Nicotine for Long COVID update December 21, 2024:

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 81 patients treated in our specialized clinic. Symptoms were evaluated using the Patient-Rated Global Impression of Change (PGIC) scale. The results showed that 48% 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 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.

Methods

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 have been informed about the potential effects of nicotine patches. Before 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 medical history questionnaire
  • The short form of the DePaul Questionnaire [7]
  • The Orthostatic Grading Scale [8]
  • The Epworth Sleepiness Scale [9]
  • The Convergence Insufficiency Symptom Survey (CISS-DLV) [10]
  • Functional Tests:

a. Stroop Test: To measure attentional control and mental processing speed [11].
b. Handgrip Strength Test: To assess muscle strength and energy production [12].
c. 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 to use 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 81 patients, divided into responders and non-responders, based on their reported improvements.

  • Responders (39 patients, 48%): These patients reported significant improvements within a week (PGIC score > 1), with 26% achieving a PGIC score of 2 and 22% a PGIC score of 3.
  • Non-responders (42 patients, 52%): This group reported no improvement or could not tolerate the nicotine patch.

Gender distribution showed that nicotine therapy was more successful among men:

  • 60% of male patients responded positively to the treatment.
  • 43% 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 retrospective evaluation 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 provided significant symptom improvement for 48% of Long COVID patients. A portion of the group could resume work or school after one week.
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).
  2. Changeux JP, Amoura Z, Rey FA, Miyara M: A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications. C R Biol 2020, 343(1):33-39.
  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.
  5. Hippisley-Cox J, Tan PS, Coupland C: Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: cohort study including 8.3 million people. Heart 2020.
  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.
  9. Goncalves MT, Malafaia S, Moutinho Dos Santos J, Roth T, Marques DR: Epworth sleepiness scale: A meta-analytic study on the internal consistency. Sleep Med 2023, 109:261-269.
  10. Rouse M, Borsting E, Mitchell GL, Cotter SA, Kulp M, Scheiman M, Barnhardt C, Bade A, Yamada T, Convergence Insufficiency Treatment Trial Investigator G: Validity of the convergence insufficiency symptom survey: a confirmatory study. Optom Vis Sci 2009, 86(4):357-363.
  11. Dyer FN: The Stroop phenomenon and its use in the study of perceptual, cognitive, and response processes. Memory and Cognition 1973, 1(2):106-120.
  12. Jakel B, Kedor C, Grabowski P, Wittke K, Thiel S, Scherbakov N, Doehner W, Scheibenbogen C, Freitag H: Hand grip strength and fatigability: correlation with clinical parameters and diagnostic suitability in ME/CFS. J Transl Med 2021, 19(1):159.
  13. Lee J, Vernon SD, Jeys P, Ali W, Campos A, Unutmaz D, Yellman B, Bateman L: Hemodynamics during the 10-minute NASA Lean Test: evidence of circulatory decompensation in a subset of ME/CFS patients. J Transl Med 2020, 18(1):314.

Treatment of Long COVID and ME/CFS with Ketotifen (Zaditen®)

Summary

Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are debilitating chronic conditions with overlapping symptoms, including fatigue, cognitive dysfunction, and post-exertional malaise. Emerging evidence suggests that mast cell dysfunction may contribute to these symptoms. This report explores using ketotifen, a histamine-1 receptor antagonist and mast cell stabilizer, as a potential treatment. A retrospective evaluation involving 100 patients, 32 with Long COVID and 68 with ME/CFS, revealed that ketotifen improved symptoms in over half of the participants. While the findings highlight ketotifen’s promise, they also underscore the need for further research to address high discontinuation rates and optimize its use. These results suggest that mast cells could play a central role in the pathophysiology of both conditions, providing a potential target for future therapies.

Introduction

Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are among the most debilitating chronic conditions worldwide and have a significant impact on the quality of life for millions of people [1]. Although the precise mechanisms behind these conditions are not yet fully understood, recent studies point to the potential role of mast cell activation [2, 3]. Mast cells are essential in the immune system [4,5] and can, upon excessive or uncontrolled activation, cause a wide range of symptoms, such as allergy-like reactions, chronic fatigue, and neurological complaints [3]. The mast cell instability, as seen in mast cell activation syndrome (MCAS), is an irreversible process with complex consequences. The large number of mediators that mast cells can produce may play a role in this [6]. Mast cell activation is often triggered by an infection but can also result from other traumas, such as surgery or cancer [5].
A positive effect of the histamine 2 receptor antagonist famotidine has been described in patients with Long COVID [7, 8]. Ketotifen, a histamine 1 receptor antagonist, leukotriene inhibitor [9], and mast cell stabilizer [10, 11], was first described in 1977 [12]. It is registered for the treatment of allergic rhinitis and skin conditions. It is currently used off-label for the treatment of MCAS [13]. Ketotifen can reduce the release of inflammatory mediators such as histamine and leukotrienes, which may relieve symptoms such as gastrointestinal complaints, fatigue, muscle pain, and cognitive issues. The mast cell-stabilizing properties of ketotifen are attributed to its ability to counteract the deformation of the plasma membrane in degranulating mast cells [10].
The similarity between the symptoms of Long COVID, ME/CFS, and the symptoms of MCAS [14] prompted us to propose a treatment for patients consulting at the Long COVID clinic or the ME/CFS medical center commonly used for MCAS [15]. This report describes the initial findings on the effectiveness and tolerability of ketotifen in Long COVID and ME/CFS.

Methods

This retrospective evaluation investigated whether ketotifen is effective in treating Long COVID and ME/CFS.
Patients consulting the Long COVID clinic or ME/CFS center were informed about the possibility of treatment with a histamine receptor 1 antagonist at a dose commonly used in MCAS treatment.

Before treatment, a routine combination of standardized questionnaires, medical history, and functional tests were performed to document the diagnosis and symptoms of the patients, as per usual practice in both centers.

Screening included the following steps:
1. Screening and Baseline Measurements: Patients underwent a comprehensive medical history focused on fatigue, pain, cognitive functions, and quality of life via video consultations.
2. Questionnaires: All patients completed the following questionnaires:

  • A medical history questionnaire
  • The short-form version of the DePaul questionnaire [16]
  • The Orthostatic Grading Scale [17]
  • The Epworth Sleepiness Scale [18]
  • The Convergence Insufficiency Symptom Survey (CISS-DLV) [19]

3. Functional Tests:

  • Stroop Test: To measure attention control and mental processing speed [20].
  • Handgrip Strength Test: To measure muscle strength and energy production [21, 22].
  • NASA 10-Minute Lean Test: To assess orthostatic intolerance as a measure of autonomic dysfunction [23].

Treatment with Ketotifen: Patients were prescribed 0,5 mg to a maximum of 2 to 6 mg of ketotifen daily, depending on tolerance and response. The treatment period lasted three months, with interim monthly evaluations.

Evaluation of Treatment Effects:
* 4-Point Patient Rated Global Impression of Change (PGIC): Assessment of overall symptom changes on a four-point scale.
* Repeated Handgrip Strength Test: The test was repeated for some patients after the treatment period to measure changes in energy production. Results will be subject to further analysis.
All patients signed informed consent for the off-label use of ketotifen and provided written permission to use anonymized clinical data for evaluation and publication.

Results

Long COVID
All patients met the WHO criteria for Long COVID [24].
Of the 32 patients, 8 (25%) stopped after the first tablet due to intolerance.
Of the 24 (75%) patients who continued taking ketotifen, 18 (83%) reported improvement.
Of all 32 patients in de Long COVID group, 53% improved according to our criterion (PGIC > 1).

  • 1 patient scored 1
  • 15 patients scored 2
  • 3 patients scored 3

ME/CFS
All patients met the 2003 criteria for ME/CFS [25].
Of the 68 patients, 23 (34%) stopped after the first tablet due to intolerance.
Of the 45 (66%) patients who continued taking ketotifen, 37 (82%) reported improvement.
Of all 68 patients in the ME/CFS group, 54% improved according to our criterion (PGIC > 1).

  • 0 patients scored 1
  • 26 patients scored 2
  • 11 patients scored 3

Discussion

The results provide an impression of the tolerability and effectiveness of ketotifen in Long COVID and ME/CFS patients. Both the high percentage of patients forced to discontinue ketotifen use immediately due to drowsiness, lethargy, or emotional symptoms and the high rate of improvement indicate a particular effect of ketotifen in these patients, either negative or positive. The similar positive and negative responses in the Long COVID and ME/CFS groups suggest similar processes underlying these symptoms, potentially related to changes in mast cell function.
An interesting symptom improvement was the reduction of post-exertional malaise (PEM), a key feature of the post-infection syndrome, seen in 83% of Long COVID patients and 95% of ME/CFS patients who continued ketotifen (data not shown). This suggests that the loss of control of mast cells may be central to this symptom and may represent a common cause of PEM in both syndromes.

Conclusion

The treatment outcomes analysis indicates that ketotifen improved symptoms in a significant proportion of patients with Long COVID and ME/CFS. The high percentage of improvement suggests that ketotifen may become a treatment for Long COVID and ME/CFS. We are still looking for an explanation for the large number of patients who could not use the drug. A second conclusion is that mast cells may play an important role in Long COVID and ME/CFS.

Recommendation

Studies are needed better to understand the optimal dosage and side-effect profile of ketotifen and to evaluate its long-term effectiveness in patients with Long COVID and ME/CFS. Currently, not enough is known about ketotifen in these patients to recommend its use in general practice.

Limitations

This report describes the first clinical experiences with ketotifen in Long COVID and ME/CFS patients. It is not a scientific study report; no control group was used, and the outcome evaluation was limited to spontaneous remarks and patient assessments.

References

1. Wang HI, Doran T, Crooks MG, Khunti K, Heightman M, Gonzalez-Izquierdo A, Qummer Ul Arfeen M, Loveless A, Banerjee A, Van Der Feltz-Cornelis C: Prevalence, risk factors and characterisation of individuals with long COVID using Electronic Health Records in over 1.5 million COVID cases in England. J Infect 2024, 89(4):106235.
2. 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.
3. 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.
4. Migalovich-Sheikhet H, Friedman S, Mankuta D, Levi-Schaffer F: Novel identified receptors on mast cells. Front Immunol 2012, 3:238.
5. Kempuraj D, Selvakumar GP, Thangavel R, Ahmed ME, Zaheer S, Raikwar SP, Iyer SS, Bhagavan SM, Beladakere-Ramaswamy S, Zaheer A: Mast Cell Activation in Brain Injury, Stress, and Post-traumatic Stress Disorder and Alzheimer’s Disease Pathogenesis. Front Neurosci 2017, 11:703.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. Martin U, Roemer D: Ketotifen: a histamine release inhibitor. Monogr Allergy 1977, 12:145-149.
13. 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.
14. 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.
15. Molderings GJ, Haenisch B, Brettner S, Homann J, Menzen M, Dumoulin FL, Panse J, Butterfield J, Afrin LB: Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebergs Arch Pharmacol 2016, 389(7):671-694.
16. 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.
17. 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.
18. Johns MW: A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991, 14(6):540- 545.
19. Rouse MW, Borsting EJ, Mitchell GL, Scheiman M, Cotter SA, Cooper J, Kulp MT, London R, Wensveen J, Convergence Insufficiency Treatment Trial G: Validity and reliability of the revised convergence insufficiency symptom survey in adults. Ophthalmic Physiol Opt 2004, 24(5):384-390.
20. Dyer FN: The Stroop phenomenon and its use in the study of perceptual, cognitive, and response processes. Memory and Cognition 1973, 1(2):106-120.
21. Jammes Y, Stavris C, Charpin C, Rebaudet S, Lagrange G, Retornaz F: Maximal handgrip strength can predict maximal physical performance in patients with chronic fatigue. Clin Biomech (Bristol, Avon) 2020, 73:162-165.
22. Paffrath A, Kim L, Kedor C, Stein E, Rust R, Freitag H, Hoppmann U, Hanitsch LG, Bellmann-Strobl J, Wittke K et al: Impaired Hand Grip Strength Correlates with Greater Disability and Symptom Severity in Post-COVID Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Clin Med 2024, 13(7).
23. Lee J, Vernon SD, Jeys P, Ali W, Campos A, Unutmaz D, Yellman B, Bateman L: Hemodynamics during the 10-minute NASA Lean Test: evidence of circulatory decompensation in a subset of ME/CFS patients. J Transl Med 2020, 18(1):314.
24. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV, Condition WHOCCDWGoP-C-: A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis 2022, 22(4):e102-e107.
25. Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lemer AM, Bested AC, Flor-Henry P, Joshi P, Powles ACP et al: Myalgic encephalomyelitis/chronic fatigue syndrome: Clinical working case definition, diagnostic and treatment protocols. Journal of Chronic Fatigue Syndrome 2003, 11(1):7-115.