Cystagon is the brand name of the chemical cysteamine bitartrate, which has been used to treat cystinosis (a rare genetic disease leading to kidney damage in children) successfully for decades. In the last couple of years there have been several in vitro, in vivo, mouse, and human studies on this drug in CF, and there is a form of cysteamine currently in development for treatment of CF specifically (called Lynovex). What it does in CF (only the deltaF508 mutation has been studied extensively) is essentially rescue the CFTR (i.e. bring it to the cell membrane surface), allowing it to be in the proper place in order to function [1, 2]. In the deltaF508 mutation, sometimes the CFTR is functional but not in the right place, so it can't do its job correctly. Cystagon gets it in the right place by correcting intracellular autophagy (our intracellular protein recycling mechanism). In CF, our faulty autophagy process will often tag a functional CFTR protein for destruction when it shouldn't be. So cystagon fixes this process, which can allow functional CFTRs (specifically deltaF508's) to get to the cell membrane to work properly.
In the studies that have been conducted so far, cystagon has been shown to improve CFTR placement in the cell and reduce chloride concentrations in the sweat . But that's not all. Cystagon/cysteamine is also strongly mucolytic (breaks apart mucus) by targeting its disulfide bonds. Lynovex is being formulated specifically for this purpose, and as a bacterial biofilm-buster and a direct antimicrobial . Therefore, cysteamine acts synergistically with antibiotics to more effectively kill bacteria by reducing the overall mucus load, breaking down bacterial biofilms, and acting as an antibiotic itself! CF wonderdrug or what?! Lynovex is not yet available on the market, so if we want to experience similar benefits, the only way to do that is to get an off-label prescription for Cystagon from your doctor.
So in several of the in vitro and human studies, EGCG (epigallocatechin gallate, a constituent of green tea) was used alongside cystagon to stabilize the CFTR in the cell membrane, essentially making the effect of cystagon last longer (the regular peak plasma level of cystagon is at about 1.5 hours and clearance is super fast, about 6 hours; that's why normal dosing for cystinosis patients is every 6 hours). EGCG is essentially a tannin, and tannins bind proteins together, so it makes sense that it would help keep the CFTR (a protein) in the right place for longer. It is, however, drying and I noticed myself developing a drier cough when I first started it (I'll get to that later). I used cystagon alone for over a month, then added EGCG in slowly. I used the Teavigo brand of EGCG, which I got from vitacost.com for about $15, which makes for a month's supply (at full dose).
Getting Ahold of It
It took me months to convince my doctors to let me try cystagon (only one person on my 3-person team would agree to write me a rx), and I was only successful with the help of my old pediatric CF doc who talked to my adult CF docs on my behalf (I think pediatric docs are more open-minded in general to trying new things). Beware that doctors are hesitant at this point in time to write up scripts for cystagon because it's an off-label use that has not had a significant amount of phase 3 trial evidence to back it up (though one 10-person trial using Cystagon has already been done in Italy and another is currently being done in Scotland ). You should also know that because it's an off-label use and because cystagon is not a cheap drug (though WAY cheaper than the Vertex drugs), many insurance companies require a prior-authorization from a doctor confirming that you have cystinosis. Well, I don't have cystinosis, so I changed insurance companies (I have Medicare Part D so this is doable for me) to one that covered the drug without any prior-autorization (to Humana Preferred Rx, which is great by the way). I asked my doctor to write me my first script for 400mg 3xday in 50mg capsules (the drug comes in 50mg or 150mg capsules). I chose to use the smaller capsules at the beginning because I was going to titrate the dose up very slowly and document all the effects carefully.
I'll give you a summary of it's effects, dose by dose, and how long I stayed at each dose. Also - and this is important - I will mark down what I took that interacted or synergized with cystagon, and why it's relevant.
In the beginning (March 2015): Right off the bat, I started taking a daily B-vitamin complex, as I was told from others who have used cystagon that vitamin B2 is necessary to prevent developing a rotten egg body odor. I stayed on the B-complex the whole time, so I never had that problem. Also, I chose to use a B-complex instead of a straight B2 supplement because many B vitamins work in proportion to one another, and so to throw the balance of their levels off may cause problems. By the way, a B-complex will turn your pee florescent yellow, but that's normal. In addition, I took a magnesium chelate supplement the whole time I was on cystagon. Magnesium is a good idea for CFers to take to begin with since we're often deficient, but cystagon itself can deplete magnesium stores even further. The exact mechanism by which magnesium is depleted by cystagon is related to the fact that it is a potent biofilm breaker and it does this in part by chelating minerals from bacterial biofilms, and unfortunately also from our bodies. I did not feel the side effects of depleted magnesium until I got up to the higher doses, as I will elaborate later. I was also using St. John's Wort at the time when I began cystagon, and since St. John's Wort increases the activity of CYP450 enzymes in the liver, I looked into whether cystagon was metabolized by that mechanism. Although there wasn't conclusive evidence on that front, I talked to my herbalist and he found enough evidence to suggest that I stop talking St. J, as a precaution. If it did in fact interact, the result would be a reduced plasma level of cystagon, and thus a reduced effect overall. Later on I took EGCG with cystagon, as you'll see. I also took oral antibiotics (my usual, minocycline and bactrim) with cystagon because it works synergistically with antibiotics, and since cystagon breaks down biofilms, it's a good idea to have an antimicrobial on board to clean up what spills out of the biofilms.
50 mg 3xday: I generally took three doses a day: once upon waking, once in the early afternoon, and once before bed. I tried to get these doses to be as close to 8 hours apart as I could. I also took cystagon away from food, as it is a chelator of minerals and if you eat it with food (or supplements containing minerals) it will reduce its effect. Later on I did end up eating a little snack with cystagon once in a while (as long as it wasn't too high in minerals like magnesium, calcium, or iron) and I didn't notice any problems with this. The first dose I took I got slightly nauseus and had an almost undetectable reflux-like sensation in my gut, but it went away and never came back. One of the most common side effects that other CFers who had tried cystagon before me reported was reflux, but I never experienced any. I have a theory about this which is simply an educated guess: CFers commonly have low stomach acid and cystagon may increase stomach acid production slightly, which at first can cause a feeling of reflux. This is a good sign as the body begins to correct itself and if left alone the sphincter would begin to function correctly and close normally upon contact with stomach acid. But the conventional theory on stomach acid is that it's "bad" and should be suppressed by an antacid or PPI. Instead, I take bitters everyday to increase my stomach acid production, and so I never have any issues. Read more about stomach acid here and here. If you have reflux, you may want to correct it with bitters/Betaine HCL before starting cystagon.
Anyway, after several days of the 50mg 3xday dose I felt my mucus thin a little, my coughing patterns changed, and I began to be able to breath more deeply. For a few nights I didn't sleep very well and coughed a bit, but then after that I slept better than ever. I began to notice pretty quickly that I was less short of breath on my daily hikes up hill. My before-bed fevers started to go away. In a week my mucus load was reducing from a 2-3 out of 5 beforehand, to a 1-2 now. I was very surprised I could notice effects so quickly and at such a low dose! My blood sugar began to get a little bit more normal too, judged by a lower fasting glucoses and post-meal glucoses. I got a few more green plugs out of my nose than usual when sinus rinsing. Best of all, my normal morning fever disappeared!
100mg 3xday: I stayed at the previous dose for about a week and a half, then upped the dose. My mucus load further declined slowly to the point where even during exercise I didn't cough all that much, and my exercise tolerance improved and my shortness of breath declined rapidly. My blood sugar got more and more resilient. My guts didn't react to nibbles of weird foods like they usually would. Overall, my digestion was pretty stable, which is normal for me. I even felt so good that I traveled on the train to go see my family - something I hadn't felt well enough to do for a long time - and I didn't bring my Vest!
150mg 3xday: I was at the previous dose for a week and then increased the dose to 150mg. For the first couple of days during this transition (and I used this method at all future dose transitions too) I took one dose of 150mg and 2 doses of 100mg, then on the third day switched to 150mg 3xday. On the second day I tried 150mg I experienced what I call "water nose", or an endless stream of watery snot for several hours. It could have been a result of the cold outside, but it was unusual enough that I thought the drug might have caused it. It only happened once. That night I coughed up about 2 tablespoons of blood before bed. I believe that was the last time I've coughed up blood since (besides streaking). My AM fever started to come back, so I took tylenol again to suppress it in the morning. I hypothesize that although cystagon itself was helping me cut down my infection and that's why it initially removed my fever at lower doses, but at higher doses cystagon is mildly inflammatory, given that it causes a build up of cysteamine in the cells. I experienced worsening fever symptoms as I increased the doses from this point on.
200mg 3xday: After about a week at the above dose I transitioned to a higher dose (always increasing by 50mg increments). Mucus began to reduce even more significantly, now only a 1 out of 5 or so in the morning and with very little out during my Aerobika/huffing sessions. I can breath deeper with less crackles and less irritation. Poops are perfectly formed and on schedule: 2 in the morning and 1 at night. I stayed at this dose for 4 days. I began to notice that my pancreas was beginning to progressively want to contribute more insulin when I ate carbs. My fasting blood sugar got lower and my post-meal blood sugars were mostly normal, even if I used less insulin than usual. However, because my pancreas wanted to "help out" more than usual but it would do so at the wrong times, I was getting more frequent bouts of reactive hypoglycemia, especially in the mornings. It got to the point where I would get reactive hypo even if I ate the smallest bit of carbs in the morning, even if only about 15g or less. So my solution has been to reduce my carb intake a bit, especially in the mornings. My HA1c has also significantly improved: in October it was 6.0, and in May (two months after starting cystagon) it was 5.7.
250mg 3xday: It is at this point that I began to feel my first major side effect: fatigue. I'd feel an intense brain fog in the morning, then in the early afternoon I felt an intense lack of energy in my legs, like it took all of my energy just to stand up, and the only way to perk myself up was a 20 minute nap. Later in the day I felt fine again. I felt these symptoms for about a week and then as I changed the dose again, it seemed to subside a bit. At the highest doses (which I'm coming to) it got even worse. My mucus load continued to reduce and my mucus continued to be relatively thin and easy to cough out. Occasionally, I'd cough out blood-streaked sputum (not unusual for me) and sometimes spots or streaks of brown stuff, but mostly my mucus color was yellow. I spent 11 days at this dose.
300mg 3xday: Two things I noticed at this dose: my insulin production started to get a little more under control (probably because I now had more systemic inflammation, which was increasing my insulin resistance again) and I started to develop low-grade fevers in the evenings again (in addition to my morning fevers). Both of these changes I think are symptoms of the increased inflammation caused by cystagon at high doses. However, my mucus load continued to decline and my lungs felt clearer than ever. I continued to feel fatigued, but it was manageable. I stayed at this dose for 22 days, the longest period of any one dose. I did this because I had initially thought 300mg 3xday would be my "ideal" dose. I also stayed here this long because it is at this dose that I introduced EGCG. I did about of week of the 300mg dose alone, then 9 days of taking one pill of EGCG (135mg) with my morning dose of cystagon, then thereafter I took 270mg of EGCG per day (one pill with my morning cystagon and one pill with my evening cystagon). The morning after I took my first dose of EGCG my sinuses and throat felt very dry and painful upon waking. For the first few days I used EGCG I felt more dried out in general, like all of my mucus membranes were lacking a mucus layer to keep them moist. Eventually that balanced out though and I felt normal, or maybe I just got used to it. EGCG (and tannins in general) are known to have a strong drying effect. My mucus load continued to slowly improve. During the day I hardly coughed at all, even when exercising, and when I did cough it was pretty dry and I didn't get much up (because I felt empty!).
350mg 3xday: At this dose I felt the extreme fatigue come back, and after reaching out to my genius friends (i.e. Francis Via) I realized that the fatigue was due not only to the increased inflammation but also to magnesium deficiency caused by cystagon. Francis informed me that cystagon inhibits ATPase, an enzyme used in the metabolism of ATP, our cells' energy molecule. Increasing my intake of magnesium should reduce this effect. So the next morning I took 750mg of magnesium (up from 250mg) and guess what? No fatigue! I also increased my dose of andrographis and baikal skullcap tincture (potent anti-inflammatory herbs) to help prevent evening fevers. I continued to stay on high dose magnesium in proportion to my dose of cystagon - so the more cystagon I took, the more magnesium I took. At one point (when I was using the highest doses of cystagon - 450mg 3xday) I took 750mg of magnesium in the morning and 500mg at night (away from cystagon of course, because they bind to each other). I stayed at the 350mg dose for 9 days.
400mg 3xday: Now my AM mucus load was a 1 out of 5 and my PM mucus load was a 0-1, with virtually no coughing or mucus all throughout the day. Amazing! It is at this point that I retested my sweat chloride levels. I had done a baseline sweat test before starting cystagon and I was at 101/105. At this dose of cystagon with EGCG on board, my sweat test was 110/112. Essentially no change. This surprised me, as others who has tried cystagon had seen changes in their sweat chloride. I didn't sweat it though (haha I'm so funny) because I was certainly feeling the mucolytic effects of cystagon, even if my CFTRs weren't functioning better. At this stage I thought that the sweat test results were higher because maybe, like with correctors/potentiators, doses that are too high can actually inhibit CFTRs (this thought was disproven by a later sweat test at a lower dose). So I scheduled a sweat test to be done when I had come back down to a lower dose of cystagon in the future. Also, this day my FEV1 was 40%, essentially no change since before starting cystagon - also a surprise! But I felt like it was at least 10% higher than that!
At this dose I tried stopping minocycline and bactrim, which I had been using together for the previous 4 months. I wanted to see if I could get off of the oral antibiotics and still feel good. That experiment failed. It seems that minocycline acts as an anti-inflammatory and immunomodulator for me, in addition to being an antibiotic. There are studies showing its effective use as an anti-inflammatory/immunomodulator in autoimmunity and inflammatory diseases, like multiple sclerosis . Without it (even for 3 days) I started to get extra tired midday, and I developed that spasmy tickle-cough that I get once in a while (feels like it's IgE-mediated). So I started the minocylcine back up, but kept off the bactrim. I stayed at 400mg 3xday for 18 days.
Interlude: At this point I titrated back down a little on my dosing because I was running out of cystagon. I went down to 350mg 3xday for 6 days, then to 300mg 3xday for 5 days. During this time I got a lot of green plugs out of my nose with my saline nasal rinse (which I add Dr. Bronner's soap and tea tree oil to). I also started taking rhodiola tincture to try to help with my fatigue, but it didn't help so I stopped it after two weeks. During this interlude and at the 400mg 3xday dose I experienced significant GI discomfort and bloating, most likely due to eating something that didn't agree with me. It lasted for a few weeks and increased my lung mucus load (all epithelial tissues are connected reflexively, so an increase in mucus production in the guts causes me to have an increase in mucus production in the lungs. Fact.).
450mg 3xday: So I got my cystagon shipment in the mail and this time I started using 150mg pills instead of the 50mg I had been using previously. So this limited the dose amounts I could use. So I started on 450mg 3xday. This was going to be my highest dose I was going to try (a normal dose of cystagon for cystinosis is 450mg 4xday). I increased my magnesium accordingly, but I still got slammed with fatigue immediately upon raising the dose. Then I noticed that my left hip was hurting, as if I had over-stretched it or hurt it somehow. I remembered that about 2 weeks ago I had fallen in the woods (slipped on some wet logs) and landed on that hip, but it seemed fine when it happened. Why would it start hurting now? Had it not healed properly? The next day (day 2 at this dose) my jaw muscles on the left side got very sore to the point where it was painful to chew at all. That went away in a couple of days, but the hip pain remained. A few days later the tendons in my ankles started hurting, even though I didn't remember injuring them at all. Then my right wrist started hurting. I took these as signs that all this muscle and tendon pain could be side effects of the high-dose cystagon, so I decided that I should reduce my dose. I read somewhere that high-dose cystagon can cause hyperextension of the joints, so maybe that's what I was experiencing. I was at this dose for a week.
Titrating down: I was afraid this high-dose was going to really hurt my joints, so I reduced my dose quickly. I went down to 300mg 3xday, then the next day down to 150mg 3xday. At this point my mucus load returned back to normal (1-2 out of 5) as my guts balanced out, but I started to get more "hot breath" (low-grade fevers) in the evening. After two days of 150mg I dropped down to 100mg 3xday.
Adverse event: Let's differentiate between an adverse effect and an adverse event. In clinical studies, an "adverse effect" means that there was a side effect studied that was most likely caused by the experiment (i.e. drug), but an "adverse event" means that something happened to the patient during the observation period that was likely not caused by the drug/experiment and would have happened anyway. So I experienced an adverse event at this point. It was at peak summer when the weather is hot and humid and I went out hiking with my herbalism class, and I started to notice intense pleural pain on my left side. After a little while I realized what was happening, because the same thing had happen almost exactly one year before under similar circumstances: a collapsed lung. And it was on the same side too. So I went to the ER for some scans and sure enough, it was a pneumothorax. So I checked myself in for a 10-day IV clean out and to stay under observation. After a week the pneumothorax almost completely disappeared, and the IV antibiotics made me feel great! I got my FEV1 up to 46%! All throughout this hospitalization I stayed at the 100mg 3xday dose of cystagon. I think it was due to the fact that I was on cystagon before and throughout the hospitalization that allowed the IV antibiotics to work so well and so quickly. Plus, my vancomycin blood level never got up to a good therapeutic dose (I ended with my trough at 11 when it should be between 15 and 20), but it still made me feel great, which to me indicates that cystagon is indeed synergistic and allowed the vanco to work even at lower doses than normal. I had never felt that good during a hospitalization before (minus the pneumo)! I left there essentially not coughing at all and my lungs felt completely clear and I was full of energy. I even gained about 5 pounds while I was in there.
Oh and also, while I was in the hospital I did another sweat test (documenting the effect that 100mg 3xday had on my CFTRs). The result was 109/112, essentially unchanged from the last two tests. Another surprise!
The end: Five days after being discharged I started to feel the fever come back, even though I had started minocycline right after getting out. Two days after that I started to get a spasmy tickle-cough in the mornings once again, and this time nothing seemed to help (inhaling essential oils or changing my diet usually helps). So a week later I decided to start bactrim back up again. The next day the spasm-cough started to improve and in a couple of days it was gone. At this point I was still using 100mg 3xday of cystagon, plus EGCG and minocycline. Then I got news that Orkambi was going to be shipped to me soon. Because I want to start Orkambi but cystagon may interact with it, I needed to stop cystagon and wait at least 2 weeks before starting Orkambi. So two days after starting bactrim I reduced my cystagon dose to 50mg 3xday, then the day after that I stopped it and EGCG completely. I think it's important to mention here that my intention at the end was to slowly ween myself off of the drug, not get off it cold turkey from 450 to 0 mg overnight. This is because there may be some evidence that our cells need to slowly be reeducated to make their own endogenous cysteamine after stopping supplementation with an external source (similar to the way we need to reeducate our adrenals to produce their own cortisol by weaning off of prednisone slowly). Some CFers who have all the sudden quit cystagon cold turkey without weaning off have had some side effects as a result, so I do recommend weaning off over a period of days or weeks, like I did.
Follow up: Even though I've been off of cystagon for more than a week I still feel pretty clear and my energy is good. This may mean that it's still persisting in my body (due to the EGCG) and that I may need to wait longer (until I feel crappier) to make sure the drug is out of my system before starting Orkambi. By the way, at about the same time that I stopped cystagon I somehow re-tweeked my right ankle (the one that had given me such trouble before) and it got so bad that I could hardly walk on it. So I finally stopped procrastinating and used a comfrey leaf poultice on it overnight. The next day the pain was 90% gone. Why hadn't I done that a month ago?! I poulticed it again the next night and the pain was completely gone. My hip pain is almost completely gone now too. I am frustrated at myself that I didn't poultice it earlier, but I am so grateful that comfrey is such a powerful herb for healing soft tissue injuries! Now that I've been off of cystagon for over a week, my blood sugar and insulin production is returning back to pre-cystagon patterns, meaning that I have less reactive hypoglycemia but need to take more insulin overall.
After doing thorough experimentation at all of the possible dosages, I have concluded that for myself low-dose cystagon (100-150mg 3xday) is best for long-term maintenance of health and that higher-dose cystagon (300-400mg 3xday) may be helpful for its strong mucolytic and antibiotic synergistic effects, but should not be used for long periods of time (probably no longer than 2 weeks at a time). It seemed very clear to me that the normal cystinosis dosing (≥450mg 4xday) is inappropriate for CF and will cause significant side effects (for me it was joint hyperextension, fatigue, and systemic inflammation). Some of the side effects associated with appropriately-dosed cystagon can be ameliorated with increasing magnesium supplementation, B2 supplementation, and increasing antioxidants in the diet and via herbal supplementation. In CF, it's a good idea to take cystagon with an antibiotic, at least at the beginning, and for me cystagon significantly improved the efficacy of IV antibiotics (i.e. vancomycin and ceftazadime). Cystagon also had a positive effect on my pancreas's ability to produce insulin, my insulin sensitivity, my fasting blood glucose levels, and my HA1c, however it did increase the occurrence of reactive hypoglycemia. Although it seemed quite clear that cystagon was a potent mucolytic agent for me, it did not seem to have any measurable effect on my chloride efflux/CFTR function, which was surprising. Overall, I think cystagon/cysteamine is a very effective mucolytic drug that will be an important drug option for CF people in the future. For now, I think those that wish to experiment with it should contact their doctors and provide them with as much convincing evidence as possible (including my experiences and the studies that I've linked to) to procure a prescription. In the absence of a CFTR corrector like the Vertex drugs, cysteamine may be the most powerful single-drug option we have out there right now for certain CF mutations. I would love to see if it works for mutations other than deltaF508.