Caffeine against persistent fatigue in long-COVID: a randomized clinical trial, 2025, Cardoso

https://www.tandfonline.com/doi/abs/10.1080/21641846.2025.2483112

Research Article
Caffeine against persistent fatigue in long-COVID: a randomized clinical trial
Liziane Rosa Cardoso
Maria Cristine Campos
Tatyana Nery
Ana Cristina de Bem Alves
Ana Elisa Speck
Naiara Souza dos Santos
Izabel Feltrin Fabroa
Josiane Gress
Rodrigo Oliveira
Vanessa Damin
Maria Paula Matos de Almeida
&
Aderbal Silva Aguiar Junior
Received 19 Nov 2024, Accepted 19 Mar 2025, Published online: 03 Apr 2025



ABSTRACT

Background & Objective:
Long COVID causes persistent symptoms, such as fatigue and cognitive impairment, which caffeine may help mitigate. This study aimed to evaluate the acute effects of caffeine on these symptoms.

Methods:
This randomized, double-blind, placebo-controlled trial with a within-subjects design was conducted between October 2021 and January 2023 in Araranguá, Brazil. Twenty-eight participants (13 caffeine, 15 placebo) received a single administration of either caffeine (3 mg/kg) or placebo capsules. Participants met the Myalgic Encephalomyelitis: International Consensus Criteria, with fatigue assessed using the Chalder Fatigue Questionnaire. The cohort was predominantly of females (64.3%), with a mean age of 44.6 ± 7.7 years. Most were sedentary (82.1%) with moderate baseline fatigue. Exclusion criteria included significant cardiovascular or respiratory diseases. Primary outcomes included the Incremental Shuttle Walk Test, Borg Scale, Short Physical Performance Battery, Stroop Test, Montreal Cognitive Assessment, and biochemical markers. Data are presented as mean (standard deviation) or median [interquartile range, IQR], with statistical analyses performed using independent t-tests, Mann–Whitney U tests, and effect size calculations according to data distribution. Statistical significance was set at p < 0.05.

Results:
Caffeine increased walking distance (476 [70.1] m vs. 284.4 [83] m; p < 0.05) and improved executive function (Stroop test: 47.3 [IQR 43.2–54.2] vs. 68.2 [IQR 60.9–72.2]; p < 0.05). Perceived exertion decreased pre- and post-exercise (p < 0.05).

Conclusion:
Caffeine alleviates fatigue and cognitive dysfunction in Long COVID, supporting its potential role in rehabilitation.

 

I did 3 years without caffeine. It didn’t help. I now take 100mg when I wake up and it’s really helped me. Just my experience but I don’t think it needs to be vilified if it doesn’t cause you harm.

 

When I had a holiday let I would have a can of Coca Cola (other brands of caffeinated fizzy drinks are available) to get me through the change over days. This would get me through but generally I still had PEM the next day.

I don’t normally drink any tea or coffee, though pre ME I would occasionally have one if I felt the need for a stimulant. However some years ago at a point when my ME was deteriorating, with a predictable six hour delay drinking any caffeinated drink would trigger a migraine, though high sugar fizzy drinks without caffeine do not. Though more recently these now trigger IBS type symptoms.

I am assuming I developed an intolerance to caffeine though can’t be certain it is caffeine alone triggering the migraines. However the easiest thing to do, as I never developed a dependance on tea or coffee, neither of which I like, is to avoid caffeine completely and more recently to combat weight gain I have also cut out all sugary drinks too.

I would be wary of any use of stimulants for people at risk of PEM and more generally caffeine intolerance is thought to be more common in ME/CFS than in the general population.

 

Unfortunately the full article is behind a paywall, but the abstract makes no mention of PEM and we can’t tell from the abstract if participants were regular coffee, tea, etc drinkers or not.

Did participants have advanced warning that this research was investigating caffeine, such that anyone with a known or suspected caffeine intolerance might choose not to participate? I certainly would now go no where near such a study.

 

Researchers missed a trick not including healthy controls. If caffeine also improves the walk distance, perceived fatigue and so on of control participants, then they've found a treatment that can support healthy people being rehabilitated from, um, healthiness.

 

The got one dose of caffeine, and presumably tested them before and shortly after.

An average Brazilian woman weighs ~62 kg according to google, so they got ~190 mg of caffeine. The amount of caffeine in a normal cup varies based on type, roast, grind and brew method, but 100 mg is often used as an average.

This means that they got ~2 cups of coffee in a pill format.

 

I agree. A stimulant made people do more. Nothing new here.

 

I quit coffee once and the withdrawal gave me full body cramps and reduced my fitness. Took me a few weeks to get back to my baseline (which was good, I was in a decent remission at the time). Never again!

I corresponded with Chris Armstrong about it at one point and he was interested that caffeine helped me because I had also mentioned activity with pauses was much more manageable than sustained efforts.

"Haven't yet been able to get a study going on this because of funding but I've noted the link of sustained vs unsustained and caffeine in many ME/CFS patients. Muscles use AMPK for activity but once they need to do sustained exercise they switch to CaMK. CaMK is also stimulated by caffeine. So you see, this may be something of note in your condition. The likely link may be that you have a decrease in calcium channels, something that's often been linked to ME/CFS before."

Not sure if that hypothesis is still live.

 

I believe I’ve seen calcium channels mentioned in relation to LDN:
https://www.s4me.info/threads/inves...19-sasso-marshall-gradisnik-et-al-2024.38025/

A search for trpm3 on s4me: https://www.s4me.info/search/38768930/?q=Trpm3&o=date

 

I loooove coffee, I used to drink 1-2 cups per day, but since becoming severe, I am histamine intolerant and coffee causes a big skin reaction. I also get jittery in an unpleasant way from even half a cup.

This study is missleading. People like me who are severe don’t tolerate caffeine and feel sick from it. If we had been included in this kind of study, the results would be much different.

 

So stimulants make you able to do more and decrease fatigue, I thought we knew that a long time ago. We don’t prescribe them though for obvious reasons.

This study blantantly forgets about PEM, and is only focusing on fatigue which is problematic.

Like if I take a coffee, obviously my fatigue will go down and I’ll be able to do more (though long term this could worsen my codnition), but also my tatychardia, bowel problems, jitteriness/spasms, will get worse.

 

As rightly pointed out, any stimulant will erm, stimulate you.
Interested to see if they repeat the study but with amphetamines

 

I don't think I get any ill effects from coffee/caffeine.

I also didn't get any effects, other than slight irritability, from the three times I tried cocaine, although my friends did.

I suspect that I have a kind of immunity to coffee and cocaine, but I love the taste of coffee.

 

This study does basically mirror the improvements I see on vyvanse (dextroamphetamine).

I was surprised when I joined ME/CFS communities that the majority of others didn't tolerate them well, but the explanations make sense. I may have a slightly different physiology with pre-existing ADHD or something else.

I had quite the learning curve trying to figure out my body's cues for when I should stop moving so as not to hurt myself later on. I agree with others that they should have accounted for PEM!

 

Coffee exhausts my energy both cognitive and physical. I didn't tolerate coffee before I got ME. I can only tolerate two cups a week and when I stop for 2-3 weeks I have more energy to go out for walks.