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Treatment of Post COVID-19 Syndrome

After recovering from COVID-19 infection, I ended up with post COVID-19 syndrome myself which rendered me essentially bed-ridden. I have read recent research papers on the topic and came up with an effective treatment. Here are my findings.



The COVID-19 is a nasty little bug that has the capacity to affect many organs. Unfortunately, one of those organs is the brain itself. COVID-19 has the ability to cross the blood-brain-barrier (BBB) [1] as well as through a direct route of entry into the CNS via the olfactory & vagal nerves [2], which leads to CNS invasion and anosmia.



When it reaches the brain, it triggers a multitude of symptoms such as depression, anxiety, confusion [3], and, rarely, even acute psychosis [4].

COVID-19 was found to trigger an intense neuroinflammatory response in the CNS and a cytokine storm in patients, as COVID-19 can activate mast cells, neurons, glial cells, and endothelial cells. COVID-19 infection can cause psychological stress and neuroinflammation [8]. Although rare, severe neuroinflammatory conditions such as myelitis, ADEM, AHNE and CLOCC can be associated with COVID-19 infection [5]

The microglia is right at the center of this neuroinflammatory response. Allow me refresh your knowledge on the microglia:

The microglia are the representative of immune cells in the relatively immune-privileged central nervous system (CNS) and account for 10% of the total glial cell population in the brain. The microglia has two phenotypes it can exist in: the resting state and the activated or reactive state.

Due to COVID-19 entry into the CNS, the microglia switch to its reactive state which is detrimental and pro-inflammatory. This leads to elevation of cytokines called a 'cytokine storm' and excessive release of glutamate within the CNS [6, 7].



After patients have recovered from COVID-19 infection, the neuroinflammatory state and immune dysregulation can persist leading to post COVID-19 syndrome in some patients [9, 10].

The consequences of this are a plethora of symptoms such as chronic fatigue syndrome (CFS), brain fog, impaired cognitive functions, anhedonia, and depression [11 ,12].

Depending on the severity of post-COVID-19 syndrome, it can leave a person either mildly affected, bed-ridden, or anything in between.


Treatment Rationale:

It's a well-known medical fact that, rarely, the microglia can remain in its M1 detrimental 'activated' phenotype long after the trigger/virus is gone [13, 14]. As long as the microglia remain activated, they lead to consistent elevation of cytokine levels as well as persistent immune dysregulation within the CNS, abnormalities with markers which can be detected in the cerebrospinal fluid (CSF).

I've explained, with references, in a previous article how certain cytokines, which are elevated, act as potent dopamine antagonists, and how they raise glutamate even more, leading to a state of chronic fatigue, cognitive dysfunction, anhedonia, depression and general malaise.

So, in order to fix the root of the problem, we must switch off the microglia and revert it back to its M2 phenotype which is neuroprotective, neurotrophic and anti-inflammatory.

- Low Dose Naltrexone (LDN):

Naltrexone acts as a Toll-like receptor (TLR) 2/4 antagonist. These receptors are present on the microglia and they can limit its detrimental state when inhibited. For me, Naltrexone wasn't enough for post-COVID-19 syndrome.

I personally believe that Naltrexone failed to improve this syndrome for two reasons: one is because Naltrexone doesn't completely inhibit the microglia (too weak) and two because there is neurotoxicity and loss of neurotrophy (i.e. loss of dendritic spines or synapses).

This leads us to neurotrophic drugs. This class of drugs act on TrkB receptors either directly on through elevating brain-derived neurotrophic factor (BDNF), nerve growth factors (NGFs), which is a TrkA agonist, and ciliary neurotrophic factor (CNTF).

Neurotrophy improves neuronal maturation, neurogenesis, restoration of dendritic spines, and synaptogenesis. Furthermore, BDNF inhibits the microglia via the TrkB-Erk-CREB pathway [15]. Two birds, one stone type of deal.


Treatment Options:

Now that we know what to target, let's review some drugs on the market that are potently neurotrophic.

- Semax: An analog of ACTH(4-10) and a nootropic which increases BDNF and upregulates its TrkB receptors. It's one of the best since not many drugs upregulate TrkB receptors [16].

This neuropeptide also increases dopaminergic and serotonergic neurotransmission without affect SERT [17] and has a neuroprotective effect [18] while activating mGluR [19].

Since it's a peptide, it has to be administered either through intramuscular/intravenous injection or through intranasal spray.

- Cerebrolysin: It's a neurotrophic peptidergic drug used in dementia, stroke, TBI, and cognitive impairment. It modulates the neurotrophic factor (NTF) and sonic hedgehog (Shh) signaling pathway [20] while reducing the production of free radicals.

Cerebrolysin reduces microglial activation in vivo [21].

The only disadvantage of this drug is that it needs to be administered through IM/IV injection.

- NSI-189: This small molecule, which is orally active unlike Semax/Cerebrolysin, increases BDNF [22]. It has significant neuroprotective and neurorestorative effects through a significant decrease in the numbers of activated microglia as well as a significant increase in neurogenesis [23].

- Polygala Tenuifolia: An orally active herbal extract. It has suppressive effect on the NF-κB and toll-like receptor signaling pathways, leading to microglial deactivation [24]. Furthermore, it increases BDNF level while upregulating its TrkB receptor [25]. Upregulation of TrkB receptors is a rare effect only shared with Semax.

It is also [26]:

- 5HT2A receptor antagonist.

- α₂-adrenoceptor agonist.

- β-adrenoceptor agonist.

- Dopamine D1 and D2 receptor agonist.

While this means it has antidepressant effect, it also significantly modulates the prefrontal cortex (PFC), leading to significant nootropic and pro-cognitive effect [27].



Personally, what worked for me is a regimen of high dose Cerebrolysin + Polygala Tenuifolia. This completely ameliorated all symptoms of post-COVID-19 syndrome. However, I took it for only a month due to financial reasons and this was not enough to cure the condition. As soon as I dropped the regimen, the symptoms came back in full force.

I believe a regimen of the aforementioned drugs can cure this syndrome if taken for a prolonged period of time. However, keep in mind that COVID-19 alters the microbiome [28], so you need to address this as well with a competent physician who specializes in microbiome dysbiosis.


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