Disclaimer: I have no medical credentials to make any statement of fact. The following is personal research I am doing in an effort to help myself, and hopefully others like me based on my experiences with post-vaccine syndrome (PVS).
Discussion:
The IMA article Breaking the silence: Recognizing post-vaccination syndrome by Halma and Varon contains a graphic which implicates nicotinic acetylcholine receptor α7 in post-vaccination syndrome (PVS). This article posits that Post Exertional Malaise (PEM) is a product of α7 downregulation. PEM is mentioned in the article, however, the mechanism behind it is not elucidated.
There are many subtypes of acetylcholine receptors. The main two receptor types are nicotinic and muscarinic. They are so named because of the substances which are known to act upon them. If one looks at the binding affinity of nicotine among the nicotinic subtypes of acetylcholine receptors, one finds that it is quite varied.
As an individual with PVS, I tried a regimen of low-dose nicotine patching (LDNP) (see the Leitzke article) and discovered it helped completely resolve my POTS symptoms and regain energy. However, I was surprised to learn that I was still encountering PEM symptoms, albeit less than previously experienced.
In looking at the nicotinic receptor subtypes and nicotine’s binding affinity to each, a pattern emerges of which PVS symptom might be associated with which subtype, as well as which symptoms might be more effectively treated than the others by LDNP.
Nicotinic Receptor Subtypes and Nicotine Binding Affinity
Receptor Subtype: α4β2
Composition: Heteromeric
Location: CNS (most abundant)
Nicotine Binding Affinity (approx. Kd): ~1 nM
Notes: High affinity; major target for nicotine’s addictive effects
Receptor Subtype: α7
Composition: Homomeric
Location: CNS, immune cells, mitochondria
Nicotine Binding Affinity (approx. Kd): ~4 μM
Notes: Lower affinity; involved in anti-inflammatory and neuroprotective signaling
Receptor Subtype: α3β4
Composition: Heteromeric
Location: Autonomic ganglia
Nicotine Binding Affinity (approx. Kd): ~100 nM – 1 μM
Notes: Moderate affinity; regulates blood pressure and autonomic tone
Receptor Subtype: α6β2β3
Composition: Heteromeric
Location: Dopaminergic neurons
Nicotine Binding Affinity (approx. Kd): ~10 nM
Notes: Implicated in reward and addiction pathways
Receptor Subtype: α9α10
Composition: Heteromeric
Location: Cochlea, immune cells
Nicotine Binding Affinity (approx. Kd): Low affinity
Notes: Not a major nicotine target; involved in auditory and inflammatory signaling
Receptor Subtype: α2β2 / α2β4
Composition: Heteromeric
Location: CNS
Nicotine Binding Affinity (approx. Kd): Variable
Notes: Less studied; may contribute to fine-tuning of cholinergic tone
Receptor Subtype: α5 (accessory)
Composition: Modulates α4β2 or α3β4
Location: CNS, PNS
Nicotine Binding Affinity (approx. Kd): N/A
Notes: Doesn’t form receptors alone; alters sensitivity and calcium signaling when co-assembled
α7 nAChRs Regulate:
· Mitochondrial calcium uptake via VDAC modulation
· Anti-inflammatory signaling via NF-κB inhibition
· Cellular stress responses, including apoptosis and ROS handling
If Spike Protein Interferes with α7 nAChRs:
Mechanism: ↓ α7 nAChR activity
Consequence: ↓ Regulation of mitochondrial Ca²⁺ uptake
Mechanism: ↓ VDAC modulation
Consequence: ↑ Cytosolic Ca²⁺, ↓ mitochondrial buffering
Mechanism: ↑ Ca²⁺ overload
Consequence: Mitochondrial swelling, cytochrome c release, impaired ATP production
Mechanism: ↑ ROS and inflammation
Consequence: Amplified muscle damage post-exertion
Mechanism: ↓ Anti-inflammatory tone
Consequence: ↑ TNF, IL-6, IL-1β → muscle fatigue and pain
Key Findings from the Two Papers
Appleman et al. (2024)
Post-exertional malaise (PEM) in Long COVID is associated with:
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Exercise-induced myopathy
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Amyloid-containing deposits in skeletal muscle
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Mitochondrial dysfunction and metabolic disturbances
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Muscle biopsies showed worsening abnormalities after exertion, including structural damage and impaired oxidative metabolism.
Scheibenbogen & Wirth (2025)
ME/CFS and post-COVID syndromes share:
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Sodium and calcium overload in skeletal muscle
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Mitochondrial damage, especially subsarcolemmal
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Impaired Na⁺/K⁺-ATPase and NCX (Na⁺/Ca²⁺ exchanger) function
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A vicious cycle of ionic imbalance → mitochondrial dysfunction → energy deficit → PE
Mapping Muscarinic Receptors to PVS Symptoms
Muscarinic Subtype: M1
Location: CNS (cortex, hippocampus)
Function: Cognitive function, memory
Potential Consequences of Blockage: Brain fog, impaired learning
Muscarinic Subtype: M2
Location: Heart, CNS
Function: Parasympathetic tone, heart rate
Potential Consequences of Blockage: Tachycardia, autonomic imbalance
Muscarinic Subtype: M3
Location: Smooth muscle, glands
Function: GI motility, salivation, pupil constriction
Potential Consequences of Blockage: Dry mouth, constipation, blurred vision
Muscarinic Subtype: M4/M5
Location: CNS
Function: Dopaminergic modulation, arousal
Potential Consequences of Blockage: Mood changes, sleep disruption
References
Matthew Halma, Joseph Varon, Breaking the silence: Recognizing post-vaccination syndrome, Heliyon, Volume 11, Issue 11, 2025, e43478, ISSN 2405-8440, https://doi.org/10.1016/j.heliyon.2025.e43478.
Matthew T.J. Halma, Paul E. Marik, Yusuf M. Saleeby, Exploring autophagy in treating SARS-CoV-2 spike protein-related pathology, Endocrine and Metabolic Science, Volume 14, 2024, 100163, ISSN 2666-3961, doi:10.1016/j.endmts.2024.100163.
Tommy S. Tillman, Qiang Chen, Vasyl Bondarenko, Jonathan A. Coleman, Yan Xu, Pei Tang, SARS-CoV‑2 Spike Protein Downregulates Cell Surface α7nAChR through a Helical Motif in the Spike Neck, ACS Chemical Neuroscience, Volume 14, Issue 4, 2023, Pages 689-698, ISSN 1948-7193, doi:10.1021/acschemneuro.2c00610.
Leitzke, M. Is the post-COVID-19 syndrome a severe impairment of acetylcholine-orchestrated neuromodulation that responds to nicotine administration?. Bioelectron Med 9, 2 (2023). doi:10.1186/s42234-023-00104-7.
Appelman B, Charlton BT, Goulding RP, et al. Muscle abnormalities worsen after post-exertional malaise in long COVID. Nat Commun. 2024;15(1):17. Published 2024 Jan 4. doi:10.1038/s41467-023-44432-3.
Scheibenbogen C, Wirth KJ.
Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated
Evidence. J Cachexia Sarcopenia Muscle. 2025;16(1):e13669. doi:10.1002/jcsm.13669.