What is the impact of nicotine on the Post-COVID-19 syndrome - a severe impairment of acetylcholine-orchestrated neuromodulation: A case series

doi:10.21203/rs.3.rs-2063399/v1

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What is the impact of nicotine on the Post-COVID-19 syndrome - a severe impairment of acetylcholine-orchestrated neuromodulation: A case series

https://doi.org/10.21203/rs.3.rs-2063399/v1

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Following SARS-CoV-2 infection, many individuals suffer from post-COVID-19 syndrome. It makes them unable to proceed with ordinary everyday activities due to weakness, memory lapses, pain, dyspnea, and other unspecific physical complaints. Several investigators have demonstrated that the SARS-CoV-2-related spike glycoprotein (SGP) not only attaches to angiotensin-converting enzyme-2 (ACE-2) receptors but also shows DNA sections highly affine to nicotinic acetylcholine receptors (nAChRs). The nAChR is the principal structure of cholinergic neuromodulation and is responsible for coordinated neuronal network interactions. Nonintrinsic viral nAChR attachment substantially compromises integrative interneuronal communication. This explains the cognitive, neuromuscular, and mood impairment and the vegetative symptoms characterizing post-COVID-19 syndrome. The agonist ligand nicotine shows an up to 30-fold higher affinity for nACHRs than acetylcholine (ACh). We hypothesize that this molecule could extrude the virus from nAChR attachment and pave the way for unimpaired cholinergic signal transmission. Treating several individuals suffering from post-COVID-19 syndrome with a nicotine patch application, we observed an immediately substantial improvement of the symptoms up to complete remission after several days.

Post-COVID-19 syndrome

neuromodulation

long haul COVID

nicotinic acetylcholine receptors

nicotine

Post-COVID-19 syndrome

The coronavirus SARS-CoV-2-evoked pandemic calamity demanded approximately 6 million victims within 30 months¹. Unprecedented scientific efforts led to a better understanding of the viral structure, transmission paths, and pathologic patterns and helped to create sufficiently protective vaccines. However, the virus always seems to be one step ahead. It presents genetic variants of SARS-CoV-2^2–7 causing higher contagiousness⁷, compromising the sufficiency of vaccines⁴, promoting escape from natural immunity ^4,7, or revealing new pathology patterns⁸. Thus, the fifth wave of rising infection rates is underway^9,10, and the medical care capacity in most countries is challenged anew¹¹. This, during the third and fourth waves, in some areas, is even harder than during the previous waves¹².

Meanwhile, we are becoming increasingly aware that after convalescence from acute COVID-19, the suffering in many cases is not over yet¹³.

Symptoms such as chronic fatigue^9,14,15, dizziness^9,16, low-grade fever¹⁵, anosmia¹⁷, memory lapses¹⁵, ageusia¹⁷, muscle weakness¹⁵, diarrhea and bouts of vomiting¹⁵, concentration and sleep difficulties^9,15, mood disorders¹⁵, headache^9,15, cognitive impairment¹⁸, motor deficits, new onset of diabetes^15,19,20 and hypertension¹⁵, dyspnea^9,15,18 and exercise intolerance^16,18 are summarized as post-COVID-19 syndrome¹⁴. (see Table 1)

The occurrence of the mentioned symptoms weeks or months after the acute phase of SARS-CoV-2¹⁵ infection is independent of the severity of the initial disease course^21,22 or baseline chronic medical conditions^21,23. Its incidence is estimated to be 35% (outpatients)²¹ and 87% (inpatients)²⁴ among all individuals experiencing SARS-CoV-2 infection. In addition, the endurance of the symptoms is unpredictable^15,22,25, and after six months, an average of 14 persistent symptoms are reported by subjects suffering from long-haul COVID²⁶.

These facts underline the enormous meaning of the post-COVID-19 syndrome to global societies regarding public health, political, sociopolitical, and financial burden to respective systems^18,27−29. Not to neglect the individual somatic and psychological misery of each suffering patient. Thus, we should be aware of this inevitable aftershock to health care systems^13,18, which is to be expected from this chronic phase of COVID-19^30,31.

We will see many more infected patients recovering from the acute phase of COVID-19 but in a large proportion needing therapy and rehab capacity^18,22,27 to cure the symptoms of the chronic phase²², the post-COVID-19 syndrome³².

Is it just the ACE2 receptor?

For the acute infection phase, physicians lack a causal therapeutic strategy to face viral assault on human organ systems and must be confined to symptomatic therapeutic approaches. These, in the severe courses of SARS-CoV-2 infections, are rather underwhelming^48,49. Unfortunately, the situation is comparably cloudy regarding post-COVID-19 syndrome^13,26. The cause of its widespread symptomatology is speculated to be ongoing systemic inflammation^16,26, peripheral organ dysfunction¹⁶, such as cerebrovascular changes⁹ and direct virus-related encephalitis¹⁶, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CSF)⁵⁰, persistent brainstem dysfunction²³, and psychosomatic disorders³⁹. This makes therapeutic approaches to long-haul COVID likewise speculative^51,52, and their effectiveness is rather dissatisfying²⁹.

Recently, our group described the crucial meaning of autonomic balance for the severity of COVID-19 courses^53,54 and highlighted the essential importance of nicotinic acetylcholine receptors (nAChRs) for the limiting regulation of cytokine liberation and virus replication at the transcriptional level, restricting nuclear factor kappa-light-chain-enhancer of activated B cells (nf-κB) action along the cholinergic anti-inflammatory pathway (CAP)^53,54. Analyzing the amino-acid (aa) sequence alignment of the motifs found in toxins from snakes of the Ophiophagus (cobra) and Bungarus genera in the G-ectodomains of three rabies lyssavirus (formerly rabies virus) (RABV) strains⁵⁵ or muscarinic toxin-like protein and cobratoxin (naja siamensis)²⁸ and comparing it to the motifs in spike glycoprotein (SGP) from SARS-CoV-2^28,55 revealed profound similarities between the highly nAChR affine toxins and SARS-CoV-2 specific proteins^28,55. Therefore, Changeux et al. (2020) recently proposed the ´nicotine hypothesis´, which implicates the propensity of SARS-CoV-2 not only to bind to ACE2-receptors (ACE2R) but also to nicotinic AChRs⁵⁵. Viral competition with acetylcholine for nAChR binding to enter the human body may lead to primary neurological infection^55,56. Furthermore, it showed that among the severe and fatal cases of COVID-19, the proportion of nicotine consumers was significantly lower⁵⁷. Since nicotine might at least protect nAChRs from viral attachment, therapeutic nicotine application was proposed to manage acute COVID-19 infections⁵⁵. This argument is convincingly supported by the cohort study of Cox et al. (2020), which included 8.28 million participants (19.486 confirmed COVID-19 cases) and showed lower odds for COVID-19 infection and COVID-19-related ICU stay in association with smoking⁵⁸. Farsalinos et al. (2020) examined and identified a “toxin-like” aa sequence in the receptor binding domain of the spike glycoprotein (SGP) of SARS-CoV-2 (aa 375–390), showing significant sequence homology with the neurotoxin homolog NL1, one of the many snake venom toxins interacting with nAChRs⁵⁹. Additionally, they performed computational molecular modeling and docking experiments using 3D structures of the SARS-CoV-2 SGP and the extracellular domain of the nAChR α9 subunit⁵⁹. Thus, they could show the primary interaction between the aa 381–386 sequence of the SARS-CoV-2 SGP and the aa 189–192 sequence of the extracellular domain of the nAChR α9 subunit⁵⁹, the core of the “toxin-binding site” of nAChRs⁵⁹. Likewise, a similar interaction could be demonstrated between the ligand binding domain of the pentameric α7 nicotinic acetylcholine receptor (α7nAChR) chimera and the SARS-CoV-2 SGP⁵⁹. The authors concluded that their findings strongly support the hypothesis declaring a dysregulation of the nicotinic cholinergic system is a considerable part of the pathophysiology of COVID-19⁵⁹. They emphasized that nicotinic cholinergic agonists may act protectively to nAChRs and thus have therapeutic value in COVID-19 patients⁵⁹.

The pivotal neuromodulational role of nicotinic acetylcholine receptors

Within the central nervous system (CNS), acetylcholine (ACh) is mainly released from projection neurons (PN), which innervate distal areas and local interneurons interspersed with their cellular targets. PN are found in several nuclei, including the medial habenula, pedunculopontine, laterodorsal tegmental areas, the basal forebrain complex, and the medial septum (reviewed in ⁶⁰). They promote extensive and diffuse innervation of numerous neurons in the CNS. Their signaling is carried out by ACh coupling to pre- and postsynaptic as well as axonal and cell body-located AChRs on a massive number of targeted neurons throughout the brain (reviewed in ⁶⁰). Regulating the velocity and amount of transmitter release into the synaptic cleft improves the signal-to-noise ratio (reviewed in ⁶⁰)(see Fig. 1). It orchestrates fine-tuned, synchronized response behavior of central and autonomic nuclear regions of the brain to internal and external stimuli (reviewed in ⁶⁰)(see Fig. 1). Moreover, they are involved in synaptic plasticity, neuronal development, and learning processes in general (reviewed in ⁶⁰).

AChRs are distinguishable into metabotropic muscarinic (mAChRs)^61,62 and ionotropic nicotinic acetylcholine receptors (nAChRs)^63,64. In addition to their different propensity binding to muscarine or nicotine⁶², they differ in their signal properties, which most of all show up in great differences in the signal transmission velocity⁶². Signal transduction of mAChRs is realized slowly via coupling to G-proteins either activating phospholipase C (PLC), inhibiting adenylate cyclase⁶⁵, or noncanonically⁶⁵, altering pathways involving phospholipase A2, phospholipase D, and tyrosine kinase as well as calcium channels⁶⁵. The excitatory or inhibitory manner of the mAChR effect depends on the targeted cell type to which muscarinic cholinergic signaling is applied⁶⁵. This diversity of mAChRs in terms of their several modes of action, together with the high degree of homology at the orthosteric ACh-binding site⁶⁵, made the development of specifically acting ligands, therapeutically influencing muscarinic AChR-related signaling pathways almost impossible until recent times ^61,65.

In contrast, nAChR activation leads to fast and nonselective opening of membrane-bound, excitatory cation channels⁶². These pentameric nAChRs⁶³ with allosteric configuration⁶⁶ are essential to the interneuronal communication within the CNS and the autonomic nervous system (ANS)⁶⁰. Even though neuromodulators commonly act in a metabotropic fashion, ionotropic nAChRs were shown to act neuromodulatory largely as well⁶⁷. They consist of a varying, either homomeric or heteromeric, combination out of nine (α2-α10) α- and three (β2-β4) β-subunits^63,68,69 and are located at presynaptic or preterminal membrane sections where they modulate transmitter release. In addition, nAChRs are found on dendrites or neuronal cell bodies, where they generate postsynaptic effects⁶³. In the CNS, nAChR neuromodulation realizes the regulation of transmitter release, cell excitability, and integrative adaptation of neuronal activity⁶³. Stimulation of nAChRs can increase the release of several neurotransmitters, such as glutamate, gamma-aminobutyric acid (GABA), and dopamine (DA) (reviewed in⁶⁰). Thus, networking and coordination of essential physiological functions such as arousal, sleep, fatigue, anxiety, nutritional behavior, cognition, and central processing of pain^{63,68,70−72} are regulated. nAChRs play a significant role in the synchronization of neuronal activity^60,67.

Gotti et al. (2006) described the α4β2 nAChR subtype as the best-characterized nAChR in animal (rat) brains⁶³. They stated this nicotinic AChR to be the primary neuromodulatory nAChR subtype in several cerebral subregions, such as the cortex, striatum, superior colliculus, lateral geniculate nucleus, and cerebellum⁶³. This was demonstrated not least in the detectable loss of high-affinity nAChRs in the CNS of α4β2 subunit knockout mice⁷³ and underlines the central role of nAChRs in the entire neuromodulatory network.

Nicotine effect on nicotinic acetylcholine receptors

The chronic application of nicotine in animal and in vitro models yielded an upregulation⁷⁴ of respective central binding sites. In contrast, the chronic increase in the natural ligand ACh via the application of a cholinesterase inhibitor led to a consecutive decrease in the central density of nAChRs⁷⁵. These changes occur quickly after nicotine exposure, making it clear that cholinergic signaling adapts quickly to nicotine and can effectively improve compromised cholinergic neurotransmission. These effects were mainly seen in α4β2-type receptors with the aforementioned prominent meaning to nicotinic cholinergic neuromodulation⁶³. Notably, nAChR upregulation is not accompanied by desensitization but rather an increased ratio of high-affinity nAChRs (from 25% baseline up to 70% under nicotine exposure) compared to low-affinity nAChRs⁷⁴. In addition, the opening frequency of the α4β2 cation channels increases up to three times under chronic nicotine exposure⁷⁴. Thus, nicotine exposure leads to functional upregulation of human α4β2 nAChRs⁷⁴. Clinically, nicotine application to animals improves vigilance, locomotor activity, cognition, respiratory function, cortical blood flow, electroencephalogram (EEG) activity, pain resilience, and gastrointestinal and cardiovascular regulation⁶⁹. French et al. (1999) demonstrated a long-lasting (up to 72 hours after nicotine exposure) increase in neurotrophic nerve growth factor (NGF) mRNA after nicotine administration to the hippocampus, suggesting long-term neuroprotective effects of nicotine⁷⁶. Altogether, nicotine works as a ligand with high affinity and profound intrinsic activity on nAChRs⁶³, substantially improving the responsiveness⁷⁴ and activity⁶⁹ of these core receptors of neuromodulation. In addition to the prescription of transcutaneous nicotine application as a substitute for weaning smokers, the transcutaneous application of this substance has been investigated in clinical trials evaluating its therapeutic effects on neurologic or gastrointestinal disorders in nonsmoking patients for several weeks^77–80. These investigations showed no substantial side effects^77–79. Using very high dosages (up to 107 mg/day), almost every patient with more than 90 mg/day showed frequent nausea and vomiting⁸⁰. Nonetheless, all individuals in this trial investigating the ameliorative effects of nicotine on Parkinson’s disease (PD) showed improved motor scores under reduced dopaminergic treatment⁸⁰. In contrast to the well-known addictive potential of chronically inhalation nicotine usage, none of the trials showed nicotine dependency after withdrawal of transcutaneous nicotine application at the end of the investigations^77–80.

The competition of SARS-CoV-2, acetylcholine, and nicotine at the nicotinic acetylcholine receptor

In terms of the central role of nAChRs in interneuronal communication and their involvement in almost every synaptic signal transmission, the possibility that SARS-CoV-2 binds to these nAChRs on a large scale in a nonintrinsic way is a plausible explanation for the widespread symptoms of long-haul COVID-19. By competitively inducing a diminished effect of its natural ligand (ACh), the viral blockade of these receptors leads to a sharp deterioration of cholinergic neuromodulation. Thus, most long-term COVID-associated deficiencies (see Table 1) can be attributed to neuromodulatory deterioration.

Referring to the abovementioned results of Changeux et al. (2020)⁵⁵, Oliveira et al. (2021) investigated the possible binding of SARS-CoV-2 SGP to nAChRs using molecular simulations of validated detailed atomic structures of nAChRs and the spike protein⁸¹. Examining the Y674-R685 loop of the viral SGP and its binding to three different nAChR types (i.e., α4β2, α7, and the muscle-like nAChR αβγδ from Tetronarce californica), their results predict an apparent nAChR affinity of SARS-CoV-2-related spike protein due to a PRRA (proline, arginine, arginine, alanine) motif in the spike binding region. Notably, this is not found in other SARS-like coronaviruses⁸¹. Using principal component analysis (PCA), the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approach⁸², and in silico alanine-scanning mutagenesis⁸³, the authors calculated AChR subtype-specific binding-related conformational behavior of the protein, such as subtype-specific but uniformly stable complex formation between nAChR and SGP⁸¹. These results confirm the data from Farsalinos et al. (2020), which showed hydrogen bonding and shape-related interaction of the extracellular domain of α9AChRs and SARS-CoV-2 SGP, as well as SGP coupling to the ligand binding domain of a pentameric α7 nAChR chimera using in silico experiments⁵⁹.

The affinity of natural or synthetic ligands to several nAChRs varies depending on the distinctive nAChR composition from the α- or β-subunits⁶³. Despite these subtype-specific differences between the agonist ligands, every binding site shows significantly higher inhibition constants (K_i) for the natural agonist (ACh) compared to nicotine (reviewed in ⁶³). In the case of α7-α7 subunit interfaces, this indicates an up to 30-fold higher affinity⁸⁴ of nicotine to respective α7 subunits containing nAChRs compared to the physiological ligand ACh⁶³.

The far higher affinity of nicotine to the nAChRs in comparison to ACh and the apparent capability of SARS-CoV-2 to displace ACh from its specific receptors suggest the assumption that nicotine might counteract the viral blockade of nAChRs and displace the virus for his part from the nAChR binding (see Fig. 2).

We investigated one female (32 years old) and three male (19, 41, and 52 years old) individuals who suffered from numerous symptoms indicative of post-COVID-19 syndrome following a polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection with a relatively mild course. The patients described weakness, dyspnea, sleep disturbances, dizziness, complete ageusia and anosmia, and various other symptoms (see Tables 3, 4, 5, and 6). Except for the youngest, the patients could not continue their daily activities compared to the period before the SARS-CoV-2 infection. Since these multiple nonspecific symptoms have not improved over a specific time without signs of acute COVID-19 infection, they visited our outpatient clinic.

Methods

After meticulously explaining the hypothesis described above, the expected effects of nicotine, and clarification of possible side effects, the patients were advised to apply a standard nicotine patch. Since all included individuals were nicotine-naïve persons, they were instructed to use the lowest available dosage (7.5 mg/24 hrs) and to place the patch once daily in the morning. All patients followed these instructions, except for the 41-year-old patient. He bought the patches mistakenly at a dosage higher (15 mg/24 hrs) than the recommended dosage. In all cases, the patients were asked to register their symptoms four days before applying the nicotine patch (see Figures 3, 4, 5, and 6) and to score the severity of their complaints from 0 to 5 daily (see Table 2).

Case 1

The 19-year-old otherwise healthy patient was diagnosed with SARS-CoV-2 infection by a positive PCR test on March 26, 2021. After a relatively mild course of the acute infectious disease with symptoms such as mild fever, sore throat, and feeling of weakness, these resolved entirely within ten days. Approximately three weeks after the detection of the infection, the patient noticed a sudden loss of sense of smell and taste and general fatigue. These complaints persisted over the next several months with minimal undulation in symptom severity. On presentation to our outpatient clinic in November 2021, we counseled the nicotine-naïve patient about the apparent expression of a post-COVID-19 syndrome. We informed him about the problematic diagnostic and therapeutic approach to the described symptoms. The patient consented to the off-label use of percutaneous nicotine application and began 24 hourly applications of a nicotine patch (7.5 mg/24 h for seven days) on 23 November 2021.

For the days before nicotine application, weakness was scored in the range of the two highest possible levels (levels 4 to 5). Anosmia and ageusia were reported consistently at the highest possible level (5). Recovery from weakness was most rapid, with a daily reduction in symptom severity by one level after nicotine exposure to remain at level 2 for three days from day three and at level 1 for three days from day 6. Finally, from day 9, the patient felt free from weakness (see Fig. 3). The loss of taste was reduced by one level on the first day, dropped to level 3 on the 3rd day, and returned to level 2 on the 10th day and to level 1 on the 13th day. From day 16, the patient described the complete restoration of the sense of taste. A similarly protracted symptom reduction was seen with anosmia. Beginning on day 3, the patient experienced a decline from level 5 to level 4, regressing to level 3 on day 7, to level 2 on day ten, and to level 1 beginning on day 13. From day 16, the patient reported being able to smell to the same extent as before his SARS-CoV-2 infection. All symptoms did not recur until an interview approximately six months after that. With the onset of nicotine administration, the patient experienced diarrhea and chest tightness for 2 and 3 days, respectively, terminating spontaneously and considered mild (level 1) by the patient. We interpreted these symptoms as classic nicotine side effects. They did not require further therapy.

Case 2

The 31-year-old female patient presented to our outpatient clinic on 17.12.2020, having survived an acute SARS-CoV-2 infection confirmed by a positive PCR test on 21.11.2020 with a moderate course (fever, reduction in smell and taste, loss of appetite, headache, and pain in the limbs, reduced memory, lack of drive, neck, limb and back pain, and rhinitis). The acute infection phase lasted until 5.12.2020, and a negative PCR test confirmed freedom from infection. From that time onwards, she had numerous symptoms, such as chronic fatigue (level 4), loss of smell and taste (level 1), marked difficulty concentrating (level 4), headache (level 4), and considerable exercise intolerance (level 4). Information, education, informed consent, and nicotine therapy were given to the otherwise healthy, nicotine-naïve patient as described above (7.5 mg/24 h for six days). From day two, after the initiation of nicotine therapy, the patient reported a reduction in fatigue of one level per day, which was completely reversed by day 4. From the 6th day onwards, the patient experienced a recurrence of fatigue to a lesser extent (level 3), which only entirely and permanently abated from the 13th day (level 2), 20th day (level 1), and 23rd day (level 0). The reduction in retentiveness was perceived as very high (level 4) before and at the beginning of the application, dropped significantly from the 3rd day after nicotine administration (level 2), and was no longer perceptible from the 4th day. In the same course, the impaired ability to concentrate was reduced until the concentration performance perceived before SARS-CoV-2 was regained from the 4th day after nicotine therapy.

Similarly, the markedly impaired exercise intolerance (level 4) dropped significantly on day 3 (level 1), becoming unreproducible on day 4, but rose again slightly on day 5 (level 2) and day 6 (level 3), and fell continuously from day eight onwards. From the 24th day after nicotine application, the patient reported full recovery of her physical performance. Starting on day 2, the patient experienced a very unpleasant feeling of tightness in the thoracic region, which was said to be undiminished (stages 3–5) until day 13 after the start of nicotine therapy and to decrease continuously from then on (day 14, level 3; day 19, level 2; day 22, level 1) until complete remission on day 23. We attributed this symptom, which began directly with the start of nicotine administration, to the active substance nicotine in the sense of a side effect. The patient considered these symptoms to be associated with nicotine. She decided to stop therapy on the 6th day and not continue until the 7th day, as we had recommended. This was due to the otherwise perfect symptom remission until the 4th day of nicotine administration (all symptoms, level 0). In a new telephone interview after approximately six months, the patient confirmed that there had been no recurrence of symptoms.

Case 3

A 41-year-old male patient visited our outpatient clinic on 20.12.2022, having been ill from a SARS-CoV-2 infection confirmed on 13.11. 2020 with a moderate course (weakness, fever, chills, headache, coughing attacks, loss of sense of smell and taste, shortness of breath, exercise intolerance, permanent fatigue, pronounced feeling of weakness). At the time of presentation, he was suffering from a variety of persistent symptoms (chronic fatigue - level 3, dyspnoea - level 3, anosmia - level 5, loss of taste - level 5, muscle weakness - level 4, difficulty sleeping - level 1, headache - level 2). The nicotine-naïve patient agreed to off-label use of nicotine patches in the manner described. Unfortunately, the patient misleadingly did not paste the dose we recommended, but twice the dose (15 mg/24 h), which led to intolerable vomiting (level 5) and diarrhea (level 5) within the next 7 hours, so that the patient discontinued the therapy after 10 hours. Despite the cessation of nicotine use, chronic fatigue decreased significantly on day two after nicotine use (level 2), continued to decline on day 3 (level 1), and was no longer detectable on day 4. As in the cases described above, the courses of anosmia and tastelessness showed a rather protracted, continuously declining course. The reduction of these two symptoms co-occurred in the presented case. On the 11th day after nicotine application, there was a slight reduction (level 4), dropping to level 3 on the 12th and 13th days. After a decrease to level 2 on the 14th day, the patient could fully perceive all smell and taste qualities on the 15th day. The mild sleep problems (level 1) had already permanently disappeared on the 1st day of application of the nicotine patch (level 0).

Regarding the feeling of weakness, the patient described a daily reduction by one level until reaching level 1 on the 3rd day, which lasted for another day to be permanently eliminated from the 5th day onwards (level 0). The residual headache reported by the patient with level 2 was entirely resolved by day two after nicotine administration (level 0). This patient also said no recurrence of the described symptoms after a new presentation at an interval of 6 months.

Case 4

A 52-year-old male patient presented to our outpatient clinic on 1.4.2022. He stated that he had been suffering from persistent complaints (chronic fatigue – level 2, shortness of breath - level 2, difficulty concentrating, difficulty sleeping – level 3, mood swings - level 2, chest tightness – level 2, palpitations - level 2) since a SARS-CoV-2 infection proven by a positive PCR test on 3.3.2022. After excluding persistent acute SARS-CoV-2 infection by a negative PCR test, we informed the patient of the apparent presence of post-COVID-19 syndrome. The nicotine-naïve and otherwise unrestrictedly healthy patient agreed to a therapy trial using a nicotine patch (7.5 mg/24 h). Without consultation and contrary to our recommendations, the patient increased the nicotine dose to double on the 3rd day of therapy and stopped the application on the 4th day after almost complete symptom remission. He stated that he had not experienced any side effects of the nicotine application, which is why he doubted the effectiveness (too low a dose) and therefore had two nicotine patches (7.5 mg/24) starting on day 3.

Chronic fatigue increased slightly on the 2nd day of nicotine application (level 3) and then decreased significantly on the 5th day after the start of therapy (level 1). On the 6th day, the fatigue was permanently terminated. The patient’s breathlessness was reduced on the 5th day (level 1) and was no longer noticed from the 7th day (level 0). The patient reported that the concentration difficulties had already ended on the day of the 1st nicotine use (level 0). Difficulty sleeping and mood swings persisted until the 4th day (level 2) and were no longer detectable from the 5th day onwards (level 0). The perceived chest tightness (level 2) was reduced on day 5 (level 1) and was no longer detectable on the following day (level 0). The intermittent palpitations (level 1), perceived as mild, had not occurred for two days at the beginning of nicotine usage. On day 3 of therapy, the patient again noticed episodes of palpitations (level 2), which were felt at this level for two days. On day 3 of nicotine administration, this discomfort (level 1) was reduced and permanently abolished on day 4. We interpreted this recurrence of palpitations as a classic substance side effect of nicotine that stopped spontaneously and did not require further therapy. In an interview three months after the intervention, the patient confirmed that he had not noticed any recurrence of the symptoms that had brought him to us.

All the cases we presented showed significant alleviation of symptoms immediately after the nicotine patch application or in rapid succession after treatment. There were clear differences in the pattern and the time course of symptom relief. The course of symptom improvement in the cases we presented was independent of their different lengths of existence before nicotine therapy. Notably, in all cases, signs of exhaustion, such as fatigue, weakness, breathlessness, and exercise intolerance, improved equally rapidly after nicotine exposure (at the latest, by the 6th day). In cases with impairment or loss of the sense of taste and smell, improvement was observed in rather lengthy courses until the complete restoration of these senses over 13 to 16 days. The perceived tightness in the chest and palpitations were described as clear (level 2) during palpitations and ended on the 2nd day after their occurrence (day three after the start of nicotine administration). Regarding chest tightness, which was almost exclusively perceived as mild to very strong, the patient stated that she had not felt any reduction in performance, so a coronary vascular genesis seems unrealistic from the author’s point of view. The patient documented recovery from this side effect until the 22nd day after starting nicotine therapy. The amount of virally blocked AChR can vary greatly among individuals, which certainly influences the course of the reduction of symptoms and may require individualized nicotine doses and application intervals. All cases described were observed in nonsmokers. We observed only severe side effects in the patient who had mistakenly applied double the dose recommended by us. Severe nausea with sweating and repeated vomiting are classic side effects of nicotine, which is why this patient discontinued the therapy. However, with continuous nicotine abstinence from then on, all symptoms previously complained of by the patient decreased until restitutio ad integrum on the 15th day after nicotine application. From the author's point of view, this course tends to support the underlying hypothesis since the displacement of SARS-CoV-2 from nAChR binding should follow a certain dose-response relationship. In the case of the patient who had independently doubled the recommended dose from day 3, we suspect that the previous administration of the recommended dose may have led to a habituation reaction that helped avoid later side effects. The release of the SARS-CoV-2 virus from nAChR receptor binding could lead to short viremia with signs of acute SARS-CoV-2 infection at the beginning of nicotine therapy. This viral load should have been shielded after a short time by the humoral component of the immune system by SARS-CoV-2 antibodies formed during the acute phase of infection. Transcutaneous administration of nicotine ensures constant serum levels without relevant peak levels. Thus, we did not see any development of nicotine dependence in the context of nicotine patch therapy. This is also not to be expected from the author's point of view. The amazing similarity between the large number of symptoms of post-COVID-19 syndrome and the long-known central and peripheral symptoms of central anticholinergic syndrome (CAS)⁸⁵ encourages the author to believe that long-haul COVID must be a profound cholinergic signal transmission disorder. This is caused by a significantly higher affinity of SARS-CoV-2 to the nAChR compared to the natural ligand ACh⁸¹ and its displacement from AChRs with subsequent blockade of the intrinsic activity of ACh on the nAChR. The presented cases only describe patients with no concomitant morbidities other than post-COVID-19 syndrome. Therefore, the uncritical use of nicotine patches in patients with relevant cardiovascular or respiratory diseases or already existing medication is not advisable. It is probably safer for this group of patients to apply nicotine under inpatient conditions. The presentation of only four individual case descriptions we have made undoubtedly does not allow any general conclusions about the therapeutic effect of transcutaneous nicotine administration in post-COVID-19 syndrome. This requires double-blinded, randomized surveys, which appear easy to carry out due to the minimal therapeutic intervention. Due to the lack of blinding, the author believes that the psychosomatic component, which other authors suspect to be a central component of long-haul COVID⁸⁶, cannot be safely ruled out as part of the therapeutic effect. On the other hand, the patients reported no relapse of symptoms in a later telephone consultation (3–6 months). The studies by Changeux et al. (2020) and Alexandris et al. (2021) show the structurally and functionally high affinity of the corresponding SARS-CoV-2 SGP sections to the nAChR without making a quantitative comparison to the dissociation constants (K_i) of ACh and nicotine^55,87. Therefore, the displacement of ACh from nAChR binding by SARS-CoV-2 and the removal of this blockade by nicotine remain speculative. The assumption of this constellation is based solely on the known, much higher affinity of nicotine for nAChR in comparison to ACh. Investigations that follow such a quantitative approach would be necessary to objectify the hypothesis put forward by the author. We see the high burden on health care systems, the expected high incidence of post-COVID-19 syndrome associated with the current extraordinarily long courses of therapy, and their unpredictable results. Compared with the low therapeutic effort of a nicotine patch and the easily controllable side effects of a well-known substance, this seems to justify carrying out larger double-blinded randomized investigations based on the described hypothesis. This is particularly so since all previous attempts at explaining etiopathogenesis and the therapeutic efforts based on them are purely theoretical considerations.

Post-COVID-19 syndrome is well explained in its pathogenesis and clinical manifestation with cholinergic neuromodulation disorder due to partial or complete blockage of nicotinic acetylcholine receptors by the SARS-CoV-2 virus. In all the cases we studied, transcutaneous nicotine use led to an immediate improvement in symptoms and rapid restitutio ad integrum. The course of symptom improvement was as individual as the clinical picture of the post-COVID-19 syndrome itself. The ease of implementation and the excellent controllability of the only minor side effects make randomized, double-blinded studies seem easily feasible. The therapeutic access to this complex clinical picture using nicotine patches looks far superior to the time-consuming, personnel- and cost-intensive, and often disappointing rehabilitation measures for patients at all these levels.

aa amino acid

ACE-2 angiotensin-converting enzyme-2

ACE2R angiotensin-converting enzyme-2 receptor

ACh acetylcholine

ANS autonomic nervous system

CAS central anticholinergic syndrome

CNS central nervous system

COVID-19 coronavirus disease 2019

DA dopamine

EEG electroencephalogram

gamma-aminobutyric acid gamma-aminobutyric acid

ICU intensive care unit

K_i inhibition constant

mAChRs muscarinic acetylcholine receptors

MM-PBSA molecular mechanics Poisson-Boltzmann surface area

myalgic encephalomyelitis/chronic fatigue syndrome myalgic encephalomyelitis/chronic fatigue syndrome

nAChRs nicotinic acetylcholine receptors - main receptor type for cholinergic neuromodulation

neurotrophic nerve growth factor neurotrophic nerve growth factor

nf-κB nuclear factor kappa-light-chain-enhancer of activated B cells

PCR polymerase chain reaction

PD Parkinson’s disease

PN projection neurons

principal component analysis principal component analysis

proline, arginine, arginine, alanine proline, arginine, arginine, alanine

RABV rabies virus

SARS-CoV-2 severe acute respiratory syndrome coronavirus type 2

SGP SARS-CoV-2-related spike glycoprotein

Conflict of interests

The author reports no financial and no nonfinancial conflict of interest.

Funding

The author received no financial support for this article's research, authorship, and/or publication.

Acknowledgments

I thank Mr. Frank Jabin for his persistent and accurate work in creating the images.

Ethics and consent

The ethics committee of our hospital approved the implementation of the treatments classified as rescue therapy and their publication as a case report series.

Consent

All included patients consented to the off-label use of the substance used after detailed information and publication of the results.

Availability of data

All data are available on request from the corresponding author.

Authors contributions

M.L. recruited the patients, collected and analysed the data, wrote and reviewed the manuscript.

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What is the impact of nicotine on the Post-COVID-19 syndrome - a severe impairment of acetylcholine-orchestrated neuromodulation: A case series

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Abstract

Figures

Introduction

Post-COVID-19 syndrome

Is it just the ACE2 receptor?

The pivotal neuromodulational role of nicotinic acetylcholine receptors

Nicotine effect on nicotinic acetylcholine receptors

The competition of SARS-CoV-2, acetylcholine, and nicotine at the nicotinic acetylcholine receptor

Material

Results

Case 1

Case 2

Case 3

Case 4

Discussion

Conclusions

Abbreviations

Declarations

References

Tables

Supplementary Files

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