Caffeine, lysine/arginine and Covid

[jyb]

I was reading about Lysine boosting strategies for Covid prevention and recovery. While doing I read a few studies recommending against caffeine, since it would go against this lysine boosting logic. One study below claims it promotes arginine in the brain. Since Lysine/Arginine/NO/Caffeine have been discussed extensively on this forum, some of you may have thoughts on this. Does the caffeine reduction argument makes sense to you? Both the study and the video linked below claim that patients get worse with caffeine during Covid recovery.

Lysine Therapy for SARS-CoV-2

(PDF) Lysine Therapy for SARS-CoV-2

PDF | On Sep 11, 2020, Christopher Kagan and others published Lysine Therapy for SARS-CoV-2 | Find, read and cite all the research you need on ResearchGate

www.researchgate.net

Effect of caffeine on metabolism of L-arginine in the brain

Effect of caffeine on metabolism of L-arginine in the brain - PubMed

Methylxanthines are widely consumed because of their stimulating effect primarily on the central nervous system. Their diuretic and respiratory stimulant action is used in clinical medicine. L-Arginine metabolism in the brain is very important for normal brain function. In addition to brain...

pubmed.ncbi.nlm.nih.gov

An older thread where one of the authors of the study discussed Lysine boosting & Coffee reduction strategies for Covid.

Covid-19, neurological issues, and Coffee: Need Help

Hey everyone, Just recovering from Covid-19 but dealing with some neurological effects. I got weakness in my muscles and twitches, along with tinnitus, and generally still experience some problems here and there. What is weird is that I noticed my anxiety is through the roof lately, I get...

raypeatforum.com

 

[Tim Lundeen]

We've used lysine and it seems to be very effective as an anti-viral. What they say about caffeine also seems to be true, that it makes it hard to clear a viral infection.

 

[ddjd]

I was reading about Lysine boosting strategies for Covid prevention and recovery. While doing I read a few studies recommending against caffeine, since it would go against this lysine boosting logic. One study below claims it promotes arginine in the brain. Since Lysine/Arginine/NO/Caffeine have been discussed extensively on this forum, some of you may have thoughts on this. Does the caffeine reduction argument makes sense to you? Both the study and the video linked below claim that patients get worse with caffeine during Covid recovery.

Lysine Therapy for SARS-CoV-2

(PDF) Lysine Therapy for SARS-CoV-2

PDF | On Sep 11, 2020, Christopher Kagan and others published Lysine Therapy for SARS-CoV-2 | Find, read and cite all the research you need on ResearchGate

www.researchgate.net

Effect of caffeine on metabolism of L-arginine in the brain

Effect of caffeine on metabolism of L-arginine in the brain - PubMed

Methylxanthines are widely consumed because of their stimulating effect primarily on the central nervous system. Their diuretic and respiratory stimulant action is used in clinical medicine. L-Arginine metabolism in the brain is very important for normal brain function. In addition to brain...

pubmed.ncbi.nlm.nih.gov

An older thread where one of the authors of the study discussed Lysine boosting & Coffee reduction strategies for Covid.

Covid-19, neurological issues, and Coffee: Need Help

Hey everyone, Just recovering from Covid-19 but dealing with some neurological effects. I got weakness in my muscles and twitches, along with tinnitus, and generally still experience some problems here and there. What is weird is that I noticed my anxiety is through the roof lately, I get...

raypeatforum.com

Doesn't lysine directly oppose arginine?

 

[jyb]

We've used lysine and it seems to be very effective as an anti-viral. What they say about caffeine also seems to be true, that it makes it hard to clear a viral infection.

Yes that's why I created this thread. Coffee seems to be generally brain protective according to the study above (decreased peroxidation) and a lot of other studies cited on this forum. I therefore find it counter-intuitive the suggestions in links above that coffee is not good for covid. Since the evidence provided is weak (anecdotical level study) and the claim is counter-intuitive, this warrants more discussion.

 

[Tim Lundeen]

Coffee seems to be generally brain protective according to the study above (decreased peroxidation) and a lot of other studies cited on this forum. I therefore find it counter-intuitive the suggestions in links above that coffee is not good for covid. Since the evidence provided is weak (anecdotical level study) and the claim is counter-intuitive, this warrants more discussion.

The study linked above shows that caffeine makes more arginine available, which would enhance viral replication: Effect of caffeine on metabolism of L-arginine in the brain - PubMed

The lysine protocol authors cite their actual experience, which is that people drinking coffee have a much harder time clearing covid, or can't clear it at all.

So it looks like caffeine is neuroprotective, but that its benefits are swamped by active viral replication.

 

[Amazoniac]

The one and only, jyb!

On arginine availability and infections, the issue is more complicated than that. Below, they discuss briefly the innumological aspects of nitric oxide (sec. 3) and arginine (sec. 4):
- l-Arginine and COVID-19: An Update

- L-Arginine saves the day

The coronary virus inflammation can disturb the gut, which may lead to temporary coffee intolerance until normalization. Purified caffeine is safer and likely protective. If it diverts arginine towards nitric oxide, rather than substrate depletion stunts, perhaps the focus should be on enzymatic and non-enzymatic means of Remote Network Server (RNS) neutralization and anti-inflammation.

 

[Tim Lundeen]

It provides rigorous evidence that 3.2 grams per day of the amino acid L-arginine dramatically hastens the improvement in respiratory function in patients that already have confirmed pneumonia and are already suffering from hypoxemic respiratory distress. It may turn out to be lifesaving. -- The One Amino Acid That Could Cure COVID

This is a different use case for arginine -- after hypoxemic respiratory distress, supplemental arginine helps improve blood flow.

The lysine protocol we are discussing is for early treatment, to suppress viral replication, so you get minimal spike and no risk of severe illness.

These pieces of evidence seem to go against the recently proposed strategy of l-Arginine depletion in COVID-19, based on the assumption that some steps in the viral lifecycle of SARS-CoV-2 could depend on l-Arginine residues (for instance, the nucleocapsid protein has a 6.9% l-Arginine content) [75]. -- l-Arginine and COVID-19: An Update

The lysine protocol is not about depleting arginine, it is about having a high ratio of lysine to arginine. (Good paper, thanks!)

 

[jyb]

The study linked above shows that caffeine makes more arginine available, which would enhance viral replication: Effect of caffeine on metabolism of L-arginine in the brain - PubMed

The lysine protocol authors cite their actual experience, which is that people drinking coffee have a much harder time clearing covid, or can't clear it at all.

So it looks like caffeine is neuroprotective, but that its benefits are swamped by active viral replication.

That's a good summary.

I wish it were possible to take lysine long term, preventively. I feel off when taking 1-3g/daily lysine after a few days - side effects start to develop and it's clear I should only be taking it for a few days max. For a Covid protocol this is still useful: take lysine at first sign of suspicious symptoms.

 

[Tim Lundeen]

I wish it were possible to take lysine long term, preventively. I feel off when taking 1-3g/daily lysine after a few days - side effects start to develop and it's clear I should only be taking it for a few days max. For a Covid protocol this is still useful: take lysine at first sign of suspicious symptoms.

If you look at your diet ratio of lysine:arignine, you might not need much if any lysine (I use cronometer.org). You might only need 250mg with breakfast, for example. Milk and dairy are high lysine to arginine, and include lactoferrin, which is also protective. I think the goal is to maintain positive lysine:arginine balance throughout the day, stop or minimize caffeine if feeling sick.

 

[Amazoniac]

This is a different use case for arginine -- after hypoxemic respiratory distress, supplemental arginine helps improve blood flow.

The lysine protocol we are discussing is for early treatment, to suppress viral replication, so you get minimal spike and no risk of severe illness.


The lysine protocol is not about depleting arginine, it is about having a high ratio of lysine to arginine. (Good paper, thanks!)

It's relevant, nitric oxide synthase is 'induced' in infections for the antimicrobial properties. The synthesis should to be controlled and it has to be effective fast to not overwhelm the protective mechanisms against collateral damage, someone that's normally on the edge is likely prone to a net negative impact.

If it wasn't an attempt to antagonize arginine, decrease the availability or inhibit its utilization, they wouldn't be considering pounding up to 3 g of lysine while relativizing it with arginine. I don't expect much therapeutic effect from small adjustments in ratio, this should work when the situation isn't critical.

It could be argued that a lower level of arginine and higher arginase activity in those people was meant to prevent overproduction of nitric oxide, but they responded positively to supplementation, maybe arginine continues to be channelled to where it's desirable. So far, there's more support for the use of arginine than lysine. I understand the concern, but it's important to live life without convictions.

On hold:
- Arginine-dependent immune responses
- Arginine and Immunity
- Regulation of immune responses by L-arginine metabolism

 

[TheSir]

This is a timely thread, I just began doing the arginine depletion/lysine protocol yesterday on my third symptomatic day of COVID, and as of now my symptoms are at least 50% improved (within 30 hours since first dose), having had only worsened up until today. Fever is down to 37.7C/99.86F from 38.6C/101.48F. Muscle aches, pulse and dizziness have improved too. Lysine really is quite miraculous. It was interesting to discover that the most pro-lysine diet is basically the Peatarian diet of dairy and fruits.

I feel off when taking 1-3g/daily lysine after a few days - side effects start to develop and it's clear I should only be taking it for a few days max.

What kind of side effects?

 

[Amazoniac]

In the arginine trial, victims were coerced to take extra 1.66 g twice a day. It's an amount that some of you can be obtaining from collagen supplementation without realizing.

Spoiler

We can overlook its occurrence and pretend that it's a glycine product to minimize remorse.

 

[cs3000]

Combining L-Arginine with vitamin C improves long-COVID symptoms: The LINCOLN Survey

1390 patient study

1 month of 1.66g x2 L-Arginine + 500mg Vit C daily showed massively improved scores of weakness, shortness of breath, chest tightness, gastrointestinal disorders, headache, loss of smell, concentration, sleepiness compared to placebo

So great to take at least post infection


But how about in early phase of infection?

this mentions T-Cell proliferation being suppressed in covid patients, and arginine restored the T Cells ability to proliferate SARS-CoV-2-Induced ARDS Associates with MDSC Expansion, Lymphocyte Dysfunction, and Arginine Shortage - Journal of Clinical Immunology

Our results showed a prolonged decrease in plasma arginine levels along with enhanced arginase activity among COVID patients, particularly in the most severe forms. arginase activity could negatively have a negative impact on T cell functions, and T cell proliferation is in particular dependent on arginine supply

We found that COVID-19 was significantly associated with lymphopenia at admission, mostly affecting CD8 EM cells, and that T cell defects were correlated with M-MDSC expansion and decreased arginine level. . CD8 T cells are essential for controlling the spread of the virus and for limiting pulmonary damage and mortality, by eliminating infected epithelial cells, thus decreasing virus replication

To summarize, COVID-19 is responsible for MDSC expansion and T cell dysfunction, mainly CD8 T cells, through arginine depletion. This dysfunction is sustained in ARDS patients, the most severe form of COVID-19. Restoring arginine availability could be of value to restore lymphocyte function and prevent patients from acquiring nosocomial infections during their ICU stay.


Altered functions of natural killer cells in response to L-Arginine availability - PubMed L-Arg deficiency induces T-cell dysfunction. depleting arginine results in less Natural Killer cell cytotoxicity & proliferation [doesn't sound like a good approach]

https://www.europeanreview.org/wp/wp-content/uploads/1090-1094.pdf lymphocyte counts went up in these 2 groups who had arginine as part of intervention

Arginase activity is upregulated in COVID‐19 patients in a disease‐dependent fashion, favoring the production of ornithine and its metabolites from arginine over the synthesis of NO.
This rewiring of arginine metabolism in COVID‐19 promotes immune and endothelial cell dysfunction, vascular smooth muscle cell proliferation and migration, inflammation, vasoconstriction, thrombosis, and arterial thickening, fibrosis, and stiffening, which can lead to vascular occlusion, muti‐organ failure, and death. Strategies that restore the plasma concentration of arginine, inhibit arginase activity, and/or enhance the bioavailability and potency of NO represent promising therapeutic approaches that may preserve immune function and prevent the development of severe vascular
disease in patients with COVID‐19.



the 3.2g arginine is probably working by enhancing immunity

Antiviral Activity of L-Arginine and Extended-release Vitamin C

The immunological actions of arginine were highlighted inthe 1980’s by Dr Barbul, surgeon from Baltimore, while trying to improve wound healing and recovery after surgery using a substance with no serious risks or side effects. His team has conducted experiments in rats on wound healing with arginine treatment and showed arginine’s effects on the thymus: increases its weight in the healthy animal; minimizes the involution of the thymus linked to the wound healing process; significant increase in lymphocyte content of thymus, especially the total number of lymphocyte and lymphoid blastogenesis in response to mitogens.

A 1990 study (3) with 36 healthy volunteers – has shown the effect of arginine supplementation on wound healing and T lymphocyte function. 3 groups of 12 patients each: administration for 2 weeks with 30 g arginine HCl (24,8 g free arginine); 30 g arginine aspartate (17 g L-arginine); and placebo. It involved measuring mitogenesis in peripheral lymphocytes in response to phytohemaglutinin and concanavalin A initially, and after 1 and 2 weeks. Arginine has stimulated lymphocyte mitogenesis in a dose-dependent manner, confirming its effect on healing and improving immune response.

Should Immunonutrition Become Routine in Critically Ill Patients?

Context Several nutrients have been shown to influence immunologic and inflammatory responses in humans. Whether these effects translate into an improvement in clinical outcomes in critically ill patients remains unclear.Objective To examine the relationship between enteral nutrition supplemented...

jamanetwork.com

Twenty-two randomized trials with a total of 2419 patients compared the use of immunonutrition with standard enteral nutrition in surgical and critically ill patients.
We found that studies using commercial formulas with high arginine content were associated with a significant reduction in infectious complications and a trend toward a lower mortality rate compared with other immune-enhancing diets. The rate of infectious complications was significantly lower in patients receiving formulas with high arginine content. In addition, the subgroup of studies evaluating formulas with high arginine content was associated with significantly shorter length of hospital stay

L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity

Metabolomic and proteomic profiling unveil intracellular L-arginine as a crucial regulator of metabolic fitness, survival capacity, and anti-tumor activity of central memory T cells.

www.cell.com

^ mice given double daily intake of arginine showed 3x more CD44hi CD4+ TCR transgenic T cells by 15 days. promoted T cell survival.
Remarkably, when adoptively transferred into wild-type mice bearing B16 melanoma tumors expressing the OVA antigen, L-arginine-treated OT-I T cells mounted a superior anti-tumor response, as measured by the reduction of tumor size and by the increased survival of mice.
Collectively, these data demonstrate that elevated L-arginine levels increased the survival capacity of CD8+ T cells and their anti-tumor activity in vivo.

We found that activated T cells heavily consume L-arginine and rapidly convert it into downstream metabolites, which lead to a marked decrease in intracellular levels after activation

We have shown that moderately reduced uptake of L-arginine has a negative impact on T cell survival without affecting proliferation. However, when L-arginine was completely depleted from the culture medium, T cells no longer proliferated.
Lack of L-arginine in T cells can be sensed by GCN2, leading to an amino acid starvation response (Rodriguez et al., 2007) and by SLC38A9, leading to inhibition of mTOR (Rebsamen et al., 2015, Wang et al., 2015), which in turn inhibits T cell growth and proliferation.


L-arginine improves mitochondrial function and reduces apoptosis of bronchial epithelial cells after injury induced by allergic airway inflammation (
Mabalirajan et al., 2010)

Stimulation of lymphocyte natural cytotoxicity by L-arginine - PubMed
In vitro L-arginine enhanced natural-killer (NK) and lymphokine-activated-killer (LAK) cell activity; this cytotoxicity was mediated by CD56+ cells. In vivo arginine supplements (30 g/day for 3 days) increased the number of circulating CD56+ cells by a median of 32% in eight volunteers (p less than 0.01); this increase was associated with a mean rise of 91% in NK cell activity (p = 0.003) and of 58% in LAK cell activity (p = 0.001) in thirteen volunteers. These findings have potentially important implications for the modulation of natural cytotoxicity in a wide range of disease states.


Indeed, arginine depletion has been proposed as a potential treatment for COVID‐19 [146,147]. However, given that circulating levels of arginine are already low in COVID‐19, a further reduction may potentially exacerbate the illness. Moreover, interim results from a randomized clinical trial found that the addition of arginine to standard therapy in patients hospitalized with COVID‐19 reduced respiratory support and in‐hospital stay relative to placebo‐treated controls, supporting
the use of arginine in the treatment of COVID‐19 [148]

^ We present here the results of the initial interim analysis on the first 101 patients. No treatment-emergent serious adverse events were attributable to L-arginine. At 10-day evaluation, 71.1% of patients in the L-arginine arm and 44.4% in the placebo arm (p < 0.01) had the respiratory support reduced; however, a significant difference was not detected 20 days after randomization.
Strikingly, patients treated with L-arginine exhibited a significantly reduced in-hospital stay vs placebo, with a median (interquartile range 25th,75th percentile) of 46 days (45,46) in the placebo group vs 25 days (21,26) in the L-arginine group (p < 0.0001); these findings were also confirmed after adjusting for potential confounders including age, duration of symptoms, comorbidities, D-dimer, as well as antiviral and anticoagulant treatments.


It is thus very likely that arginine – with pKa 9.0 and 12,5-(and possibly other basic amino-acids - lysine, histidine, ornithine) defeats some viral activities by simply raising the pH of the membranes above a threshold pH where fusion of viral particles with the cellular membrane stops, thus limiting and preventing viral replication. The interplay between arginine and vitamin C is yet to be elucidated, but it is probable that vitamin C helps destroy the viral nucleic acids(both DNA and RNA) while they are freely circulating outside the cells and while their fusion with the cell membrane is being hindered by arginine's actions

while the separate roles of arginine and vitamin C in improving immunity are well studied, there is not much information on the concomitant action of the two substances, which clearly act in synergistic ways and greatly improve the functioning of the immune system against viral infections.
We are making efforts to obtain research support in this direction(12). This is one of the rare situations where clinical success precedes laboratory research, and the promise of an efficacious and very affordable antiviral treatment which acts in ways yet to be detailed is too great to go unheeded

 

[FrostedShores]

This is a timely thread, I just began doing the arginine depletion/lysine protocol yesterday on my third symptomatic day of COVID, and as of now my symptoms are at least 50% improved (within 30 hours since first dose), having had only worsened up until today. Fever is down to 37.7C/99.86F from 38.6C/101.48F. Muscle aches, pulse and dizziness have improved too. Lysine really is quite miraculous. It was interesting to discover that the most pro-lysine diet is basically the Peatarian diet of dairy and fruits.


What kind of side effects?

I, too, am interested in the side effects. I've been taking lysine consistently for some time now and have only experienced benefits.

 

[TheSir]

@cs3000

Interesting, so instead of min-maxing arginine/lysine it might be helpful to get ample amounts of both for covid.

 

[cs3000]

@cs3000

Interesting, so instead of min-maxing arginine/lysine it might be helpful to get ample amounts of both for covid.

yep seems so, or out of the 2 arginine as the more important one as amazoniac mentioned. that 1000+ person study is nice. i have covid rn so gonna grab some, will take it at the same time as vit C as they could work synergistically

 

[TheSir]

yep seems so, or out of the 2 arginine as the more important one as amazoniac mentioned. that 1000+ person study is nice. i have covid rn so gonna grab some, will take it at the same time as vit C as they could work synergistically

Cool, keep us updated!

If not arginine, I wonder what it is about coffee that was causing the lysine therapy to fail in the covid study.

 

[toolhead]

Back when I was doing research on Covid treatments, I seem to remember arginine being recommended only during severe acute lung involvement due to its effect on capillary function, but NOT recommended during the early phase of the infection because it could “feed viral replication” or some such?

 

[cs3000]

Back when I was doing research on Covid treatments, I seem to remember arginine being recommended only during severe acute lung involvement due to its effect on capillary function, but NOT recommended during the early phase of the infection because it could “feed viral replication” or some such?

that put me off arginine at first but looking into it it was just speculation based on a covid protein being made of 6.9% arginine. is the body lowering arginine to prevent replication? or is the virus lowering arginine creating worse state of health? if 1st was the case it would be self-fixing as covid patients have lower arginine, as the arginine gets depleted by the illness the covid would diminish and patients would improve. but it doesn't work that way, one of the studies said particularly bad outcomes come with even worse arginine status -> as the arginine depletes patient immunity gets worse, T cells get rekt lung cells get more damaged and patient outcomes worsen

which is why that meta review of a bunch of studies showed protocols containing arginine lead to increased recovery from infections

studies show direct involvement of arginine on immunity, so not just the NO angle, improving T cells early is probably good. also does have beneficial effect on preventing lung cell damage from inflammation L-arginine reduces mitochondrial dysfunction and airway injury in murine allergic airway inflammation - PubMed so to me it looks key to correct the drop in arginine from the infection

Cool, keep us updated!

If not arginine, I wonder what it is about coffee that was causing the lysine therapy to fail in the covid study.

I wonder if that's as simple as the coffee drinkers just didn't tend to rest as much from the caffeine stimulation - causing worse outcomes? body should be basically immobilized for best healing so all resources go into growth & repair mode, sometimes even walking around with a viral infection causes acute worsening of symptoms in my experience or even playing video games that are too stimulating - like the body is telling you to chill. probably not gonna get much sleep or closed eyes rest in the day to enhance recovery with coffee

 

[cs3000]

Cool, keep us updated!

If not arginine, I wonder what it is about coffee that was causing the lysine therapy to fail in the covid study.

Update So initially I had a bad cough from it and voice went dodgy, like constantly non stop coughing & coughing up stuff. breathing affected a bit. and bone pain that started in my hips impacting sleep (luckily i had some melatonin which helped get a bit). which then went to my kidneys and eventually to my upper back where it stayed & got worse when breathing in / coughing

I wasn't resting enough while this was happening & i did start getting more rest around the same time i started the arginine. 2g+500mg or 1g of C, x2 a day. so it's hard to say if the arginine+C was the thing that helped. but i can say it didn't get worse as i only saw improvement from there

I've reduced the arginine to just 1g in the morning as maybe was giving an increase in anxiousness / worsening gut issues i have after a while. but hard to narrow it down to that with a bunch of stuff going on just the vibe i got. now i just have a slight cough and slightly runny nose left over