, in “Autonomic balance determines the severity of COVID-19 courses“, Dr. Marco Leitzke and his German colleagues asserted that the more depressed the “vagal tone” was; i.e. the more depressed the parasympathetic nervous system (PNS) or rest and digest system was, the worse off people with COVID-19 were. They proposed using nicotine (as well as biofeedback and vagus nerve stimulation) to enhance the activity of that system and help patients return to health.
They based this on the hypothesis that the SARS-CoV-2 virus is binding to the nicotinic receptors called nAChRs. This hypothesis is based on close resemblance between the amino acids found in the coronavirus spike protein and a snake venom toxin that binds to nAChRs.
The idea is that by binding to the nAChRs, nicotine should be able to knock the coronavirus off of them. This is because nicotine has 30x greater affinity for these receptors than the spike protein does. Knocking the coronavirus off these receptors should allow them to operate normally, returning the immune and central nervous system to a healthy state. Whether the coronavirus spike protein is binding to the nAChRs and disrupting them is still speculative but is a possibility.
The 2023 Leitzke Paper
Leitzke’s 2023 paper, “Is the post-COVID-19 syndrome a severe impairment of acetylcholine-orchestrated neuromodulation that responds to nicotine administration”, really kicked off the nicotine interest in long COVID and ME/CFS. Leitzke cited several early studies suggesting that smoking reduced the incidence the COVID-19. He failed, though, to acknowledge later studies that had contrary findings.
Indeed, far from being helpful, a recent meta-analysis concluded that “the risk of COVID-19 progressing to more severe conditions and leading to mortality is 30–50% higher for both current and former smokers compared to individuals who have never smoked”.
(In his talk with Sophie Helbig, Leitzke acknowledged the damage smoking causes to the respiratory system and the added danger that smokers who get respiratory viruses like the coronavirus are in. He does not recommend smoking…nicotine patches and gummies, though, are a whole other ball game.)
Leitzke’s Four Case Reports
In his paper, Leitzke described four case reports of nicotine patch use. Each person was instructed to use the lowest available dosage (7.5 mg/24 h) and to administer the patch once daily in the morning.
One person with high weakness reported being weakness-free by day nine. Another reported her ability to concentrate was restored by day 4 and her fatigue and post-exertional malaise were gone by about the third week. Six months later she remained healthy.
One person who mistakenly doubled his dose – which led to horrendous vomiting and diarrhea – nevertheless saw his fatigue disappear by day 4. He too reported being well six months later. Fatigue disappeared for the last person on day six, her sleep returned to normal and her mood swings disappeared by day 5. Three months later she remained in good health.
Leitzke’s YouTube Talk
A couple of months ago, Leitzke talked with Sophie Helbig, a former fibromyalgia patient, on her “The Puzzle of Healing” channel.
- Nicotine – the addictive substance in tobacco smoke – may seem like a bizarre treatment option, but it appears that the addictive properties of nicotine only manifest themselves when tobacco smoke provides a quick hit to the brain.
- In fact, given its many potentially beneficial qualities, it’s a bit surprising that nicotine patches have not been tried before in diseases like ME/CFS and fibromyalgia.
- Nicotine has been shown to increase the levels of feel-good brain chemicals like dopamine, to increase mental clarity and cognition, and rebalance the immune system.
- Interestingly, nicotine enhances the activity of the parasympathetic, or “rest and digest”, branch of the autonomic nervous system/vagus nerve which appears to have taken a hit in ME/CFS, FM and long COVID.
- The long-COVID nicotine saga began when studies (falsely, it turned out) appeared to show that smoking reduced long COVID severity. That finding was bolstered by the recognition that a part of the coronavirus looked like they would bind well with nicotinic receptors that regulate the vagus nerve functioning. Doing so might throw off the immune system, brain chemicals, etc.
- Taking nicotine in the form of patches was suggested in order to knock the coronavirus off those binding sites, thus returning the subject to health.
- Indeed, the publication of four case reports by Dr. Marco Leitze reporting on the rather rapid return to health of four long-COVID patients spurred interest in the nicotine patch.
- Since then, Dr. Leitze appeared on a YouTube video talking about the use of the nicotine patch and noting that he’s seen effects ranging from no effect to complete recovery. (See blog)
- Long-COVID patient groups have created an excellent information resource on dosage, how-to’s, FAQs etc. (See blog)
- Polls from those groups suggest that the nicotine patch is not a panacea but that in some patients it can work really well, while in most people it has more moderate results when it works. That’s a not uncommon finding in our heterogeneous population for treatments that can help.
- The nicotine patch must be used correctly and can cause severe, if temporary, side effects (vomiting) if used at too high of a dose. When used correctly, while it can cause side effects at first, it appears to be pretty safe.
- Given its good (thus far) safety record and its low cost, it seems like a pretty good option for those who want to give it a go. (See the blog for more details)
Leitzke said that long-COVID patients who are not smokers can experience quite a few side effects at first. This is because Leitzke believes that when nicotine stops the coronavirus from binding to the nAChR receptors, it liberates the virus, resulting in side effects for 3-5 days until the immune system can catch up to it. All the patients he’s seen, though, pass through this stage fine.
After the 3-day low dose period, use the 7 mg patch for 7 days, stopping it after the 10th day. This is because the nicotine receptors will become temporarily desensitized and the effects will stop. (They get re-sensitized quickly.)
Leitzke recommended not pushing too hard if you see improvement. Instead, go slowly and give your body time to heal. All sorts of compensating changes can occur in people who have been ill for a long time and they will take time to reverse.
Leitzke said he’s got a lot of feedback from patients on social media who are trying the patch. People have reported everything from nothing happening to complete recoveries.
Leitzke believes that blockage of these receptors could occur in FM and ME/CFS as well. He said he talked to “very prominent colleagues who’ve been dealing with ME/CFS for a long time”…who reported they saw “massive improvements even in ME/CFS”.
While Leitzke believes in giving nicotine patches a try, he’s being cautious about their efficacy and acknowledged that “time will tell” with them.
The ACE2 Connection
ACE2 is interesting because the coronavirus enters the cells via the ACE2 receptor and the ACE2 dysregulation may be occurring in ME/CFS and POTS as well.
A 2021 laboratory study, “Nicotine upregulates ACE2 expression and increases competence for SARS-CoV-2 in human pneumocytes“, found that nicotine increases the expression of the ACE2 (angiotensin-converting enzyme 2) receptor that the SARS-CoV-2 virus uses to enter cells. That study suggested that nicotine might enhance coronavirus replication, resulting in more serious cases of COVID-19.
Other studies, however, have found that nicotine increases ACE2 expression in some cells and downregulates in others. Plus, study evidence suggests that ACE2 expression – whether up or not – does not affect infection rates. ACE2 inhibitors, for instance, do not decrease rates of coronavirus infection. Increased rates of coronavirus infection from nicotine patch use, then, do not, at this point, appear to be a problem.
An upregulation of the ACE2 enzyme might also work in favor of postural orthostatic tachycardia (POTS) and ME/CFS patients as ACE2 activity may be reduced in POTS causing high Ang II levels, inflammation, and vasoconstriction. The case for reduced ACE2 activity in ME/CFS is less clear, but a similar downregulation of the renin-angiotensin-aldosterone system appears to be present. It should be noted, though, that the available studies are small, and better ones are needed.
An October survey of 175 long-COVID nicotine patch users found a perhaps not surprising result. Some people (20%) felt more than 50% better, more people (36%) felt 0-50% better, others (20%) felt the same, a few (5%) felt worse, and others (17%) were still checking it out.
Those results are similar to those of a poll asking about Bruce Patterson’s treatment approach, which found that a smaller subset did really well and a larger group did somewhat to moderately well.
We’re always looking for the “answer”. When HIV hit, all sorts of treatments, including ones that seemed surefire answers, faded when exposed to clinical studies. With COVID-19, we saw some early treatments that were touted highly by some doctors (Ivermectin) fail when exposed to clinical trials.
With long COVID, we’ve seen Bruce Patterson’s long-COVID protocol, guanfacine, monoclonal antibodies, anti-coagulants, etc., and now there are nicotine patches. Until we get good well-sized, well-done studies – and many may never get good studies – we’re never going to know for sure. The results thus far suggest that the nicotine patch is not “the answer” for the vast majority of us but that it could help.
One thing we can do is apply the Arseneau test which tries to assess whether to try something or not.
Applying The Arseneau Test
The Arseneau test assesses the factors below to help decide whether or not to try a treatment:
- The credibility of the source – Leitzke is new to the ME/CFS community at least in the States, but the fact that it’s a doctor’s report helps a bit
- Quality of the evidence – entirely anecdotal – low
- The benefit, the cost, and the risk–benefit – appear to range from high to nothing; there is the risk of a short downturn; otherwise, the risk appears pretty low, and the cost is low.
While nicotine scores low on several measures, there is a possible benefit. While the ME/CFS/long-COVID population is very sensitive, the Chambers survey found few long-COVID patients who reported being worse off. Plus, the Nicotine Test Group provides an easy-does-it protocol. All in all, it seems like a pretty safe bet.
The Nicotine Test Group
The Nicotine Test Group is a patient-led Facebook group Build on Patient-led Model started by @RemissionBiome, @RenegadeResearch, @TheAcidTesters, etc., that is doing great work at providing information about using the nicotine patch.
It emphasizes that it does not deliver “medical advice” and recommends that you talk with your doctor first but appears to be the go-to place to learn about the nicotine patch, long COVID, and allied diseases. It provides protocols, tips, FAQs, information on the ingredients in various patches, ways to assess treatment effectiveness, etc. (see Files).
Nick Chambers opened up a private Renegade Research, #The Nicotine Test Facebook group, for people with ME/CFS who are trying the patch.
Take the Nicotine Patch Poll!
Nicotine is an interesting substance! Who knew? (Peter Attia had a show on it in 2021). While it’s still speculative, it’s possible that if nicotine is able to knock the coronavirus off of the nicotinic receptors (if it is indeed binding to them), it might return the immune system to homeostasis and health while improving mood and cognition. Not bad!
Aside from that, the central role nicotine plays in the vagus nerve/cholinergic/parasympathetic nervous system is intriguing indeed given findings that this area is underperforming in ME/CFS, FM, and long COVID. Nicotine appears able to increase the levels of feel-good brain chemicals and help with mental clarity and brain fog – all of which would be helpful in these diseases. Nicotine, then, could be having effects that have nothing to do with the coronavirus.
Nicotine patches are cheap and readily available, and the long-COVID/ME/CFS community has done great work in providing safety and other information. That said, the patient reports are mixed, with some people doing really well with most others reporting less positive results and a few not doing well. That’s pretty much par for the course for these heterogeneous diseases.
If you decide to try the nicotine patch, be sure to check The Nicotine Test, start slowly and please report back :). (Thanks to Tracey and Jutta for their links :))
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