Rambling thoughts

my experience:

i took 2 Tbsp ground sumac mixed with warm water on February 11. i tried taking it with a straw first because that's what my colonoscopy prep had said would make that go down easier but because the sumac particles were so big they didn't want to remain suspended & trying to get them in the straw was difficult, which then made it harder to swallow without, yknow, noticing that you're slurping down sediment

what worked better was getting the powder wet, putting a big clump of it on my tongue, then swallowing it with water like a pill

within about half an hour of taking the sumac it was like my fatigue just faded around me where i stood. it dissolved to the background & when i thought "oh i want to do this" or "i should do that" suddenly i found myself just doing it. i had spent the past week at least bedridden except for the bathroom, & though i took the sumac on a better day, i'd been planning to return to bed with a snack after taking it.

instead, i made myself lunch, and i sat on the couch to eat it. all of this was without taking an edible that day; usually i've gotta take at least 25mg delta 8 + 25mg cbd to even consider sitting on the couch. also, it was storming.

from my write-up the day of: "everything felt very sharp & clear & lucid." i washed the dishes from my lunch. all of these activities were about 2 hours, & at that point i emphatically needed a nap. waking up felt like after taking a muscle relaxer & sleeping: my muscles were more relaxed, & my whole body felt like it'd gotten a bit of a break

i've taken sumac at least 8 times since then on at least 5 different days (this time by modifying this sumac tart recipe to include a lot of sumac powder in the crust, which has been much more enjoyable than the Glass O' Sediment lmao) & adjusting for factors like weather, the effect has been comparable every time:

i watched Inception on the couch with my husband, & understood when she explained things to me

i watched leverage on the couch all day when it was below freezing

i worked a bit on fanfics i've barely been able to touch in a year

i "meal prepped" measuring spices, gathering ingredients, & soaking beans to make beans & rice in the instant pot later that day. i literally can't remember the last time i was able to use my instant pot, after thinking about it i think it was when i made palak paneer last summer, but that was a one-off special occasion thing, i've used it maybe 3 other times since developing ME

i wrote this post

the science:

okay a lot of this shit was over my head before i developed ME so i'm gonna be summarizing at my level lol, look to @lakeeffectbitch for a higher-level analysis

but what i do know! (all images from "The malic acid inhibiting inflammation in ankylosing spondylitis by interfering M1 macrophage polarization" by Ji et al., January 2025)

sumac contains high levels of malic acid, which is found in certain fruits (apples, peaches, etc)

the drugs.com page classifies malic acid as an inactive ingredient, so there are no known drug interactions

mice with ankylosing spondylitis had lower levels of peripheral malic acid than control mice

ID: bar graph showing mice with AS had about 0.03 micromoles per milliliter of peripheral malic acid, compared to the control mice level of over 0.2 micromoles per milliliter. the difference is labeled significant via asterisks. end ID

mice with higher malic acid concentrations had lower ESR and CRP (inflammation markers)

ID: two graphs showing lines with a downward slope. the top graph, ESR versus malic acid concentration, is labeled: r=-0.6802, 95% confidence interval =-0.8843 – -0.2578, p=-0.0053. the graph shows ESR, an inflammation marker, decreasing as malic acid concentration increases. the bottom graph, CRP versus malic acid concentration, is labeled: r=-0.6068, 95% confidence interval =-0.8537 – -0.1371, p=-0.0165. the graph shows CRP, an inflammation marker, decreasing as malic acid concentration increases. end ID

mice treated with malic acid had lower levels of TNF-alpha than the mice with untreated ankylosing spondylitis. humira & similar biologics that treat autoimmune diseases are TNF-alpha blockers

ID: a bar graph of relative mRNA expression of TNF-alpha. M0, the control mice, has a relative expression of 1. M1, the mice with ankylosing spondylitis that did not receive treatment, has a relative expression of slightly less than 4.5. M1+MA, the mice with ankylosing spondylitis who received the malic acid treatment, has a relative expression slightly less than 3. this indicates that the mice treated with malic acid had lower expression of TNF-alpha than the untreated mice. asterisks between M0 and M1 and between M1 and M1+MA indicate significance. end ID

the mitochondrial function of M2 macrophages in mice treated with malic acid "was significantly enhanced"

analysis of the mice's spinal tissue blew my fucking socks off. trying not to jump to conclusions & i know journal articles are full of errors but that looks potentially disease-modifying.

ID: a 5x3 presentation of samples of mouse spinal tissue. the control mice, which are healthy, have thick, undamaged, glowing tissue. the mice with ankylosing spondylitis have thin, curved, cracked-looking tissue. the mice treated with celecoxib, a common prescription NSAID for arthritis, appear very similar to the untreated mice. the mice treated with 250mg/kg of malic acid per day have tissue in between the untreated and healthy appearances; the tissue is "glowing" like the healthy tissue but still narrower and curved, although less so than the untreated tissue. the mice treated with 500mg/kg of malic acid per day have tissue which looks even closer to the healthy appearance, with less curvature than the other treatment groups. end ID

since i started drafting this post i've started taking these malic acid supplements from Nature's Life – the full dose made me feel weird including some heartburn so i cut the capsules & take roughly 2/3 – 3/4 of it at a time (i drop the rest into a spare pill jar to make more doses from). it's been similarly effective for me

My background

First, a little information about me:

I'm currently a graduate student in a biomedical sciences PhD program (focusing on computational biology due to physical limitations making it difficult to work in the lab). I've had ME/CFS for about 8 years.

I've been on a stimulant for several years, which gives me enough energy to read/work for about 3-4 hours a day non-consecutively and do one or two physical activities (i.e. making dinner, going grocery shopping, etc.) per day without triggering PEM. Before the stimulant, I was mostly homebound and could occasionally make dinner or walk my dog around the block.

I don't consider myself an expert, but I have been working in ME/CFS and Long COVID research for a few years (with an LC publication currently being submitted to journals!). All this is to say: I'm not trying to be anyone's doctor, but I do have pretty good knowledge in the field.

What is malic acid and what does it do?

Malic acid is a form of the organic molecule malate. As @crippleprophet already mentioned, it's present in many fruits (it is primarily responsible for the sourness in white grapes, apples, cherries, etc.). Malic acid is just malate with 2 extra hydrogen atoms (malic acid on the left, malate on the right).

Malate is an intermediary metabolite in the tricarboxylic acid cycle (aka TCA cycle/citric acid cycle/Krebs cycle), which supplies ATP production in the mitochondria. To explain its significance, I need to explain a little bit of cell biology first:

ATP is the main source of cellular energy, used to power millions of reactions that keep you alive. Mitochondria are organelles in the cell with many functions, but the main one is ATP production (mitochondria are the powerhouse of the cell etc. etc.). They do this through the electron transport chain, which is a series of protein complexes lodged in the inner membrane of the mitochondria.

To simplify a complex process, the way mitochondria generate ATP is by hoarding electrons (bound to hydrogen atoms, H+) and then moving them across the membrane in a controlled way, so that the energy generated by that movement can be "captured" and stored within an ATP molecule (that's what is happening at ATP synthase all the way to the right).

In this diagram you'll notice that NADH becomes NAD+ at complex I, and FADH2 becomes FAD at complex II. NAD+ and FAD are basically storage molecules that hold onto H+ and release it when they come into contact with these protein complexes. NAD+ is called NADH when it's holding onto an extra H+, same for FAD/FADH2.

You'll also notice that there is a lipid membrane in this photo (the blue/yellow double layer). In order to hoard H+, mitochondria need to tightly regulate what can cross this membrane. Your cells actually have a pool of NAD(H)/FAD(H2) inside and outside of the mitochondria for the purpose of holding onto H+, but the two pools do not mix because NAD(H)/FAD(H2) cannot cross the membrane. So how does H+ make its way into the mitochondria? By two shuttles: the G3P shuttle and malate-aspartate shuttle.

I'll focus on the malate-aspartate shuttle, since it is primarily used by most tissues in the body. However, keep in mind that some organs (such as the brain and skeletal muscle) preferentially use the G3P shuttle to bring FADH2 to complex II because it is faster for short-term energy production even though it is less efficient.

The malate-aspartate shuttle is a way for H+ to hitch a ride on something that can pass through the membrane. Basically, oxaloacetate becomes malate when it takes H+ from NADH outside of the inner mitochondrial membrane (in the intermembrane space, in the diagram above).

Malate is transported across the inner membrane by the malate/alpha-ketoglutarate antiporter. Malate then loses its H+ and becomes oxaloacetate again, and that H+ binds to mitochondrial NAD to form NADH, which is then used in the electron transport chain at complex I. Malate is then eventually converted into another form (aspartate) which can cross the membrane the other way, and the cycle repeats.

The malate-aspartate shuttle is a smaller cycle that ties into the TCA cycle, which can generate malate and its precursors to replace anything that's degraded over time and produces a bunch of other things that are needed to maintain mitochondrial function.

In summary, malate is the shuttle that brings the main ingredient for cellular energy production into the mitochondria.

How is malate/malic acid relevant to ME/CFS?

There's plenty of evidence that mitochondrial function is much less efficient in ME/CFS (here's an overview written in pretty accessible language, for anyone who is interested). I started looking into malate specifically because it seemed to tie together a couple other pieces of evidence. The main pieces of evidence are:

reduced mitochondrial membrane potential, which might be explained by less H+ making it into the mitochondria.

Consistent findings of reduced sex steroid hormones (also in Long COVID), cortisol, and bile acids all of which need NAD(P)H (a modified form of NADH) to be present inside the mitochondria in order to be produced.

In addition, this mechanism would also explain some other semi-consistent findings in ME/CFS such as alcohol intolerance, circadian rhythm dysregulation, and as @crippleprophet has already pointed out, PEM (I won't go into all of those details here since the post is already getting long, but message me if you're interested!).

To put it all together, dysfunction somewhere in the malate-aspartate shuttle would likely lead to reduced mitochondrial ATP production, which would be strongly correlated with fatigue and reduced activity level. Other downstream effects of this dysfunction in certain immune cells may explain PEM.

My experiences with a malic acid supplement

Since all the evidence I listed above is indirect, I decided to use myself as a lab rat see if supplementing malic acid might have any noticeable effect. It turns out the effect was huge! I've already detailed my experiences with sumac in the reddit post linked in the original post above.

Adding the malic acid supplement to my regimen had a noticeable effect on my physical endurance and energy levels. I normally have to walk 15 minutes to the train once a week which would leave me exhausted and out of breath, and I'd be dealing with PEM once I got home. On the supplement I felt no pain, no shortness of breath, no PEM, and I felt like I could have walked for longer if needed. I also had noticeably more energy throughout the day to cook, clean, and meet up with friends.

I still experience brain fog if I try to use my brain for too long for reading/coding/problem solving, but I noticed that it fades away much faster once I allow myself to rest.

Adverse effects

I went down to half of the supplement due to some heartburn (which makes sense, since it's basically a capsule full of acid) as well as some weird brain-foggy effects.

I got the heartburn on the full dosage, as well as on the half dosage if I took it later in the day. As long as I take the half dosage with food and don't take it after 3-4 pm, I don't usually have any heartburn problems.

I normally experience brain fog after trying to read or problem solve for a few hours, but the malic acid seemed to induce some new, albeit mild, neurological effects. I had much more difficulty reading, I noticed that I would get my directions mixed up, my eyes felt more foggy, and I kept getting distracted when I was trying to focus. None of these effects were as severe as my normal brain fog, but they were definitely noticeable.

Additionally, on the full dosage I experienced the need to eat more often and got a headache/nausea if I didn't eat, but this mostly went away when I went down to 1/2 a pill.

Mitigating neurological side effects with CoQ10

I hypothesized that the neurological effects might be due to the fact that the brain prefers using the G3P shuttle over the malate-aspartate shuttle. By supplementing malate, I might be forcing those cells to shift towards using the malate-aspartate shuttle instead. I happened to have some old CoQ10, which accepts H2 from FADH2 as part of the G3P shuttle. I figured that increasing the amount of CoQ10 might increase G3P shuttle activity in the cells that prefer using it.

Since I started taking the CoQ10, the neurological side effects have been substantially reduced, and my capacity for physical activity increased even more. For the first time in years, I was able to walk for more than 2 miles (over an hour on my feet) and only felt a tiny bit tired and sore afterwards--exactly how you would expect for a person without ME/CFS who just isn't used to walking that far. Since then, I've been able to take long walks every single day and haven't experienced PEM even once.

My current regimen

I've been taking around 1/2-2/3 of the Nature's life malic acid supplement with breakfast, and then once again around 1-2 pm with lunch.

I initially took 2 tablets of mito-Q (a more expensive, better absorbed form of coQ10) alongside half the malic acid supplement, and increased to 3 if I needed to focus more for school. I recently switched to a generic "ultra Coq10" 100 mg ubiquinone supplement from CVS, and I take 3-4 first thing in the morning followed by 1-2 in the afternoon with the malic acid.

How I tried to control for placebo effect for the malic acid supplement

To test for potential placebo effect, I had a family member randomize the malic acid supplement with another supplement I was taking (serrapeptase) which happens to look very similar. I put the two supplements in two different empty pill bottles and wrote on a piece of paper which was which (without showing my family member). I then gave the two bottles to my family member and asked them to randomly select a bottle and hand me the supplements directly so I couldn't see the bottle (and I did my best not to look too closely at the supplement they gave me). I tried the two supplements on different days, trying to be consistent about time of day and ingesting them with food.

I've been taking the serrapeptase for years and it has a slight anti-inflammatory effect that helps if I'm experiencing PEM, but nothing close to the effect of the malic acid. There was a noticeable boost in energy within 15 minutes of taking the supplement that turned out to be malic acid vs. the serrapeptase "placebo". Obviously there might still be some placebo effects due to imperfect procedure, but if anyone is interesting in taking extra steps to confirm this isn't placebo effect, this might be a good option!

Next steps

Unfortunately, the evidence from the literature doesn't give answers for where exactly there issue might be in the malate-aspartate shuttle. I've been exploring some avenues for trying to narrow this down via a formal study, but unfortunately that will take a lot of time and funding to organize. However, I've been in contact with some other researchers who might be able to provide proof of reduced mitochondrial NAD(P)H with existing samples, which would be indirect proof of my hypothesis and could support a grant proposal for a more comprehensive experiment in the future.

In the mean time, I'm just personally interested in getting this information to more people with ME/CFS. If you decide to try out the sumac or malic acid supplement, I'd love to hear how it affects you, whether that is positive, negative or no effect (feel free to message me or reply to the post!). Please boost the post so it can potentially reach more people with ME/CFS.