Rhexical Plus Tablet
- Rhexical Plus Tablet replenishes nutritional deficiency.
- Elemental Calcium is used to prevent or cure low blood calcium levels in patients who do not ingest enough calcium.
- Vitamin D3 (Cholecalciferol) regulates calcium and phosphate levels in the body.
- L-5-Methyltetrahydrofolate aids in the treatment or prevention of low folate levels.
- Methylcobalamin helps to enhance the nervous system and is essential for DNA synthesis and maturation.
- Pyridoxine-5-Phosphate is responsible for various functions such as energy production and amino acid metabolism.
- Vitamin K2-7 is essential for calcium metabolism (the main mineral found in the bones and teeth).
Neurofeedback for long COVID
NEUROFEEDBACK
What is neurofeedback?
Neurofeedback is a brain training process that allows people to self-control their brain functions by measuring their brain waves and then providing a feedback signal to encourage or discourage a certain brain activity.1 This is done by placing electrodes on a particular part of the patient’s head to obtain their electroencephalographic (EEG) or brain wave activity. When the detected EEG activity is in an optimal range, the patient receives a visual or auditory cue that is perceived as “good” and is considered a reward. When the EEG activity is abnormal, the patient receives feedback that it is “bad” to encourage the patient to change their brain activity.
Consistent sessions are needed to reinforce positive changes in brain function. Typically, patients will notice a difference of about ten sessions; however, 20 sessions are generally required to retrain the brain.
How can neurofeedback help alleviate certain long COVID symptoms?
Neurological symptoms of long COVID can include headache, insomnia, anxiety, depression, dizziness, seizures, and fatigue.2 There are several proposed mechanisms for why COVID can cause these symptoms. Damage to neural tissue can be caused by direct and indirect interaction of the SARS-CoV-2 virus with the brain. The SARS-CoV-2 virus is believed to reach the brain through the blood and infect neurons and astrocytes, which make up a large portion of the central nervous system. COVID can also indirectly impact the brain with respiratory symptoms that prevent sufficient oxygen from reaching the brain and a heightened pro-inflammatory response that can damage neural tissue.2
Various studies have also noted EEG abnormalities in COVID patients.3 Retraining the brain to allow a patient to correct these EEG abnormalities is believed to be able to make micro-structural changes of white and gray matter in the brain and improve plasticity with improvement in the trained brain areas.2 Neurofeedback has been studied for headaches, insomnia, depression, and fatigue and has been used in multiple sclerosis patients who can experience symptoms similar to those of neurological long COVID symptoms.
What evidence supports the use of neurofeedback for long COVID?
A pilot study looking at the use of neurofeedback therapy on post-COVID fatigue, anxiety, and depression included 10 participants experiencing these symptoms for at least three months. Electrodes were placed on the right and temporal lobes, and the participants underwent five sessions, each 25-45 minutes, completed within two weeks. The study found a significant reduction in anxiety and depression persisting for at least one month but an insignificant effect on fatigue.4
A review of 12 studies assessing the effect of EEG-based neurofeedback on depression found significant cognitive, clinical, and neural improvements in patients’ depressive symptoms.5 Thus, it appears that neurofeedback therapy can be an effective non-pharmacologic treatment method for new-onset anxiety and depression in post-COVID individuals; however, more studies are needed to assess its efficacy in long COVID.
What should you be aware of with neurofeedback?
Neurofeedback therapy has a relatively low risk of side effects, but side effects can include anxiety, agitation, emotional lability, headaches, and fatigue.6 These side effects are often transient. Severe side effects are rare but include seizures, depression, manic attacks, and memory problems.
References:
Vitamin E for long COVID
VITAMIN E
What is vitamin E?
Vitamin E is an antioxidant known for its free radical scavenging properties [[1]]. It is a fat-soluble vitamin [[2]]. We get vitamin E entirely from dietary sources [[3]].
What does vitamin E do in the body?
Vitamin E is potent against cancer, aging, arthritis, and cataracts. It is also vital for the health of our visual and reproductive systems. It also prevents platelet aggregation and can combat atherosclerosis [[3]].
Vitamin E is an antioxidant, which means that it protects the body’s cells from free radicals. Free radicals are a form of oxidative stress that causes cell and tissue damage. Vitamin E also supports immune health, enabling the body to fight off viruses. Its functions include widening blood vessels, preventing blood clots, and improving communication between cells [[2]].
How can vitamin E help alleviate certain Long COVID symptoms and pathophysiology?
Because of its role as a scavenger of harmful free radicals, vitamin E can protect against oxidative damage caused by COVID-19, both in the acute and post-acute phases. Research suggests that vitamin E may have anticlotting effects, which can be useful for acute COVID-19, given that blood thickening is a common symptom associated with severe COVID-19 and is also a feature of Long COVID [[4]].
Vitamin E may also have anti-platelet and anti-clotting effects, which can promote vasculature health. Given that clotting abnormalities can be a feature in severe COVID-19 and Long COVID, vitamin E can potentially reduce blood clot risks for both patient populations [[4]].
Vitamin E may lower levels of an inflammatory substance known as C-reactive protein or CRP [[5]], which can be elevated in patients with Long COVID [[6]].
Dimenhydrinate for long COVID
DIMENHYDRINATE
What is dimenhydrinate?
Dimenhydrinate is a first-generation antihistamine commonly used for motion sickness, nausea, vomiting, and vertigo (a sensation that you or your surroundings are spinning). It is similar to meclizine (another over-the-counter antihistamine used for motion sickness and vertigo), but dimenhydrinate is considered to be more sedating. Compared to meclizine, which takes an hour to take effect but lasts 24 hours, dimenhydrinate has a faster onset of action of about 15 to 30 minutes but takes about an hour. Dimenhydrinate can be taken as 50-100 mg every four to six hours as needed for a maximum of 400 mg daily.
How can dimenhydrinate help alleviate certain long COVID symptoms?
Some patients have reported neurological symptoms of long COVID, such as vertigo and persistent dizziness. While rare, there have been reports of new-onset vertigo associated with a COVID infection.1 It is known that the SARS-CoV-2 virus can infiltrate the central nervous system and directly invade the brain. The mechanism of its association with vertigo is still unclear. Still, it is thought to be due to the effect of the virus on neural networks impacting our hearing and balance or cytokine storm that occurs when immune cells become hyperactivated and trigger an excess release of inflammatory mediators.2 Dizziness can also be due to multiple factors such as dehydration, headache, and lightheadedness due to stress from the infection.
Dimenhydrinate can block certain receptors in the chemoreceptor trigger zone in our brain, which is responsible for causing feelings of nausea and dizziness. This allows for relief of vertigo and dizziness from neurological long COVID symptoms.
What evidence supports dimenhydrinate’s use for long COVID?
More studies are currently needed to explore the use of dimenhydrinate specifically for new-onset vertigo or dizziness after a COVID infection. In addition, patient case reports and anecdotal reports are mixed, with some reporting beneficial effects and others stating partial or no improvement in their vertigo. A case report of a patient treated with dimenhydrinate and beta-histamine (a prescription antiemetic not available in the US) led to partial improvement in vertigo.3 For patients with gastrointestinal effects from COVID, such as nausea and diarrhea, dimenhydrinate can help with oral intake and rehydration.4
Overall, dimenhydrinate is a reasonable option to consider for post-COVID vertigo or dizziness and can be trialed with other prescription medications. However, it should not be used chronically if these symptoms persist.
What should you be aware of when taking dimenhydrinate?
Due to its sedating effects, dimenhydrinate should not be taken while driving or operating heavy machinery. Other side effects of the medication include a fast heartbeat or palpitations, dizziness, headache, restlessness, blurred vision, difficulty urinating, or constipation. Some of these side effects can be worsened with other medications and older age. If used more frequently, it should be used with caution in patients with cardiovascular disease, angle-closure glaucoma, and urinary obstruction.
References:
Olfactory Training for longCOVID
OLFACTORY TRAINING
What is olfactory training?
Olfactory training is a non-pharmacological and non-surgical treatment option for people experiencing olfactory (or smell) dysfunction that can occur after an infection, trauma event, or Parkinson’s disease. Typically, patients expose themselves to 4 different odors twice daily for at least 24 weeks. Each odor is sniffed for at least 20-30 seconds without a break. Each odor should ideally represent a different category of smells, including a fruity or sweet smell (ex, lemon), flowery smell (ex, rose), spicy smell (ex, clove), and resinous smell (ex, eucalyptus).2 Olfactory training can also be done for up to 12 odors, which may demonstrate better symptom improvement.1 It is more effective in younger individuals and those with more severe olfactory dysfunction.
How can olfactory training help alleviate certain long COVID symptoms?
It is estimated that up to one-third of COVID patients can have post-infection smell dysfunction.3 The loss of smell is likely due to multiple mechanisms such as inflammation of the nasal epithelium, damage of olfactory neurons and microglial cells, early cell death of olfactory cells, changes in the nasal cilia, and changes in odor transmission. Olfactory training is believed to help rebuild neural connections between the nose and the brain to help relearn and identify different types of smells.2
What evidence supports olfactory training’s use for long COVID?
A case series of 8 patients (five female, three male) with post-COVID smell dysfunction lasting over three months followed a 30-day olfactory training protocol using plant-derived essential oils. Participants had one training session in the morning and one in the evening, each lasting approximately 15 minutes. Each patient was asked to smell ten plant-derived essential oils through deep inhalation and rapid sniffing. The order of smells included peppermint, lavender, lemon, red spruce, frankincense (orange-like smell), Hyssop CT pinocamphone (spice and herbaceous scent), cinnamon, cloves, savory, and eucalyptus. Based on their self-reported olfactory functioning, there was a significant improvement from 3.6 at baseline to 5.6 out of 10.3
Olfactory training is typically done over a longer time span of 12-24 weeks. However, additional studies have looked at using an expanded number of smells for a shorter time span. One study enrolled 80 patients assigned to olfactory training with four or eight smells over four weeks.4 Significant improvements were subjectively measured in both groups, and there were no significant differences between groups in identifying smells. This suggests that utilizing four scents for four weeks may be sufficient for olfactory training.
Another study investigated the efficacy of combined visual-olfactory training compared to olfactory training alone in 275 patients with post-COVID olfactory loss.5 Visual-olfactory training included digital images of each scent shown to the participants while smelling it. The study also examined differences between patients choosing scents vs. physicians selecting scents. Results showed no clinically meaningful difference in all groups’ smell identification test scores.
What should you be aware of with olfactory training?
Olfactory training is safe and considered a first-line therapy for olfactory dysfunction. However, certain conditions may benefit from surgery rather than olfactory training, so it is important to ask your doctor before starting it. Smoking tobacco products can worsen olfactory functioning and prevent improvement with olfactory training.
References:
2) Windsor M. Smell training is brain training, parosmia success – and five other insights from a new UAB clinic. The University of Alabama at Birmingham. March 27, 2023. Accessed November 2, 2023. https://www.uab.edu/reporter/patient-care/advances/item/10005-smell-training-is-brain-training-parosmia-success-and-five-other-insights-from-a-new-uab-clinic#:~:text=Treatments%20—%20starting%20with%20olfactory%20training,training%20can%20boost%20cognitio
Specialized Pro-Resolving Mediators for long COVID
SPECIALIZED PRO-RESOLVING MEDIATORS (SPM)
What are specialized pro-resolving mediators?
Specialized pro-resolving mediators, or SPMs, are fatty substances produced within the body that work to reduce inflammation.
What do specialized pro-resolving mediators do in the body?
SPMs have many functions, including ending chronic inflammatory processes, reducing pain, affecting innate and adaptive immune cells, clearing dead cells and debris, breaking down blood clots, and attacking pathogens. SPMs can also help support tissue regeneration [[1]].
SPMs are bioactive lipids (fats) that occur via the breakdown of certain polyunsaturated fatty acids after the inflammatory cascade has started. They may aid in the inflammatory process that helps resolve the inflammation. This is why SPMs could help improve the overall course of heart and lung tissue inflammation events. SPMs also have many other immune functions, such as regulating macrophages, cytokine production, and stimulation of macrophages that resolve inflammatory courses [[2]].
The list of SPM compounds includes lipids (fats) such as lipoxins, resolvins, protectins, and maresins [[2]]. Lipoxins are anti-inflammatory, pro-inflammation resolution molecules that can reduce chronic inflammation and tissue injury [[3]]. Resolvins and protectins are derived from omega-3 fatty acids and work to resolve inflammation [[4]]. Maresins are analgesic and anti-inflammatory macrophages that mediate the resolution of inflammation [[5]].
How can specialized pro-resolving mediators help alleviate certain Long COVID symptoms and pathophysiology?
Prolonged inflammation after COVID-19’s acute phase is over can damage tissues in the brain, lungs, and kidney [[6]]. SPM’s role in resolving pro-inflammatory processes can help Long COVID survivors with the resolution phase of inflammation, improving the overall course of chronic inflammation.
Diphenhydramine for long COVID
DIPHENHYDRAMINE
What is diphenhydramine?
Diphenhydramine is an antihistamine used to relieve symptoms of allergies, hay fever, or a cold, such as red, itchy, or watery eyes, sneezing, runny nose, and cough. It can also prevent nausea and vomiting, motion sickness, and vertigo. Compared to other antihistamines, diphenhydramine is the most sedating and can help you fall asleep. It also has a shorter duration of action and may need to be taken every four to six hours as needed.
How can diphenhydramine help alleviate certain long COVID symptoms?
Histamine is a chemical our immune system releases that causes our allergy symptoms. Cells in our body called mast cells release histamine, and in some patients after COVID, they may release too much, leading to some of the symptoms of long COVID. Long COVID is believed to be a state of prolonged hyper-inflammation that follows the infection. Because diphenhydramine can block histamine type 1 receptors, it has the potential to relieve certain long COVID symptoms and has been reported to improve fatigue and cognitive symptoms specifically.1
What evidence supports diphenhydramine’s use for long COVID?
There has been extensive research on the use of antihistamines in general for long COVID. Unfortunately, no evidence directly supports diphenhydramine’s use for long COVID. Two case reports noted considerable improvement in fatigue, “brain fog” or ability to concentrate, abdominal pain, and loss of smell and taste with diphenhydramine 25 mg or 50 mg.1 The addition of diphenhydramine to a combination of ibuprofen and cimetidine was also found to help treat adult respiratory distress syndrome (ARDS) in a porcine model; however, these results may not extend to humans.2
What are some things to be aware of when taking diphenhydramine?
Diphenhydramine should be used sparingly in older adults. It can cause blurred vision, urinary retention, nausea, and constipation, which may be worsened with other medications. Avoid taking diphenhydramine during the day, as it can cause drowsiness. While diphenhydramine can help with insomnia, it should not be routinely taken for this purpose.
References:
Oxymetazoline (Afrin) for long COVID
OXYMETAZOLINE NASAL SPRAY
What is oxymetazoline?
Oxymetazoline (Afrin) is a decongestant that constricts the blood vessels in your nose to reduce nasal swelling and congestion. It can be applied by spraying 2-3 sprays in each nostril twice a day, with a maximum daily dose of 2 doses in a 24-hour period.
How can oxymetazoline help alleviate certain long COVID symptoms?
Oxymetazoline can be used for nasal congestion that persists after a COVID infection, but it should not be used long-term. Unlike oral decongestants like pseudoephedrine or phenylephrine, which can increase blood pressure in people with high blood pressure, oxymetazoline has fewer effects on blood pressure and can be more beneficial in these patients.
What evidence supports oxymetazoline’s use for long COVID?
Few studies have examined the use of oxymetazoline for long COVID symptoms. While using oxymetazoline with nasal corticosteroids has demonstrated improvement in nasal congestion and lack of smell specifically in patients with nasal polyps,1 oxymetazoline has not been shown to influence loss of smell following a COVID infection.
What should you be aware of when taking oxymetazoline?
If used for more than three consecutive days, oxymetazoline can cause the blood vessels in your nose to swell up again, leading to rebound congestion. Therefore, it is essential to limit use to three to five consecutive days. Side effects of oxymetazoline include temporary burning or stinging and dryness in the nose. Oxymetazoline is not recommended for use in children younger than six.
References:
Tricarboxylic Acid Cycle Intermediates for long COVID
TRICARBOXYLIC ACID CYCLE INTERMEDIATES (Specifically: Malic Acid, Citric Acid, and Succinic Acid)
What are tricarboxylic acid intermediates?
The tricarboxylic acid cycle (TCA), also known as the Krebs or citric acid cycle, is a cyclic reaction used by the body to generate energy from the foods we eat. The TCA cycle occurs in the mitochondria, the cell’s energy powerhouse. The TCA cycle has intermediates, including malic acid, citric acid, and succinic acid, which are known to be involved in energy metabolism in the mitochondria.
What do tricarboxylic acid intermediates do in the body?
While these intermediates used to be thought of as byproducts of cellular metabolism to make lipids, nucleotides, and proteins, they are now known as important molecules with many different functions. Metabolites of the TCA cycle may be involved in remodeling the contents of the chromosome, regulating gene expression, modifying proteins, acting on platelets, and performing immune functions [[1]]. TCA cycle intermediates also regulate the production of reactive oxygen species, a class of free radicals [[2]].
Evidence suggests these intermediates also play a role in maintaining cellular immunity. When cells are in stress conditions, the membrane enclosing the mitochondria within the cell can become compromised, releasing TCA cycle intermediates into the cytosol or the fluid flowing inside the whole cell, directly influencing cellular immunity through its interactions there [[2]].
How can tricarboxylic acid intermediates help alleviate certain Long COVID symptoms and pathophysiology?
Supplementation with TCA cycle intermediates can help boost mitochondrial function and help patients recovering from COVID-19, especially older people. Supplemented along with amino acids, TCA cycle metabolites can play a supporting role in helping prevent mitochondrial damage, oxidative stress, and muscle loss. A combined supplement that includes amino acids and TCA cycle intermediates such as citric, succinic, and malic acids may be relevant to maintaining mitochondrial function. Such a supplement cocktail was studied in a mouse aging model and was found to preserve mitochondrial function, support muscle mass, and preserve physical and cognitive abilities [[1]]. While more work is needed to elucidate the exact role of TCA cycle intermediates in Long COVID pathophysiology, the research seems promising.
Doxylamine for long COVID
DOXYLAMINE
What is doxylamine?
In contrast with other antihistamines typically used for allergy symptoms, doxylamine is a first-generation antihistamine commonly used as a short-term treatment for insomnia. However, it can also be used for allergy symptoms such as nasal congestion, sneezing, runny nose, and itchy nose, as well as nausea and vomiting in pregnancy (when combined with pyridoxine or vitamin B6). For adults or children ages 12 and older, it can be taken as 25-50 mg at bedtime as needed for insomnia.
How can doxylamine help alleviate certain long COVID symptoms?
Sleep-related disturbances are common after COVID and may be present in up to 52% of long COVID patients.1 Insomnia can also contribute to downstream effects such as metabolic and cardiovascular diseases, immune responses, and increased depression and anxiety. While non-pharmacological measures for treating insomnia are preferred, such as maintaining good sleep habits, maximizing exposure to natural daylight, especially in the morning, and following a night routine, pharmacological measures such as doxylamine can improve sleep.
Doxylamine can also be an active ingredient in Nyquil, along with dextromethorphan and acetaminophen (Tylenol). Nyquil helps reduce cough, nasal congestion, a runny nose, and insomnia, but it should not be solely taken to fall asleep. When taken in excess, it can also cause more serious side effects, such as dizziness, dry mouth, headaches, and the potential for liver damage if taken with other acetaminophen-containing products.
What evidence supports doxylamine’s use for long COVID?
There is currently a lack of studies assessing the use of doxylamine for long COVID. Prescription medications used to treat insomnia include benzodiazepines, which are not preferred for long-term use and have a risk of abuse and dependence when used chronically. Thus, doxylamine may be a safer alternative available over-the-counter that can be used to treat short-term insomnia in long COVID patients.
What are some things to watch out for with doxylamine?
Doxylamine should not be taken longer than two consecutive weeks, as it can become less effective. Patients can also build up a tolerance to the medication, so it should not be taken regularly.2
Due to its sedative effects, doxylamine should not be taken during the day before driving or operating heavy machinery. It should not be taken with alcohol or a drug class called monoamine oxidase inhibitors (MAOIs) and should be used with caution when taking other drugs that depress the central nervous system (CNS).
Doxylamine can also cause constipation, urinary retention, and blurred vision, especially when taken with certain other medications. If you are taking this medication more frequently, you should let your doctor know, as it can contribute to the side effects of other medications. Doxylamine is meant as a short-term treatment for insomnia and should not be taken chronically, particularly in older adults. It should also be used with caution in patients with narrow-angle glaucoma, urinary obstruction or gastrointestinal obstruction, and peptic ulcers.
References:
2) Pacheco D and Rehman Anis. Does Nyquil make you sleepy? Sleep Foundation. May 4, 2023. Accessed November 13, 2023. https://www.sleepfoundation.org/sleep-aids/does-nyquil-make-you-sleepy#:~:text=fully%20worn%20off.-,Should%20You%20Take%20Nyquil%20for%20Sleep%3F,for%20more%20than%20two%20weeks.
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