Dextromethorphan ameliorates symptoms of Postural Orthostatic Tachycardia Syndrome (in me):

Potential involvement of dysregulated glutamate signalling and increased activity of NADPH oxidase in POTS pathophysiology.

Recount:

I developed Postural Orthostatic Tachycardia Syndrome (POTS) in April 2023 following a COVID-19 infection. Prior to this I had just recovered from severe iron deficiency anaemia (causing hypovolemia which may have influenced POTS). I concurrently developed Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
I had a POTS flare up during winter 2023 and found it extremely difficult to sleep due to the accompanying thermoregulation issues making me unable to warm up. I took 30mg of pure dextromethorphan hydrobromide as from previous experience I know it has a numbing effect on physical sensation. Not only did this help with the thermoregulation issues but I also noticed in the coming days that my tachycardia was significantly reduced and I was able to stand up properly again. This was after a period of not being able to stand up for more than a few seconds without becoming lightheaded. I had another flare up when summer began and once again took 30mg DXM to the same effect- my symptoms subsided.
In 2024 my POTS became drastically less severe, with flare ups involving tachycardia usually only occurring after infection. I am however still affected by Long COVID and ME/CFS. There are times, usually following an infection, where I experience neurological impairment to the point where I forget the context of my surroundings and can’t recall how I got to where I physically am. For example, entering a room and not knowing how or why I got there. This is usually accompanied by extreme fatigue that makes it difficult to walk to another room. When I am in this state, taking 30mg DXM drastically reduces my fatigue and neurological symptoms. I wouldn’t say I return to 100% mental acuity but I can think relatively clearly again and the memory issues and disorientation subside. My fatigue is still present, but basic tasks within my apartment become doable without significant pain and effort.

Since experiencing this I’ve been trying to figure out how and why it works. In my particular case, physiological changes induced by COVID-19 play a role in my POTS development and current state. Many subtypes of POTS and variations of Long COVID exist and the results I experience may not be applicable to all.
I believe that dysregulation in glutamate signalling and NADPH oxidase play a significant role in the pathophysiology of POTS and Long COVID. Additionally, DXM through blockade of the NMDA receptor and inhibition of NADPH-oxidase exerts anti-inflammatory, anti-excitotoxic and antioxidant effects that ameliorate symptoms of POTS and Long COVID. Here, I give a breakdown of the potential role of glutamatergic dysfunction and NADPH oxidase in POTS. From the pharmacology/mechanisms of action of DXM as well as currently known biomarkers and disease mechanisms of POTS, Long COVID and ME/CFS I infer where the interactions that led to significant improvement of disease severity may occur.
This is of course only theoretical and I have no feasible means to measure glutamate activity in my brain at home. Either a lumbar puncture or magnetic resonance imaging/spectroscopy would be required for that. However, the relief from symptoms I have experienced from using DXM have been genuinely life changing and I can’t overlook that. Anyone with POTS knows how debilitating it can be.

Glutamate, Excitotoxicity, NADPH Oxidase and POTS:

POTS is a form of dysautonomia (dysfunction of the autonomic nervous system) characterised by an increase in heart rate on sitting/standing and blood pooling in the lower extremities. This is due to an inability to correctly regulate blood pressure and heart rate and may result in presyncope or syncope (fainting). It is often accompanied by other symptoms such as nausea, headaches, digestive issues, increased sensitivity to sensory stimuli (light, sound), chronic pain and sleep disturbances. The disease mechanism behind this is not fully known and a great deal of ambiguity surrounds this condition. Several subtypes are proposed; neuropathic, hypovolemic and hyperadrenergic as well as secondary POTS. These are however not universally defined categories. POTS presents heterogeneously and overlap exists between these subtypes. The COVID-19 pandemic saw the most significant increase in the incidence rate of POTS recorded1 suggesting an underlying link in pathogenesis.

Recent evidence has confirmed that glutamatergic dysregulation and excitotoxicity occur in Long COVID patients2-3. Glutamate is the most abundant excitatory neurotransmitter and free amino acid in the brain. Excitatory neurotransmitters increase the chance of neurons to fire a nerve impulse, sending an electric signal down the axon. This allows messages to be passed to other neurons. To exert this function, glutamate must bind to one of several types of receptors. Ionotropic glutamate receptors are responsible for excitatory neurotransmission in the brain. They are fast-acting ion-gated ligand channels that activate upon binding to glutamate, opening their pores and allowing an influx of positively charged ions to pass through the cell membrane. Three subtypes of ionotropic glutamate receptors exist; AMPA, kainate and NMDA. Of the three ionotropic glutamate receptors, the NMDA receptor possesses the highest affinity for glutamate4.

Although necessary for regular functioning, an excess of glutamate can be toxic to neurons. Excitotoxicity is the process by which excessive or prolonged activation of glutamate receptors leads to neuronal damage and cell death via influx of Ca2+ ions. Under normal conditions, astrocytes maintain glutamate homeostasis by uptaking glutamate from the extracellular space via glutamate transporters and subsequently recycle it through the glutamate-glutamine cycle5-6.
Dysfunction in glutamate transporters, receptors and/or modifications to calcium and glutamate metabolism disrupt glutamate homeostasis and can trigger excitotoxicity. Primarily, this is mediated by the NMDA receptor7. Continuous neuronal exposure to glutamate leads to depolarisation of the cell membrane, causing hyperstimulation of the NMDA receptor and a subsequent high influx of Ca2+ into the cell. This triggers a downstream cascade that ultimately leads to neuronal death and rupture.

Upon rupture, neurons release internally stored glutamate which leads to continued excitotoxicity in surrounding neurons. Ca2+ ions are also released into the extracellular space. These ions are transported into the mitochondrial matrix, disrupting the electron transport chain. This leads to a decrease in ATP production and increase in the production of reactive oxygen species (ROS). The accumulation of ROS leads to further mitochondrial dysfunction8. Damaged neurons trigger inflammatory responses leading to the release of pro-inflammatory cytokines. This leads to further glutamate release and increases the susceptibility of cells to excitotoxicity9.

NMDA-receptor Overstimulation: Capable of Inducing Tachycardia:

Although mostly recognised for playing critical roles in the CNS, functional NMDA receptors are also expressed in extraneuronal tissues both central and peripheral to the CNS. Investigation into the role of NMDA receptors in the cardiovascular system has indicated involvement in regulation of heart rate, arterial blood pressure and cardiac contraction10-13. It has been shown that activation of the NMDA receptor, through glutamate injection, triggers tachycardia in rats14. It has also been reported that the NMDA receptor participates in the modulation of cardiovascular responses following haemorrhagic shock in rats. More specifically, tachycardia evoked by haemorrhage was decreased upon treatment with MK801, a non-competitive NMDA receptor antagonist with structural similarity to DXM15-16.

NADPH oxidase (NOX2) and Cardiovascular Function

An additional downstream effect of neuronal NMDA receptor activation is the activation of NADPH oxidase-2 (NOX2) which results in subsequent production of superoxide17. When present in excess, superoxide contributes to glutamate neurotoxicity via the production of reactive oxygen species (ROS)18. NOX2 is implicated in endothelial dysfunction and vascular diseases via damage to the endothelium via ROS production resulting in impaired regulation of blood vessel function 19-20.

Factors Contributing to Glutamate Dysregulation/Excitotoxicity in POTS

Excitotoxicity and glutamatergic dysregulation are theorised to be implicated in the cognitive dysfunction seen in Long COVID21 and a significant increase in glutamate levels in the brains of Long COVID and ME/CFS patients has been found when compared to healthy controls, as well as presence of markers of excitotoxic neuronal injury and blood brain barrier disruption2-3. As a significant percentage of Long COVID patients go on to develop POTS22, elevated glutamate levels are likely involved in POTS pathophysiology. Multiple factors that may contribute to glutamate dysregulation in POTS have been identified.
Plasma proteomic analysis of POTS patients has revealed a significant upregulation and downregulation of proteins that together induce a state of enhanced platelet assembly, activation and aggregation and a pro-inflammatory state23. Enhanced platelet activity is associated with glutamatergic dysregulation and has similarly been identified in Long COVID patients24-25.
Additionally, elevated levels of pro-inflammatory cytokines, growth hormone, decreased serotonin levels and autoantibodies against the nicotinic α3β4 and G-protein-coupled adrenergic A1 receptor have been identified26-30, which are all capable of contributing to glutamatergic dysregulation.

Enhanced Platelet Activity

Platelets play a significant neurological role, involved in mediating brain function and facilitating communication between the blood and the brain. They possess molecules allowing for the trafficking, storage and secretion of glutamate. This includes all three ionotropic glutamate receptors31,external glutamate transporters EAAT1, EAAT2 and EAAT332 as well as VGLUT1 and VGLUT2, which allow intracellular glutamate to be stored within granules. Upon activation, platelets release stored glutamate via the exocytosis of granules. This causes an increase in plasma glutamate concentration in platelet-rich plasma33. Hence, an increase in platelet aggregation/activation leads to an increase of extracellular glutamate and increases the risk of glutamatergic dysregulation and excitotoxicity. Elevated platelet activity and subsequent excitotoxic damage are believed to contribute to both Parkinson’s and Alzheimer’s disease34.

At present, the underlying cause of enhanced platelet activity in POTS and Long COVID is unknown. Platelet Activating Factor (PAF) has been postulated to be involved in the pro-coagulant state observed in Long COVID, as it is the most potent mediator of platelet aggregation35. PAF is an endogenous phospholipid that plays a variety of roles in the body. Notably, it is known to enhance excitatory postsynaptic transmission36-37, initiates neurotoxicity38-39 and is among the most potent mediators of inflammation. Xu et al (2003) provide evidence that excessive activation of the NMDA receptor and downstream nitric oxide signalling mediates PAF-induced neurotoxicity in mouse neurons40.

Pro-inflammatory Cytokines

Pro-inflammatory cytokines are signalling molecules released from cells that stimulate immune response. Release of pro-inflammatory cytokines triggers activation of immune cells and release of additional pro-inflammatory cytokines, amplifying immune response and creating a feedback loop. If left unresolved, this inflammation can damage tissue and organs. Damage to the nervous system via this prolonged inflammation is a proposed mechanism of COVID-19 induced POTS41.
Elevated levels of pro-inflammatory cytokines including interleukin 1β(IL-1β), tumour necrosis factor alpha (TNFα) and interferon gamma (IFN-γ) have been identified in POTS patients26. These cytokines alter the release, uptake and metabolism of glutamate in the brain leading to a higher extracellular glutamate concentration42. Glutamate itself is capable of inducing the upregulation of pro-inflammatory cytokines that further increase glutamate levels -further exacerbating excitotoxicity43.

Elevated levels of IL-1β have been identified as a key mediator of neuroinflammatory disease, contributing to the severity of conditions such as multiple sclerosis and Alzheimer’s disease44-45. It has been shown to enhance NMDA receptor function, reduce uptake of glutamate by downregulating glutamate transporters on astrocytes, enhances release of glutamate as well as increase glutamate synthesis, factors which increase neuronal susceptibility to glutamatergic excitotoxicity46-49.

TNFα is similarly identified as a key contributor to the pathogenesis of neuroinflammatory diseases and potentiates glutamatergic excitotoxicity via several mechanisms. TNFα inhibits glutamate transporters, leading to an accumulation of glutamate extracellular space50. It increases expression of NMDA and AMPA receptors while simultaneously downregulating expression of inhibitory GABAA receptors on neurons, increasing excitatory synaptic strength. Additionally, microglia are activated by TNFα which in turn are stimulated to release more TNFα, creating a positive feedback loop51-52.

IFN-γ enhances glutamate mediated neurotoxicity via AMPA receptors, but not NMDA receptors. It does so by increasing Ca2+ influx, eventually resulting in NO production and reduced ATP production53. It is also able to activate astrocytes and microglia, resulting in the release of glutamate, nitric oxide and reactive oxygen species54. IFN-γ also significantly enhances production of TNFα, enhancing the cytokine feedback loop55.

Elevated Serum Growth Hormone

Elevated levels of growth hormone (GH) have been identified specifically in female POTS patients, which may additionally contribute to glutamatergic dysregulation. GH has been found to enhance the expression of both NMDA and AMPA receptors56. It also enhances the function of these receptors, increasing NMDA receptor-mediated excitatory post-synaptic potentials in the hippocampus57-59.

Autoimmunity: Anti- G-protein-coupled Adrenergic A1 Receptor Antibodies

Autoimmunity is another proposed mechanism of POTS. A significant portion of POTS patients possess autoantibodies against the alpha-1 adrenergic receptor (A1 receptor). Autoantibodies are proteins that target and generate immune response against the body’s own tissue, cells and proteins. The A1 receptor is involved in causing blood vessels to constrict, and autoantibodies directed against it can lead to issues in vasoconstriction and blood pressure regulation as seen in POTS60. Autoantibodies against the A1 receptor are capable of binding to the receptor, causing abnormal activation of the receptor signalling pathway. This activation leads to an increase of intracellular calcium, leading to neuronal damage and excitotoxicity61-62.

NADPH Oxidase Activation and Vascular Endothelial Dysfunction

Increased activity of NADPH oxidase and subsequent ROS production may contribute to the vascular dysregulation that is characteristic of POTS, potentially via angiotensin II63. Increased levels of plasma angiotensin II as well as abnormalities in angiotensin regulation have been observed in POTS patients64-65. Angiotensin II is a hormone involved in regulation of blood pressure, fluid balance and also functions as a pro-inflammatory mediator. It increases oxidative stress via activation of NADPH oxidases, in turn increasing mitochondrial ROS production66. Increased oxidative stress leads to a reduced availability of tetrahydrobiopterin (BH4). BH4 is an essential cofactor of endothelial nitric oxide synthase (eNOS) that regulates the function of NOS enzymes and controls production of NO in the endothelium. NO is a crucial metabolic regulator of blood pressure, vascular tone and cardiovascular function. Reduction in availability of BH4 may therefore lead to cardiovascular dysfunction.

In the presence of excessive ROS, oxidation of BH4 occurs, uncoupling it from eNOS. This process, known as uncoupling, results in production of superoxide by eNOS instead of NO. This is detrimental as superoxide is capable of producing further ROS, significantly increasing overall oxidative stress67.

CSF/ME patients with orthostatic intolerance have shown elevated levels of serum BH4 when compared to both CSF/ME patients without orthostatic intolerance and healthy controls68. This suggests involvement of BH4 elevation in the pathogenesis of orthostatic intolerance.

DXM Pharmacology + Mechanisms of Action

DXM is a non-opioid morphinan derivative widely used as an antitussive agent with a high safety profile when used at recommended doses. It is most commonly known for its function as a non-competitive NMDA receptor antagonist, however it possesses a complex pharmacology; additionally interacting with serotonin transporters, noradrenaline transporters, sigma-1 receptors and α3β4 nicotinic acetylcholine receptors69. In recent years, DXM has received significant attention for its potential neuroprotective and anti-inflammatory effects, largely mediated through NMDA blockade and resultant reduction of glutamate-induced neurotoxicity.

Glutamate Regulation

Through blockade of the NMDA receptor (primary excitatory receptor), DXM suppresses overactivity of glutamatergic signalling, leading to a downstream suppression of excitotoxicity. It has also been shown to assist in modulating glutamate uptake. In a rat model of traumatic brain injury (TBI), treatment with DXM was shown to significantly increase levels of glutamate/aspartate transporter and glutamate transporter-1 in the cortex of the brain following TBI, promoting glutamate uptake and reducing extracellular glutamate levels. This led to a reduction of excitotoxic damage and increased rates of neuronal survival70.

NADPH Oxidase/NOX2 Targeting: Potent Antioxidant and Anti-inflammatory Effects and Vascular Protection

The production of ROS by superoxide as a byproduct of NOX2 via activation of the NMDA receptor is a major component of cell damage. NOX2 is the primary enzymatic system for the generation of ROS by microglia. DXM is capable of directly targeting NADPH oxidase/NOX2, preventing membrane translocation of its cytosolic components and significantly decreasing its activity71. The resultant antioxidant effects of this process are potent. Preclinical studies have shown a significant reduction of ROS burden in experimental models of CNS disorders including dementia, Parkinson’s disease and Multiple Sclerosis72-76.

NOX2 is also a mediator of neuroinflammation which has shown to be significantly reduced via treatment with DXM. In a mouse model of endotoxemia, microglial activation and brain IL-1β levels were significantly lower in mice treated with DXM77. A similar effect was observed in a model of Parkinson’s disease, with microglial inhibition and lowered TNFα. Protection against degradation of dopaminergic neurons was also achieved75. These responses are shown to be NOX2-dependent as they were not observed in NOX2 knockout mice (mice genetically altered to not possess the NOX2 gene). Notably, both IL-1β and TNFα have shown to be upregulated in POTS patients.

DXM is capable of suppressing major inflammatory signalling pathways in an NADPH-oxidase dependent manner. ROS production via NADPH oxidase inactivates the NF-Kβ pathway in a variety of cells78.This is a key pathway responsible for the expression of a variety of genes necessary for the production of pro-inflammatory cytokines. It is integral to the regulation and activation of a range of immune cells and pro-inflammatory responses79-82. Hence, inhibition via DXM leads to a significant reduction of pro-inflammatory cytokines produced from inflammatory cells83.

Increased NADPH oxidase activity and resultant ROS production is thought to contribute to the vascular dysfunction seen in POTS via eNOS uncoupling. Inhibition of NADPH oxidase has been shown to prevent eNOS uncoupling, subsequently reducing superoxide formation and significantly reducing oxidative stress84. As DXM is an inhibitor of NADPH oxidase, it may contribute to endothelial protection via this mechanism. Treatment with DXM has previously been shown to improve endothelial function and reduce vascular oxidative stress and inflammation markers in heavy smokers85.

Antiplatelet Action

As previously mentioned, POTS is characterised by enhanced platelet activity. DXM is capable of exerting a range of anti-platelet mechanisms that may contribute to a lessening of disease severity. NF-κβ plays an important role in platelet activation, secretion and aggregation. DXM, through its NADPH-oxidase-dependent blocking of the NF-κβ pathway has been shown to inhibit platelet activation in human endothelial cells80,86-87.

Platelet activation is also triggered by an increase in platelet cytosolic calcium through secretion from intracellular stores or calcium influx. NMDA receptors are key mediators of this calcium influx65. DXM and its metabolite 3-methoxymorphinan (LK3) have been shown to inhibit this calcium mobilisation, inhibiting further activation88.

Alteration in the membrane fluidity of platelets can modulate their function. Decreased membrane fluidity results in hyperactivity of platelets to agonists, stimulating activation89. DXM and LK3 enhance platelet membrane fluidity, which further contributes to their antiplatelet effect88. The GPIIb/IIIa receptor on the surface of platelets is responsible for binding to fibrinogen which results in platelet aggregation89. LK3 inhibits platelet membrane surface GPIIb/IIIa activation, thus reducing platelet activation88.

Inhibition of Serotonin Reuptake

DXM is a nonselective serotonin reuptake transporter inhibitor, increasing the amount of serotonin available at the synapse91. Several studies have shown that POTS patients possess lower levels of serotonin in their platelets compared to healthy controls92-93. Platelet dense granules are the major storage pool of serotonin peripheral to the CNS. Peripheral serotonin plays a key role in cardiovascular function, producing a direct vasoconstriction response on smooth muscle as well as potentiating other vasoconstrictor agents. Low peripheral serotonin levels result in poor vascular tone and impaired cardiac function and has been implicated in syncope disorders94 and likely contributes to POTS pathophysiology. Hence, increasing available serotonin is another mechanism by which DXM may ameliorate symptoms.

Additionally, serotonin is involved in the modulation of glutamate95 and evidence suggests that low serotonin can lead to an increase in glutamate activity in certain brain regions, facilitating excitotoxicity96. However, it is important to note that central and peripheral serotonin stores are separated. It is not clear whether central serotonin levels are decreased in POTS or if deficiency of peripheral serotonin increases excitotoxicity.

Nicotinic α3β4 Antagonist

DXM is a noncompetitive antagonist of the Nicotinic α3β4 receptor. This specific subtype of nicotinic acetylcholine receptor (nAChR) is found in autonomic ganglia and the adrenal medulla. It acts as a primary relay between the central and peripheral nervous systems and is involved in mediating excitatory postsynaptic transmission in the autonomic ganglia97. It also plays a role in cardiovascular regulation98. Autoantibodies against the Nicotinic α3β4 receptor have been found in some POTS patients99.

Inhibiting acetylcholinesterase, an enzyme that breaks down acetylcholine (nAChR agonist) has shown to significantly improve symptoms of tachycardia in POTS100. It is important to note that acetylcholinesterase inhibits all nAChRs, and it is not clear whether direct targeting of α3β4 nAChRs specifically results in clinical improvement.

Conclusion

Overall, there is substantial reason to believe that glutamatergic dysregulation and NADPH oxidase signalling play a role in POTS as numerous confirmed factors are capable of contributing to this state. I hope that in the future a study using a methodology similar to that outlined in Chaganti et. al (2024)3 is conducted in POTS patients to confirm this. Such studies may inform more targeted treatment possibilities- something that is sorely lacking.

Important to note is that I am deficient in the CYP2D6 enzyme. This enzyme is responsible for breaking down DXM into dextrorphan. It is known for being highly genetically polymorphic, meaning that there is a great deal of variation in DXM metabolism between individuals. In my case, having this deficiency extends the duration of action of DXM and leads to prolonged presence in systemic circulation and increased bioavailability. This may explain the significant multisystemic effects I experience. In extensive metabolisers (those with a high level of CYP2D6 activity), bioavailability is reduced. These differences in oral bioavailability are significant, with extensive metabolisers ranging from 1-2% and poor metabolisers up to 80%101.

In non-antitussive therapeutic medications, DXM is often combined with agents that increase its bioavailability and increase plasma concentration. Examples include Auvelity; a combination of DXM and bupropion and Nuedexta; a combination of DXM and quinidine. Both bupropion and quinidine are potent inhibitors of CYP2D6 that ensure therapeutic effect is achieved. In the general population, combining DXM with a CYP2D6 inhibitor would likely yield more effective results.

References

  1. Dulal D, Maraey A, Elsharnoby H, Chacko P, Grubb B. Impact of COVID-19 Pandemic on the incidence and prevalence of postural orthostatic tachycardia syndrome. Eur Heart J Qual Care Clin Outcomes. Published online January 7, 2025. doi:10.1093/ehjqcco/qcae111
  2. Thapaliya K, Marshall-Gradisnik S, Eaton-Fitch N, Eftekhari Z, Inderyas M, Barnden L. Imbalanced Brain Neurochemicals in Long COVID and ME/CFS: A Preliminary Study Using MRI. Am J Med. Published online April 6, 2024. doi:10.1016/j.amjmed.2024.04.007
  3. Chaganti J, Poudel G, Cysique LA, et al. Blood brain barrier disruption and glutamatergic excitotoxicity in post-acute sequelae of SARS COV-2 infection cognitive impairment: potential biomarkers and a window into pathogenesis. Front Neurol. 2024;15:1350848. Published 2024 May 2. doi:10.3389/fneur.2024.1350848
  4. Dong X, Wang Y, Qin Z. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin.2009;30:379–87.
  5. Hertz L, Dringen R, Schousboe A, Robinson SR. Astrocytes: glutamate producers for neurons. J Neurosci Res. 1999;57(4):417-428.
  6. Andersen JV, Markussen KH, Jakobsen E, et al. Glutamate metabolism and recycling at the excitatory synapse in health and neurodegeneration. Neuropharmacology. 2021;196:108719. doi:10.1016/j.neuropharm.2021.108719
  7. Hedrick TL, Sweeney TM, Criss BA. Platelet Physiology and Pathology. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate; 2023. Available at: https://www.ncbi.nlm.nih.gov/books/NBK27972/. Accessed January 23, 2025.
  8. Luetjens CM, Bui NT, Sengpiel B, et al. Delayed mitochondrial dysfunction in excitotoxic neuron death: cytochrome c release and a secondary increase in superoxide production. J Neurosci. 2000;20(15):5715-5723. doi:10.1523/JNEUROSCI.20-15-05715.2000
  9. Ralay Ranaivo H, Craft JM, Hu W, et al. Glia as a therapeutic target: selective suppression of human amyloid-beta-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration. J Neurosci. 2006;26(2):662-670. doi:10.1523/JNEUROSCI.4652-05.2006
  10. Bozic M, Valdivielso JM. The potential of targeting NMDA receptors outside the CNS. Expert Opin Ther Targets. 2015;19(3):399-413. doi:10.1517/14728222.2014.983900
  11. Soda T, Brunetti V, Berra-Romani R, Moccia F. The Emerging Role of N-Methyl-D-Aspartate (NMDA) Receptors in the Cardiovascular System: Physiological Implications, Pathological Consequences, and Therapeutic Perspectives. Int J Mol Sci. 2023;24(4):3914. Published 2023 Feb 15. doi:10.3390/ijms24043914
  12. Dumas SJ, Bru-Mercier G, Courboulin A, et al. NMDA-Type Glutamate Receptor Activation Promotes Vascular Remodeling and Pulmonary Arterial Hypertension. Circulation. 2018;137(22):2371-2389. doi:10.1161/CIRCULATIONAHA.117.029930
  13. Chitravanshi VC, Kawabe K, Sapru HN. GABA and glycine receptors in the nucleus ambiguus mediate tachycardia elicited by chemical stimulation of the hypothalamic arcuate nucleus. Am J Physiol Heart Circ Physiol. 2015;309(1):H174-H184. doi:10.1152/ajpheart.00801.2014
  14. Resstel LB, Corrêa FM. Injection of l-glutamate into medial prefrontal cortex induces cardiovascular responses through NMDA receptor - nitric oxide in rat. Neuropharmacology. 2006;51(1):160-167. doi:10.1016/j.neuropharm.2006.03.010
  15. Busnardo C, Fassini A, Rodrigues B, Antunes-Rodrigues J, Crestani CC, Corrêa FMA. N-Methyl-D-aspartate Glutamate Receptor Modulates Cardiovascular and Neuroendocrine Responses Evoked by Hemorrhagic Shock in Rats. Biomed Res Int. 2021;2021:1156031. Published 2021 Aug 13. doi:10.1155/2021/1156031
  16. Busnardo C, Crestani CC, Fassini A, Resstel LB, Corrêa FM. NMDA and non-NMDA glutamate receptors in the paraventricular nucleus of the hypothalamus modulate different stages of hemorrhage-evoked cardiovascular responses in rats. Neuroscience. 2016;320:149-159. doi:10.1016/j.neuroscience.2016.02.003
  17. Brennan AM, Suh SW, Won SJ, et al. NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nat Neurosci. 2009;12(7):857-863. doi:10.1038/nn.2334
  18. Guemez-Gamboa A, Estrada-Sánchez AM, Montiel T, Páramo B, Massieu L, Morán J. Activation of NOX2 by the stimulation of ionotropic and metabotropic glutamate receptors contributes to glutamate neurotoxicity in vivo through the production of reactive oxygen species and calpain activation. J Neuropathol Exp Neurol. 2011;70(11):1020-1035.
  19. Sukumar P, Viswambharan H, Imrie H, et al. Nox2 NADPH oxidase has a critical role in insulin resistance-related endothelial cell dysfunction. Diabetes. 2013;62(6):2130-2134. doi:10.2337/db12-1294
  20. Murdoch CE, Alom-Ruiz SP, Wang M, et al. Role of endothelial Nox2 NADPH oxidase in angiotensin II-induced hypertension and vasomotor dysfunction [published correction appears in Basic Res Cardiol. 2014 May;109(3):410]. Basic Res Cardiol. 2011;106(4):527-538. doi:10.1007/s00395-011-0179-7
  21. Mohamed MS, Johansson A, Jonsson J, Schiöth HB. Dissecting the Molecular Mechanisms Surrounding Post-COVID-19 Syndrome and Neurological Features. Int J Mol Sci. 2022;23(8):4275. Published 2022 Apr 12. doi:10.3390/ijms23084275
  22. Fedorowski A, Sutton R. Autonomic dysfunction and postural orthostatic tachycardia syndrome in post-acute COVID-19 syndrome. Nat Rev Cardiol. 2023;20(5):281-282. doi:10.1038/s41569-023-00842-w
  23. Johansson M, Yan H, Welinder C, et al. Plasma proteomic profiling in postural orthostatic tachycardia syndrome (POTS) reveals new disease pathways. Sci Rep. 2022;12(1):20051. Published 2022 Nov 21. doi:10.1038/s41598-022-24729-x
  24. Cervia-Hasler C, Brüningk SC, Hoch T, et al. Persistent complement dysregulation with signs of thromboinflammation in active Long Covid. Science. 2024;383(6680):eadg7942. doi:10.1126/science.adg7942
  25. Wei Y, Gu H, Ma J, et al. Proteomic and metabolomic profiling of plasma uncovers immune responses in patients with Long COVID-19. Front Microbiol. 2024;15:1470193. Published 2024 Dec 27. doi:10.3389/fmicb.2024.1470193
  26. Gunning WT 3rd, Stepkowski SM, Kramer PM, Karabin BL, Grubb BP. Inflammatory Biomarkers in Postural Orthostatic Tachycardia Syndrome with Elevated G-Protein-Coupled Receptor Autoantibodies. J Clin Med. 2021;10(4):623. Published 2021 Feb 6. doi:10.3390/jcm10040623
  27. Medic Spahic J, Ricci F, Aung N, et al. Proteomic analysis reveals sex-specific biomarker signature in postural orthostatic tachycardia syndrome. BMC Cardiovasc Disord. 2020;20(1):190. Published 2020 Apr 22. doi:10.1186/s12872-020-01465-6
  28. Johansson M, Ricci F, Schulte J, et al. Circulating levels of growth hormone in postural orthostatic tachycardia syndrome. Sci Rep. 2021;11(1):8575. Published 2021 Apr 21. doi:10.1038/s41598-021-87983-5
  29. Watari M, Nakane S, Mukaino A, et al. Autoimmune postural orthostatic tachycardia syndrome. Ann Clin Transl Neurol. 2018;5(4):486-492. Published 2018 Feb 28. doi:10.1002/acn3.524
  30. Arocha-Piñango CL, Marín P, Ordóñez A, et al. Platelet delta granule and serotonin release in essential thrombocythemia. Blood. 2009;114(22):2419-2427. doi:10.1182/blood-2009-03-214406.
  31. Hitchcock IS, Skerry TM, Howard MR, Genever PG. NMDA receptor-mediated regulation of human megakaryocytopoiesis. Blood. 2003;102(4):1254-1259. doi:10.1182/blood-2002-11-3553
  32. Begni B, Tremolizzo L, D'Orlando C, et al. Substrate-induced modulation of glutamate uptake in human platelets. Br J Pharmacol. 2005;145(6):792-799. doi:10.1038/sj.bjp.0706242
  33. Tremolizzo L, DiFrancesco JC, Rodriguez-Menendez V, et al. Human platelets express the synaptic markers VGLUT1 and 2 and release glutamate following aggregation. Neurosci Lett. 2006;404(3):262-265. doi:10.1016/j.neulet.2006.06.015
  34. Gautam D, Naik UP, Naik MU, Yadav SK, Chaurasia RN, Dash D. Glutamate Receptor Dysregulation and Platelet Glutamate Dynamics in Alzheimer's and Parkinson's Diseases: Insights into Current Medications. Biomolecules. 2023;13(11):1609. Published 2023 Nov 3. doi:10.3390/biom13111609
  35. Demopoulos C, Antonopoulou S, Theoharides TC. COVID-19, microthromboses, inflammation, and platelet activating factor. Biofactors. 2020;46(6):927-933. doi:10.1002/biof.1696
  36. Clark GD, Happel LT, Zorumski CF, Bazan NG. Enhancement of hippocampal excitatory synaptic transmission by platelet-activating factor. Neuron. 1992;9(6):1211-1216. doi:10.1016/0896-6273(92)90078-r
  37. Marcheselli VL, Rossowska MJ, Domingo MT, Braquet P, Bazan NG. Distinct platelet-activating factor binding sites in synaptic endings and in intracellular membranes of rat cerebral cortex. J Biol Chem. 1990;265(16):9140-9145.
  38. Bazan NG, Zorumski CF, Clark GD. The activation of phospholipase A2 and release of arachidonic acid and other lipid mediators at the synapse: the role of platelet-activating factor. J Lipid Mediat. 1993;6(1-3):421-427.
  39. Marcheselli VL, Bazan NG. Platelet-activating factor is a messenger in the electroconvulsive shock-induced transcriptional activation of c-fos and zif-268 in hippocampus. J Neurosci Res. 1994;37(1):54-61. doi:10.1002/jnr.490370108
  40. Xu Y, Tao YX. Involvement of the NMDA receptor/nitric oxide signal pathway in platelet-activating factor-induced neurotoxicity. Neuroreport. 2004;15(2):263-266. doi:10.1097/00001756-200402090-00010
  41. Mallick D, Goyal L, Chourasia P, Zapata MR, Yashi K, Surani S. COVID-19 Induced Postural Orthostatic Tachycardia Syndrome (POTS): A Review. Cureus. 2023;15(3):e36955. Published 2023 Mar 31. doi:10.7759/cureus.36955
  42. Haroon E, Miller AH, Sanacora G. Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders. Neuropsychopharmacology. 2017;42(1):193-215. doi:10.1038/npp.2016.199
  43. Alim MA, Grujic M, Ackerman PW, Kristiansson P, Eliasson P, Peterson M, et al. Glutamate triggers the expression of functional ionotropic and metabotropic glutamate receptors in mast cells. Cell Mol Immunol. 2020;18:2383–92.
  44. Shaftel SS, Griffin WS, O'Banion MK. The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neuroinflammation. 2008;5:7. Published 2008 Feb 26. doi:10.1186/1742-2094-5-7
  45. Rossi S, Furlan R, De Chiara V, et al. Interleukin-1β causes synaptic hyperexcitability in multiple sclerosis. Ann Neurol. 2012;71(1):76-83. doi:10.1002/ana.22512
  46. Viviani B, Bartesaghi S, Gardoni F, et al. Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci. 2003;23(25):8692-8700. doi:10.1523/JNEUROSCI.23-25-08692.2003
  47. Zumkehr J, Rodriguez-Ortiz CJ, Medeiros R, Kitazawa M. Inflammatory Cytokine, IL-1β, Regulates Glial Glutamate Transporter via microRNA-181a in vitro. J Alzheimers Dis. 2018;63(3):965-975. doi:10.3233/JAD-170828
  48. Charles-Messance H, Blot G, Couturier A, et al. IL-1β induces rod degeneration through the disruption of retinal glutamate homeostasis. J Neuroinflammation. 2020;17(1):1. Published 2020 Jan 3. doi:10.1186/s12974-019-1655-5
  49. Ye L, Huang Y, Zhao L, et al. IL-1β and TNF-α induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase. J Neurochem. 2013;125(6):897-908. doi:10.1111/jnc.12263
  50. Takeuchi H, Jin S, Wang J, et al. Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem. 2006;281(30):21362-21368. doi:10.1074/jbc.M600504200
  51. Chao CC, Hu S. Tumor necrosis factor-alpha potentiates glutamate neurotoxicity in human fetal brain cell cultures. Developmental Neuroscience. 1994;16(3-4):172–179. doi: 10.1159/000112104.
  52. Han P, Whelan PJ. Tumor necrosis factor alpha enhances glutamatergic transmission onto spinal motoneurons. Journal of Neurotrauma. 2010;27(1):287–292. doi: 10.1089/neu.2009.1016
  53. Mizuno T, Zhang G, Takeuchi H, et al. Interferon-gamma directly induces neurotoxicity through a neuron specific, calcium-permeable complex of IFN-gamma receptor and AMPA GluR1 receptor. FASEB J. 2008;22(6):1797-1806. doi:10.1096/fj.07-099499
  54. Hashioka S, McGeer EG, Miyaoka T, Wake R, Horiguchi J, McGeer PL. Interferon-γ-induced neurotoxicity of human astrocytes. CNS Neurol Disord Drug Targets. 2015;14(2):251-256. doi:10.2174/1871527314666150217122305
  55. Salim T, Sershen CL, May EE. Investigating the Role of TNF-α and IFN-γ Activation on the Dynamics of iNOS Gene Expression in LPS Stimulated Macrophages. PLoS One. 2016;11(6):e0153289. Published 2016 Jun 8. doi:10.1371/journal.pone.0153289
  56. Studzinski AL, Barros DM, Marins LF. Growth hormone (GH) increases cognition and expression of ionotropic glutamate receptors (AMPA and NMDA) in transgenic zebrafish (Danio rerio). Behav Brain Res. 2015;294:36-42. doi:10.1016/j.bbr.2015.07.054
  57. Ramis M, Sarubbo F, Sola J, et al. Cognitive improvement by acute growth hormone is mediated by NMDA and AMPA receptors and MEK pathway. Prog Neuropsychopharmacol Biol Psychiatry. 2013;45:11-20. doi:10.1016/j.pnpbp.2013.04.005
  58. Mahmoud GS, Grover LM. Growth hormone enhances excitatory synaptic transmission in area CA1 of rat hippocampus. J Neurophysiol. 2006;95(5):2962-2974. doi:10.1152/jn.00947.2005
  59. Le Grevès M, Zhou Q, Berg M, et al. Growth hormone replacement in hypophysectomized rats affects spatial performance and hippocampal levels of NMDA receptor subunit and PSD-95 gene transcript levels. Exp Brain Res. 2006;173(2):267-273. doi:10.1007/s00221-006-0438-2
  60. Kharraziha I, Axelsson J, Ricci F, et al. Serum Activity Against G Protein-Coupled Receptors and Severity of Orthostatic Symptoms in Postural Orthostatic Tachycardia Syndrome. J Am Heart Assoc. 2020;9(15):e015989. doi:10.1161/JAHA.120.015989
  61. Perez DM. Current Developments on the Role of α1-Adrenergic Receptors in Cognition, Cardioprotection, and Metabolism. Front Cell Dev Biol. 2021;9:652152. Published 2021 May 25. doi:10.3389/fcell.2021.652152
  62. Perez DM. α1-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition. Front Pharmacol. 2020;11:581098. Published 2020 Sep 29. doi:10.3389/fphar.2020.581098
  63. Chopoorian AH, Wahba A, Celedonio J, et al. Impaired Endothelial Function in Patients With Postural Tachycardia Syndrome. Hypertension. 2021;77(3):1001-1009. doi:10.1161/HYPERTENSIONAHA.120.16238
  64. Stewart JM, Glover JL, Medow MS. Increased plasma angiotensin II in postural tachycardia syndrome (POTS) is related to reduced blood flow and blood volume. Clin Sci (Lond). 2006;110(2):255-263. doi:10.1042/CS20050254
  65. Mustafa HI, Garland EM, Biaggioni I, et al. Abnormalities of angiotensin regulation in postural tachycardia syndrome. Heart Rhythm. 2011;8(3):422-428. doi:10.1016/j.hrthm.2010.11.009
  66. Forrester SJ, Booz GW, Sigmund CD, Coffman TM, Kawai T, Rizzo V, Scalia R, Eguchi S. Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology. Physiol Rev. 2018;98:1627–1738. (n.d.). [PubMed: 29873596]
  67. Landmesser U, Dikalov S, Price SR, et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest. 2003;111(8):1201-1209. doi:10.1172/JCI14172
  68. Gottschalk CG, Whelan R, Peterson D, Roy A. Detection of Elevated Level of Tetrahydrobiopterin in Serum Samples of ME/CFS Patients with Orthostatic Intolerance: A Pilot Study. Int J Mol Sci. 2023;24(10):8713. Published 2023 May 13. doi:10.3390/ijms24108713
  69. Taylor CP, Traynelis SF, Siffert J, Pope LE, Matsumoto RR. Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacol Ther. 2016;164:170-182. doi:10.1016/j.pharmthera.2016.04.010
  70. Pu B, Xue Y, Wang Q, Hua C, Li X. Dextromethorphan provides neuroprotection via anti-inflammatory and anti-excitotoxicity effects in the cortex following traumatic brain injury. Mol Med Report 2015; 12: 3704-3710.
  71. Liu SL, Li YH, Shi GY, et al. Dextromethorphan reduces oxidative stress and inhibits atherosclerosis and neointima formation in mice. Cardiovasc Res. 2009;82(1):161-169. doi:10.1093/cvr/cvp043
  72. Ommati MM, Jamshidzadeh A, Saeed M, Rezaei M, Heidari R. Dextromethorphan improves locomotor activity and decreases brain oxidative stress and inflammation in an animal model of acute liver failure. Clin Exp Hepatol. 2022;8(3):178-187. doi:10.5114/ceh.2022.118299
  73. Xu X, Zhang B, Lu K, et al. Prevention of hippocampal neuronal damage and cognitive function deficits in vascular dementia by dextromethorphan. Mol Neurobiol 2016; 53: 3494-3502.
  74. Werling LL, Lauterbach EC, Calef U. Dextromethorphan as a potential neuroprotective agent with unique mechanisms of action. Neurologist 2007; 13: 272-293.
  75. Zhang W, Wang T, Qin L, et al. Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase. FASEB J. 2004;18(3):589-591. doi:10.1096/fj.03-0983fje
  76. Chechneva OV, Mayrhofer F, Daugherty DJ, et al. Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord. Neurobiol Dis 2011; 44: 63-72.
  77. Wu TC, Chao CY, Lin SJ, Chen JW. Low-dose dextromethorphan, a NADPH oxidase inhibitor, reduces blood pressure and enhances vascular protection in experimental hypertension. PLoS One. 2012;7(9):e46067. doi:10.1371/journal.pone.0046067
  78. Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res. 2011;21:103–115. doi: 10.1038/cr.2010.178.
  79. Collins T. Endothelial nuclear factor-kappa B and the initiation of the atherosclerotic lesion. Lab Invest. 1993;68(5):499-508.
  80. Malaver E, Romaniuk MA, D’Atri LP, Pozner RG, Negrotto S, Benzadón R, et al. NF-kappaB inhibitors impair platelet responses. J Thromb Haemost 2009;7:1333-43.
  81. Chang CC, Lu WJ, Ong ET, Chiang CW, Lin SC, Huang SY, et al. A novel role of sesamol in inhibiting NF-κB-mediated signaling in platelet activation. J Biomed Sci 2011;18:93.
  82. Wu K, Lin TH, Liou HC, et al. Dextromethorphan inhibits osteoclast differentiation by suppressing RANKL-induced nuclear factor-κB activation. Osteoporos Int. 2013;24(8):2201-2214. doi:10.1007/s00198-013-2279-8
  83. Liu SL, Li YH, Shi GY, et al. Dextromethorphan reduces oxidative stress and inhibits atherosclerosis and neointima formation in mice. Cardiovasc Res 2009; 82: 161-169.
  84. Mollnau H, Schulz E, Daiber A, et al. Nebivolol prevents vascular NOS III uncoupling in experimental hyperlipidemia and inhibits NADPH oxidase activity in inflammatory cells. Arterioscler Thromb Vasc Biol. 2003;23(4):615-621.
  85. Liu PY, Lin CC, Tsai WC, et al. Treatment with dextromethorphan improves endothelial function, inflammation and oxidative stress in male heavy smokers. J Thromb Haemost. 2008;6(10):1685-1692. doi:10.1111/j.1538-7836.2008.03082.x
  86. Jiang SJ, Hsu SY, Deng CR, et al. Dextromethorphan attenuates LPS-induced adhesion molecule expression in human endothelial cells. Microcirculation. 2013;20(2):190-201. doi:10.1111/micc.12024
  87. Hsia CW, Wu MP, Shen MY, Hsia CH, Chung CL, Sheu JR. Regulation of Human Platelet Activation and Prevention of Arterial Thrombosis in Mice by Auraptene through Inhibition of NF-κB Pathway. Int J Mol Sci. 2020;21(13):4810. Published 2020 Jul 7. doi:10.3390/ijms21134810
  88. Nesbitt WS, Giuliano S, Kulkarni S, Dopheide SM, Harper IS, Jackson SP. Intercellular calcium communication regulates aggregation and thrombus growth. J Cell Biol 2003;160:1151-61
  89. Winocour PD, Bryszewska M, Watala C, Rand ML, Epand RM, Kinlough-Rathbone RL, et al. Reduced membrane fluidity in platelets from diabetic patients. Diabetes. 1990;39:241–4. doi: 10.2337/diab.39.2.241.
  90. Fullard JF. The role of the platelet glycoprotein IIb/IIIa in thrombosis and haemostasis. Curr Pharm Des. 2004;10:1567–76. doi: 10.2174/1381612043384682.
  91. Rickli A, Liakoni E, Hoener MC, Liechti ME. Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome. Br J Pharmacol. 2018;175(3):532-543. doi:10.1111/bph.14105
  92. Serebruany VL, Kasey T, Lasky J, et al. Platelet delta granule and serotonin release as risk markers for bleeding complications. Blood. 2009;114(22):2419-2427. doi:10.1182/blood-2009-03-214406.
  93. Gunning WT 3rd, Karabin BL, Blomquist TM, Grubb BP. Postural orthostatic tachycardia syndrome is associated with platelet storage pool deficiency. Medicine (Baltimore). 2016;95(37):e4849. doi:10.1097/MD.0000000000004849
  94. Furlan R, Freeman R, Bernardi L, et al. Neurocardiogenic syncope: patients often have unrecognized autonomic dysfunction. Blood. 2008;112(11):1242-1249. doi:10.1182/blood-2008-03-140903.
  95. Ciranna L. Serotonin as a modulator of glutamate- and GABA-mediated neurotransmission: implications in physiological functions and in pathology. Curr Neuropharmacol. 2006;4(2):101-114. doi:10.2174/157015906776359540
  96. Tran L, Lasher BK, Young KA, Keele NB. Depletion of serotonin in the basolateral amygdala elevates glutamate receptors and facilitates fear-potentiated startle. Transl Psychiatry. 2013;3(9):e298. Published 2013 Sep 3. doi:10.1038/tp.2013.66
  97. Gharpure A, Teng J, Zhuang Y, et al. Agonist Selectivity and Ion Permeation in the α3β4 Ganglionic Nicotinic Receptor. Neuron. 2019;104(3):501-511.e6. doi:10.1016/j.neuron.2019.07.030
  98. Eom S, Kim C, Yeom HD, et al. Molecular Regulation of α3β4 Nicotinic Acetylcholine Receptors by Lupeol in Cardiovascular System. Int J Mol Sci. 2020;21(12):4329. Published 2020 Jun 18. doi:10.3390/ijms21124329
  99. Bryarly M, Raj SR, Phillips L, et al. Ganglionic Acetylcholine Receptor Antibodies in Postural Tachycardia Syndrome. Neurol Clin Pract. 2021;11(4):e397-e401. doi:10.1212/CPJ.0000000000001047
  100. Raj SR, Black BK, Biaggioni I, Harris PA, Robertson D. Acetylcholinesterase inhibition improves tachycardia in postural tachycardia syndrome. Circulation. 2005;111(21):2734-2740. doi:10.1161/CIRCULATIONAHA.104.497594
  101. Capon DA, Bochner F, Kerry N, Mikus G, Danz C, Somogyi AA. The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans. Clin Pharmacol Ther. 1996;60(3):295-307. doi:10.1016/S0009-9236(96)90056-9