Nicotine for Long COVID:
Summary
The COVID-19 pandemic, which has claimed millions of lives worldwide, is now followed by a wave of chronic conditions, often referred to as Post-Acute Sequelae of SARS-CoV-2 (PASC) or Long COVID. There is no proven treatment for Long COVID, leading patients and researchers to explore potential therapeutic options.
This retrospective evaluation aims to assess the effectiveness of nicotine as a possible treatment for Long COVID symptoms in 52 patients treated in our specialized clinic. Symptoms were evaluated using the Patient-Rated Global Impression of Change (PGIC) scale. The results showed that 56% of patients reported significant improvements within a week of starting nicotine therapy, with minimal side effects. These findings suggest that nicotine could be a potential treatment for Long COVID, although further research is necessary.
Introduction
The COVID-19 pandemic has led to unprecedented global health challenges. While the acute phase of the pandemic is gradually coming under control through vaccination programs and public health measures, many people continue to experience lingering symptoms linked to the initial infection. These symptoms are now classified as Long COVID or Post-Acute Sequelae of SARS-CoV-2 (PASC).
Common Long COVID symptoms include:
– Chronic fatigue
– Physical limitations
– Cognitive dysfunction
– Sensitivity to light or sound
– Post Exertional Malaise (PEM)
– Irritability
– Sleep disturbances
– Pain and autonomic dysfunction
– Severe mood depression
Despite ongoing research, no proven effective treatment exists for Long COVID. Recent studies, however, have proposed nicotine as a possible therapy due to its interaction with the nicotinic acetylcholine receptor (nAChR), which is thought to play a role in the pathophysiology of Long COVID [1-6].
Objective
We evaluated the effect of nicotine on Long COVID symptoms in patients using nicotine patches.
Method
The evaluation included patients treated at the Long COVID clinic in Amsterdam. All patients met the diagnostic criteria for Long COVID and the SEID criteria for ME/CFS.
Since April 1, 2024, Long COVID patients in the clinic were informed about the potential effects of nicotine patches. Prior to treatment, patients underwent a combination of standardized questionnaires, medical history intake, and functional tests to document their diagnosis and symptoms, as standard in the clinics.
1. Screening and Baseline Measurements: Patients completed a comprehensive medical history focused on fatigue, pain, cognitive function, and quality of life.
2. All patients completed the following:
a. A medical history questionnaire
b. The short form of the DePaul Questionnaire [7]
c. The Orthostatic Grading Scale [8]
d. The Epworth Sleepiness Scale [9]
e. The Convergence Insufficiency Symptom Survey (CISS-DLV) [10]
2. Functional Tests:
– Stroop Test: To measure attentional control and mental processing speed [11].
– Handgrip Strength Test: To assess muscle strength and energy production [12].
– NASA 10-Minute Lean Test: To assess orthostatic intolerance to measure autonomic dysfunction [13].
3. Nicotine Treatment: Patients were advised to use a 7 mg nicotine patch daily, which was replaced every 24 hours (6). If patients experienced side effects, they were instructed to cut the patch into smaller portions (1/8 or 1/4) to adjust the dose to their tolerance. Nicotine patches are available over the counter and are commonly used for smoking cessation.
4. Evaluation of Treatment Effects:
– 4-Point Patient Rated Global Impression of Change (PGIC): Evaluation of overall symptom changes on a four-point scale.
– Repeated Handgrip Strength Test: For some patients, the test was repeated after the treatment period to measure changes in energy production.
All patients signed an informed consent form for the off-label use of ketotifen and provided written permission for the use of anonymized clinical data for evaluation and publication.
Outcomes were self-reported by patients using the PGIC scale with the following scores:
– 0: No change
– 1: Minimal improvement
– 2: Clear improvement
– 3: Significant improvement
Results were evaluated after 2 to 4 weeks of treatment.
Results
The evaluation included 52 patients, divided into responders and non-responders, based on their reported improvements.
– Responders (29 patients, 56%): These patients reported significant improvements within a week (PGIC score > 1).
– Non-responders (23 patients, 44%): This group reported no improvement or could not tolerate the nicotine patch.
Gender distribution showed that nicotine therapy was more successful among men:
– 80% of male patients responded positively to the treatment.
– 46% of female patients responded positively.
Reported side effects were generally mild and included:
– Local allergic reactions
– Nausea
– Diarrhea
– Heart palpitations
– Insomnia
No severe side effects were reported.
Discussion
The results of this evaluation suggest that nicotine could be a promising treatment option for some Long COVID patients. Approximately half of the patients reported significant improvements within a week of starting nicotine patch therapy, indicating the therapeutic potential of nicotine in this population. The notably higher response rate among men suggests potential gender-related differences in the effectiveness of nicotine.
The mechanism of action of nicotine may lie in its interaction with the nACh receptor, possibly helping to regulate autonomic functions and block viral binding.
Despite positive results, many patients, especially women, did not respond to the treatment. This discrepancy may be due to individual differences in receptor sensitivity or other underlying physiological factors that warrant further investigation.
Limitations
This evaluation is retrospective and has certain limitations, including the absence of a control group and the possibility of bias due to self-reported data. Furthermore, the long-term safety of nicotine use in this population remains uncertain and warrants further research.
Conclusion
The results of this retrospective evaluation indicate that nicotine may provide significant symptom improvement for some Long COVID patients. While these findings are encouraging, further research, including large-scale randomized controlled trials, is needed to confirm the effectiveness of nicotine for Long COVID and explore the optimal dosage and treatment duration.
We hope this evaluation contributes to the growing knowledge of potential treatments for Long COVID patients and that future research will provide more clarity on the role of nicotine in managing this debilitating condition.
References
1. Farsalinos K, Eliopoulos E, Leonidas DD, Papadopoulos GE, Tzartos S, Poulas K: Nicotinic Cholinergic System and COVID-19: In Silico Identification of an Interaction between SARS-CoV-2 and Nicotinic Receptors with Potential Therapeutic Targeting Implications. Int J Mol Sci 2020, 21(16).
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3. Oliveira ASF, Ibarra AA, Bermudez I, Casalino L, Gaieb Z, Shoemark DK, Gallagher T, Sessions RB, Amaro RE, Mulholland AJ: A potential interaction between the SARS-CoV-2 spike protein and nicotinic acetylcholine receptors. Biophys J 2021, 120(6):983-993.
4. Skok M: The role of alpha7 nicotinic acetylcholine receptors in post-acute sequelae of covid-19. Int J Biochem Cell Biol 2024, 168:106519.
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6. Leitzke M: Is the post-COVID-19 syndrome a severe impairment of acetylcholine-orchestrated neuromodulation that responds to nicotine administration? Bioelectron Med 2023, 9(1):2.
7. McGarrigle WJ, Furst J, Jason LA: Psychometric evaluation of the DePaul Symptom Questionnaire-Short Form (DSQ-SF) among adults with Long COVID, ME/CFS, and healthy controls: A machine learning approach. J Health Psychol 2024, 29(11):1241-1252.
8. Knoop I, Jones ASK, Gall N, Chilcot J, Pascoe W, Moss-Morris R: Validation of symptom measures in patients under investigation for postural orthostatic tachycardia syndrome (POTS): The Orthostatic Grading Scale (OGS) and the Symptom Screen for Small-fiber Polyneuropathy (SSS). Auton Neurosci 2023, 250:103130.
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Treatment of Long COVID and ME/CFS with Ketotifen (Zaldiar®)
Introduction
Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are among the most disabling chronic conditions worldwide, significantly impacting the quality of life for millions of people [1]. Although the precise mechanisms underlying these conditions are not fully understood, recent research points to a possible role of mast cell activation [2,3]. Mast cells play an essential role in the immune system [4], and when excessively or uncontrollably activated, they can cause a wide range of symptoms, such as allergy-like reactions, chronic fatigue, and neurological complaints [3]. As seen in MCAS, the instability of mast cells is an irreversible process with complex consequences, possibly due to the wide range of mediators that mast cells can produce [5]. Mast cell activation is often triggered by an infection but may also result from other trauma, such as surgery or cancer.
A positive effect of the histamine 2 receptor antagonist famotidine has been observed in patients with Long COVID [6, 7]. Ketotifen, a histamine 1 receptor antagonist, leukotriene inhibitor [8], and mast cell stabilizer [9, 10], is currently used to treat patients with mast cell activation syndrome (MCAS) [11]. Ketotifen may reduce the release of inflammatory mediators such as histamine and leukotrienes, potentially relieving symptoms like gastrointestinal issues, fatigue, muscle pain, and cognitive complaints. The mast cell-stabilizing properties of ketotifen may be attributed to its ability to counteract the deformation of the plasma membrane in degranulating mast cells [9].
The similarity of symptoms between Long COVID, ME/CFS, and MCAS [12] led to a treatment proposal for patients consulting the Long COVID clinic or ME/CFS medical center, based on common MCAS treatments. This report describes the initial findings on the effectiveness and tolerability of ketotifen in Long COVID and ME/CFS.
Methods
This retrospective evaluation investigated the effectiveness of ketotifen in treating Long COVID and ME/CFS.
Patients visiting the Long COVID clinic or ME/CFS center were informed about the possibility of being treated with a histamine receptor 1 antagonist at a dosage commonly used for MCAS treatment.
The treatment was preceded by a combination of standardized questionnaires, anamnesis, and functional tests to document the diagnosis and symptoms of the patients, as is standard practice in these centers.
The screening included the following steps:
1. Screening and Baseline Measurements: Patients underwent a comprehensive interview about their medical history, focusing on fatigue, pain, cognitive functions, and quality of life.
2. Questionnaires: All patients completed the following questionnaires:
– A history questionnaire
– The short-form version of the DePaul Questionnaire [13]
– The Orthostatic Grading Scale [14]
– The Epworth Sleepiness Scale [15]
– The Convergence Insufficiency Symptom Survey (CISS-DLV) [16]
3. Functional Tests:
– Stroop Test: To measure attentional control and mental processing speed [17].
– Handgrip Strength Test: To assess muscle strength and energy production [18].
– NASA 10-Minute Lean Test: To assess orthostatic intolerance as a measure of autonomic dysfunction [19].
4. Treatment with Ketotifen: Patients were prescribed 2 to 6 mg of ketotifen daily, depending on tolerance and response. The treatment period lasted three months with interim evaluations.
5. Evaluation of Treatment Effects:
– 4-Point Patient Rated Global Impression of Change (PGIC): Assessment of overall symptom change on a four-point scale.
– Repeated Handgrip Strength Test: For some patients, this test was repeated after the treatment period to measure changes in energy production.
All patients signed informed consent forms for the off-label use of ketotifen and provided written consent forms for using anonymized clinical data for evaluation and publication.
Results
Long COVID
– Patients: Of the 28 patients, 8 (29%) discontinued immediately due to intolerance. Of the 20 (71%) patients who continued using ketotifen, 18 (90%) reported improvement.
ME/CFS
– Patients: Of the 58 patients, 21 (36%) discontinued ketotifen immediately due to intolerance. Of the 37 (64%) patients who continued the treatment, 32 (86%) reported improvement.
The results give an impression of the tolerability and effectiveness of ketotifen in Long COVID and ME/CFS patients. Although a significant subgroup of patients reported improvement, many discontinued the treatment due to intolerance.
Both the high percentage of patients unable to tolerate ketotifen due to drowsiness, lethargy, or psychological symptoms and the high percentage who improved suggest a notable effect of ketotifen in these patients. The most prominent improvement was a reduction in post-exertional malaise (PEM), a key feature of post-infectious syndromes. This suggests that mast cell instability may be central to the syndrome.
Conclusion
The analysis of treatment outcomes indicates that ketotifen may improve symptoms in a substantial proportion of Long COVID and ME/CFS patients, The high improvement rate suggests that ketotifen may become a treatment for Long COVID and ME/CFS. We are looking for a solution for the patients who cannot use ketotifen yet. A second conclusion is that the mast cell is of great importance in Long COVID and ME/CFS
Recommendation
provided they can tolerate the medication.
Further studies are needed to better understand ketotifen’s optimal dosing and side effect profile and assess its long-term effectiveness in patients with long COVID and ME/CFS. Currently, there is insufficient knowledge about ketotifen in Long COVID and ME/CFS patients to recommend its use in clinical practice.
Limitations
This report describes initial clinical experiences with ketotifen in patients with Long COVID and ME/CFS. It is not a scientific study report; no control group was used, and the outcome evaluation was limited to spontaneous comments and patient assessments.
References
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- Afrin LB, Ackerley MB, Bluestein LS, Brewer JH, Brook JB, Buchanan AD, Cuni JR, Davey WP, Dempsey TT, Dorff SR et al: Diagnosis of mast cell activation syndrome: a global “consensus-2”. Diagnosis (Berl) 2021, 8(2):137-152.
- Weinstock LB, Brook JB, Walters AS, Goris A, Afrin LB, Molderings GJ: Mast cell activation symptoms are prevalent in Long-COVID. Int J Infect Dis 2021, 112:217-226.
- Migalovich-Sheikhet H, Friedman S, Mankuta D, Levi-Schaffer F: Novel identified receptors on mast cells. Front Immunol 2012, 3:238.
- Molderings GJ, Afrin LB: A survey of the currently known mast cell mediators with potential relevance for therapy of mast cell-induced symptoms. Naunyn Schmiedebergs Arch Pharmacol 2023, 396(11):2881-2891.
- Momtazmanesh S, Ansari S, Izadi Z, Shobeiri P, Vatankhah V, Seifi A, Ghiasvand F, Bahrami M, Salehi M, Noorbala AA et al: Effect of famotidine on cognitive and behavioral dysfunctions induced in post-COVID-19 infection: A randomized, double-blind, and placebo-controlled study. J Psychosom Res 2023, 172:111389.
- Kow CS, Ramachandram DS, Hasan SS: Famotidine: A potential mitigator of mast cell activation in post-COVID-19 cognitive impairment. J Psychosom Res 2023, 172:111425.
- Fink A, Bibi H, Eliraz A, Schlesinger M, Bentwich Z: Ketotifen, disodium cromoglycate, and verapamil inhibit leukotriene activity: determination by tube leukocyte adherence inhibition assay. Ann Allergy 1986, 57(2):103-106.
- Baba A, Tachi M, Ejima Y, Endo Y, Toyama H, Matsubara M, Saito K, Yamauchi M, Miura C, Kazama I: Anti-Allergic Drugs Tranilast and Ketotifen Dose-Dependently Exert Mast Cell-Stabilizing Properties. Cell Physiol Biochem 2016, 38(1):15-27.
- Kazama I: Stabilizing mast cells by commonly used drugs: a novel therapeutic target to relieve post-COVID syndrome? Drug Discov Ther 2020, 14(5):259-261.
- Asawa A, Simpson KH, Bonds RS: Ketotifen use in a patient with fire ant hypersensitivity and mast cell activation syndrome. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 2015, 114(6):443-446.
- Arun S, Storan A, Myers B: Mast cell activation syndrome and the link with long COVID. Br J Hosp Med (Lond) 2022, 83(7):1-10.