The troublemaker.

[Note added 3/31/22: This is a complex post with a long series of exchanges, but it doesn’t include some factors we didn’t know at the time. Because of improperly installed drywall, our house had a mold problem behind the walls in the basement, garage, and the closet in the guest room. Once we fixed that, what looked like a histamine problem and my food sensitivities improved a lot. Years later, the food sensitivities worsened for no reason I could discern. In 2021, I finally had my histamine and tryptase tested by Dr. Levine, and my tryptase was elevated. Treating that with ketotifen and quercetin has helped. See this post for a few more details.]

When I realized I was dealing with a histamine intolerance, and started looking around on the web about how to treat it, I felt totally bewildered and overwhelmed. There is an enormous amount of conflicting information, and I felt bad enough, and having ME/CFS on top of histamine intolerance complicates matters such that I didn’t think it would be wise to start trying things at random. So we scheduled a phone call with Dr. Cheney. If you have simple questions, they can be answered through his assistant, but when you get into a mess like this, you really need a call. We spent about an hour on the phone with him (which you pay for), and after the call he sent this summary, based on our discussion (his text in grey, mine in black):

Jocelyn,

I would approach what sounds like a histamine release problem in the order below, perhaps a week apart. I do not know what set this off – could be spontaneous or linked to declining Gabapentin levels and increasing glutamate interactions. If Gabapentin is involved then decreasing its dose will make things worse or if decreasing its dose and adding glutamate will make things worse. This will “inflame” the brain and cause anxiety, sensory overload and panic. Magnesium and a lot of it is an acute antidote for this kind of problem.

Oxidative stress in the brain will lead to methylation block and loss of SAM and then oxidation of monamines including histamine by MAO occurs which creates more oxidative stress and more methylation block until monoamine synthesis is drastically reduced at which point their receptors will expand dramatically and you are now have a histamine release problem. When I measured blood histamine in CFS cases with this problem, blood histamine was very low and therefore you become sensitive to one molecule of histamine via the dramatically expanded histamine receptors.

Avoid P5P or B6 as this directly increases histamine.

1) Anti-histamines — Try chlorpheniramine (H-1 Blocker – CVS OTC) at 4 mg QID plus Cimetidine (H-2 Blocker – CVS OTC) at 200-300 mg QID and add Cromolyn Sodium at 2 x 100 mg capsules poured into water and swallowed 30 minutes before eating QID. Continue Seroquel and Doxepin at your present doses as both are antihistamines.

2) Anti-oxidants/anti-inflammatories – Hawthorn (SOD inducer) (from Mediherb – call Dixie to order) at 2 tabs BID along with Brazil Nuts (GPx inducer) (get from health food store bins – pre-shelled) at 2-3 BID. Also use good grade olive oil (Colavita) at 1-2 tbsp per day. Consider wormwood elixir at 1 cap in water Swish and Spit BID and/or anatabloc (GNC) at 3 BID for NF Kappa B inhibition. Also consider bioavailable Turmeric at 1 cap BID and always take Turmeric with olive oil to improve bioavailability (health food store). Use alpha-Lipoic Acid at 200-400 mg/day (health food store).

3) Stimulate the methylation cycle which can help long term but be a short term problem as it paradoxically can increase histamine production but this will reduce the histamine receptor density over time. I think blocking the methylation cycle via oxidative stress caused the histamine receptor up-regulation in the first place but not sure why this happened. Use SAMe and BID hydroxy-B12 at 0.3 cc’s SQ and folapro at 800 mcg QD. Do this last and cross your fingers as it can go either way.

4) Another thought is to add colostrum from (Kirkman’s labs – Oregon) at one Tbsp in yogurt or kefir (4 oz) per day. Colostrum is a oral immune regulator in the gut and might help a lot if you can tolerate it. Let me know if you need scripts and give me a pharmacy number and I will call it in tomorrow.

PRC

I sent him some questions:

Dr. Cheney,

Thank you for the email. I will get started on this today. I have some questions, please: First of all, I started playing around with the Histame (DAO) this morning and it is extremely calming even at minute doses. I think this is how normal people react to tranquilizers. This leads me to believe that there is a problem with my DAO production. How could I best support that? Does DAO benefitting me change what you think I should do?

Why the choice of chlorpheniramine instead of the fexofenadine you mentioned on the phone?

I am taking 4 magnesium chloride tablets a day (b/c I don’t tolerate mag sulfate). The bottle tells me that is 2080 mg of mag chloride/248.68 mg of elemental magnesium. How much can I increase that safely?

We didn’t get to discuss whether the methyl group in LDN is a problem in this situation. Is it?

I think I may forego the cimetidine, as that very helpful article I read this past weekend said, “Most antihistamines have no influence on DAO activity, although inhibition of DAO by cimetidine and dihydralazine and increased activity by diphenhydramine have been observed (97).”

I checked and Seroquel is an H1 blocker; doxepin appears to be an H1 and H2 blocker.

Sincerely,
Jocelyn

His response:

Jocelyn,

It is interesting that Histame (a DAO enzyme that destroys Histamine) is similar to MAO (monamine oxidase) that destroys histamine metabolites in the brain as well as other monoamines and thereby produces hydrogen peroxide as a constituent by-product that will increase oxidative stress and places pressure on GPx which depends on GSH (glutathione) production which you are deficient in.  

With the loss of methylation via methylation block, the only metabolic pathway remaining for histamine is MAO or DAO.   MAO resides on the surface of mitochondria and [is] subject to oxidative destruction if superoxide reduction to water is impaired which is the case in CFS and increases MAO’s oxidative destruction.  As monoamime metabolism down-regulates in response to MAO or DAO induction of oxidative stress, then the monoamine receptors up-regulate and you get increased sensitivity to histamine (aka food histamine sensitivity).  Perhaps the use of Histamine helps restore a relative reactivity balance and reduces overall oxidative stress and that will lead to a calming of the CNS.  

I have no problem with you using Histame before meals to suppress the effects of histamine whether that effect is due to activation of MAO or the activation of the histamine receptors which may be in excess.  I do note that endogenous DAO is stimulated in different ways in regards to types of foods. Protein increases intraluminal DAO with more local GI effects and lipids increases DAO in the enteric lymphatics and therefore has a more systemic effect at a distance.  It might be instructive to note which foods make you worse, proteins or lipids.

2) You can use either chlorpheniramine or fexofenadine.  I chose the former because it along with cimetidine were as effective a chromolyn sodium in stopping food based histamine reactions.3) Magnesium tablets do very little to help the brain as the GI absorption of tablets is slower than the reactive kidney excretion of magnesium so there is no net improvement in intracellular magnesium with oral magnesium which is continually leaking out of cells due to low cellular energetics.  Only parenteral magnesium will impact intracellular magnesium positively and only for a short time (1-4 hours – 1 hour for SL magnesium spray and 4 hours for SQ injections and 2 hours for skin creams).  Intolerance of magnesium sulfate is likely due to reduced glutathione or GSH depletion which is at the core of your illness.  Sulfate is like oxygen and capable of producing oxidative stress from reactive sulfate molecules which can be reduced by the action of reduced glutathione (GSH).  4.5 billion years ago, life-forms used the electrons from sulfur instead of oxygen to produce energy and created the same oxidative stress that oxygen does today in mitochondrial redox reactions.4) I doubt that low dose LDN is a problem from the standpoint of its methyl group.  The problem with LDN is that it blocks the endorphin receptor and that can be a problem, especially at higher doses.

5) Be careful about deducing clinical significance from the fact that cimetidine seems to reduce DAO activity. Blocking histamine receptors creates compensatory, negative feedback down-regulation of histamine if histamine rises too much and that will feed into a DAO down-regulation as the system moves to a lower histamine level.  These systems are very dynamic and blocking one outlet yields a compensatory down-regulation or else the system is placed into a positive feedback loop and that is inherently unstable.  One can see this effect as a given anti-histamine use eventually fails over time and one sees tachyphylaxis forcing the movement to another anti-histamine.

6)  I do not believe there is such a thing as a perfectly selective H1, H2 or H3 blocker.  There is only “somewhat more” selectivity for one receptor (H1, H2, H3) over another.  Typically the selectivity is completely lost at higher doses of a selective anti-histamine.

PRC

Still more questions:

Thank you so much, Dr. Cheney. Last question (I think): Any thoughts on quercetin?

Sincerely, Jocelyn

His answer:

Jocelyn,

I like Quercetin. It is a natural anti-histamine. More importantly, it is a bioflavonoid that is a potent anti-oxidant. If you think of anti-inflammation and anti-oxidation as two sides of the same coin, then pro-inflammatory is also pro-oxidation. If you cannot control the redox state, you cannot control the state of inflammation and histamine release is at the cutting edge of inflammation as it allows inflammatory cytokines to egress the blood stream into the tissues. The new NQ-MRI technology is showing that parts of the brains of CFS cases have micro-edema and are partially swollen. This is likely characterized clinically as H/A [headache] and emotional swings and anxiety. It is highly likely that histamine release in the brain is involved with this micro-edema. Note that anti-oxidants are a core treatment of this as well as anti-inflammatory agents. Bioflavanoids and polyphenols serve both as potent anti-inflammatories and anti-oxidants and are very potent.

My response:

Thanks once again, Dr. Cheney. I skipped my b12 yesterday and today and it may be helping. Can’t be certain yet, but I feel less fragile and on edge so far today.

His answer:

Jocelyn,

I have seen B-12 induce histamine in several patients with histamine release signs. It is a rare reaction but suggests complex biochemistry involving the methylation cycle and transulfuration pathway. As you support the methylation pathway with B-12, you reduce glutathione production via the transulfuration pathway (methionine to cysteine to glutathione). This most likely happens when you are very glutathione deficient and sensitivity to magnesium sulfate suggests that you are. Glutathione deficiency means you are at risk for pro-oxidantion and pro-inflammatory events (aka histamine induction). The key to glutathione sufficiency is sufficient cysteine and NADPH. Un-denatured Whey protein (Immunopro) is the best and safest form of cysteine and NADPH is induced by MTF, DHEA and pure glucose but not fructose. VIP also induces NADPH. D-Ribose and Fructose inhibit NADPH. CAT paste and increased sympathetic tone (anxiety/stress) also inhibit NADPH. Sleep and meditation increase NADPH.

PRC

My response:

Dr. Cheney,

Interesting. As I mentioned on the phone, I wasn’t able to tolerate the ImmunoPro when I tried to switch from Xymogen’s i5 to it a few weeks ago. Terrible headache, crushing feeling. I think I will have to get the histamine receptors to calm down a little first before trying to bring it back on board. Remember that my urinary sulfite also tested very high last fall, which you said was indication of low reduced glutathione. I wish I could do VIP but I just don’t have the capacity for the two dozen blood tests needed. I can only give a tube every couple weeks at best, and even that costs me function. I was hoping to space them out over this year, but I’ve been up and down enough that I haven’t made it happen.

Sincerely,
Jocelyn

His answer:

Jocelyn,

I agree on the VIP delay. We are still learning about VIP use. Interesting that ImmunoPro made things worse as you may recall that protein induces intestinal DAO and more GI symptoms could come from DAO itself if histamine is induced as DAO likely increases oxidative stress via its “oxidation” of histamine producing hydrogen peroxide which can provoke a cytokine storm in the gut. Another possibility is that with low DAO you cannot metabolize histamine made from the protein or induced by the undigested protein. At yet another level, CFS patients have poor digestion and this exposes the intestinal lumen to immunogenic proteins and this hardwires the intestinal dendritic cells to release cytokine storms that includes histamine.

ImmunoPro is specifically made from undigested protein (“undentured” whey) so with poor protein digestion, it could be especially a problem. If your serum VIP is zero (via ARUP labs), you will not digest protein well and everything else you have could follow. VIP also has receptors on T-regs that prevent cytokine storms and excess histamine release so with no VIP means no T-reg function and continuous cytokine storms when you eat. I would at least test for serum VIP at ARUP or at The Mayo Clinic Labs, not LabCorps or Quest. 95% of my patients have zero VIP @ < 13 pg/ml or undetectable by assay (Normal VIP is 30-60 pg/ml).

My response:

Dr. Cheney,

Oh my goodness! I just realized that the catabolic paste has accidentally fallen out of my routine! It’s been at least many weeks and possibly some months since I used it. I’ve never been off it this long since starting it. I wonder if that could be contributing to the problem? Holy cow, what a screw-up. Shall I put it back and see what happens? One other question, please: We presume my nagalase is still normal because of my course of GcMAF, so I haven’t been using MTF. Should I be? Should I try it and go by how it makes me feel?

Jocelyn

His answer:

Jocelyn,

Yes, restart CAT paste as it increased ATP generation and pretty well tolerated. Catabolism via CAT paste also increased cortisol production which has potent anti-histamine effects. The dose is 1-2 drops on forearm Q AM.

One drop of MTF to the foot twice a week at sundown is the dose. Some patients cannot tolerate that much and get a loss of energy. If that happens, reduce your dose to once a week. If you are still not tolerating MTF, discontinue.

PRC

So I was faced with trying to follow all these recommendations. I started by dropping my P5P/B6 and B12. After a while my sleep started falling apart, and acting on a hunch, I added the B12 back, and my sleep improved. I think I am “topped up” on it now, as I’m starting to have some burning pain like I did earlier in this episode, which seems to be a sign that I should probably drop it for a while. I stayed on the SAM-e for a time, because it seemed like it was helping me sleep. Eventually I tried dropping it, and I found that doing so lessened my histamine reactions. I emailed Dr. Cheney’s assistant about it:

A note to pass to Dr. Cheney, please: I had kept my Sam-e in my regimen because it seemed like it was helping me sleep, though I knew it was one of the things Dr. Cheney said could cause things to go either way. I dropped it a few days ago and my reactions to foods seem somewhat lessened and my energy may be a little better. It’s only been five days, though.

Her response:

I thought you would like to know that Dr. Cheney found this particularly interesting. He quietly thought about it for a while. He then said it was a “profound” statement. He made no additional comments or recommendations. 

As far as following his other recommendations: I was already taking the wormwood. I use magnesium spray already and had Chimp make a non-alcoholic version for me to try, as alcohol is a histamine problem (have noticed some tachycardia when taking it). The alcohol version worked better than without, so I decided I would stay with that. I put the catabolic paste back into rotation.

I was able to add the Brazil nuts and olive oil without trouble.  I have had a bad reaction to both alpha-lipoic acid (tachycardia) and turmeric in the past (dissociation), although the latter has historically been fine in food, where it’s cooked. However, it’s a no-go on the histamine sensitivity list, and I haven’t had an opportunity to test whether it’s now a problem for me yet.

I experimented with the chlorpheniramine and found that it made me very tired. Allegra gave me a terrible headache, just as histamine-provoking items do, as did hawthorn. I don’t really know what that means. I could try the cromolyn sodium and the cimetidine – but with the latter, I have to admit I’m too worried about it blocking DAO activity.

I experimented with very small amounts of quercetin and DAO. Quercetin made my head hurt. DAO made me feel more relaxed, but I need to evaluate it more.

The most effective, best tolerated thing I’ve found is fennel seed, which contains quercetin naturally and if I take enough, gives me a relaxed feeling and helps with pain. I’ve also played around with flax seed and found that a little bit of it makes me feel energized, but a little more makes me feel anxious. I am not sure what that means yet either.

I was able to add back in a drink powder that really helps my energy by taking it at breakfast, when I am still covered by antihistamines (from my sleeping meds). With that on board, I am not going to try the colostrum for now, because it has a similar amino acid profile to both the drink powder and ImmunoPro whey protein, and the latter went badly recently when I tried it without histamine cover (headache, crushing feeling).

I wonder – and I have no way of proving this, but it’s a definite sneaking suspicion – whether this sudden histamine sensitivity is a result of years of me creating histamine blockade in my body. I have been taking three things that are technically antihistamines (though their primary use is something else) for sleep for various periods, some of them for as long as four years. Has my body noticed that, decided there isn’t enough histamine in my system, and increased it or my sensitivity to it accordingly? Could it be my antihistamines are thus “failing” in the way that Dr. Cheney mentions above, even though I haven’t been using them for their antihistamine effect? This line of thinking has led me to the conclusion that I don’t really want to add more antihistamines to my regimen if I can control my reactions and desensitize my system with diet modification and supplements, and that has been what I’ve been attempting. If it fails, the meds are there to try.

I have changed my diet quite a bit, and am still in the process of figuring out what I can tolerate. I have lost a lot of favorite foods – tomatoes, onions, garlic, aged cheese, cilantro, citrus, various legumes, among others. I have had to add meat in order to get enough protein, but the only meat that I’ve found I can tolerate without a headache is chicken. I am still struggling to get it down every time Chimp puts it on my tray. I just don’t like animal flesh.

The last thing that’s in play at the moment is that I also have my 23andMe results in hand, which might be helpful, but I have a lot of reading to do there in order to understand them.

So that’s where I am right now. It’s a definite work in progress. My energy is a little better than it was for a while, because I’ve added that drink powder back in, but not back up to where it was before this all began. I feel a little less overwhelmed than I did, because I have a better idea of what I can eat now and continue testing new items as often as I can. Will what I’m doing successfully downregulate my histamine receptors? I can’t say, and I don’t know whether there’s any way for this to be temporary, but I am hoping by the time I need to go for my annual appointment in March that I will have a better understanding and have it more under control.