Histamine and Mast Cell Stabilizers

Recently I have seen a lot of difference of opinions on social media on these issues. There are several blogger who write on this, for example:

I was well trained at University to always work from primary sources (hence the joys of learning at least some greek, latin, french, german, danish for history courses). Bloggers are secondary and often tertiary sources – with the risk of reading more into stuff then there may actually be, or spinning the data to gain readers.

On the flip side, some of their advice comes from experience. The unfortunate aspect of experience is that there is no control for placebo effects, or anti-placebo effects, or effects due to other factors with the person.

You may also wish to read DAO and Probiotics, a prior post

To me, the primary sources are two grades:

  • Individual specific studies (which suffer from a variety of bias risks)
  • Review Articles (unlike bloggers, these are peer reviewed)

Wikipedia lists the following as Mast Cell Stabilizers, most are prescription drugs

The drug bank list of Histamine H1 Antagonists, Non-Sedating provides a similar link with the KEGG providing nice diagrams here, with the following enzymes:

07216 Catecholamine transferase inhibitors
07219 Cyclooxygenase inhibitors
07024 HMG-CoA reductase inhibitors
07217 Renin-angiotensin system inhibitors
07218 HIV protease inhibitors
  • “Aspirin enhanced histamine release from basophils via increased Syk kinase activation” [2013]

 There is no evidence to suggest that sensitization against drugs occurs more frequently among patients with presumed histamine intolerance compared to patients with normal tolerance to histamine. However, preclinical data suggest interactions between some drugs and histamine catabolism. Nevertheless, the clinical relevance of these findings remains unclear as histamine in humans can be catabolized by different pathways[Editor: DAO and HNMT]. There are no drugs for which induction or worsening of histamine intolerance has been established clinically.

Drug hypersensitivity in patients with presumed histamine intolerance and mast cell activation disease [2019]

In terms of citizen science, we find some strong statistical associations for some bacteria shifts

From: https://microbiomeprescription.com/Explorer/ToSymptomsSummary?id1=133

The Review

Mast Cell Stabilizers

  • Twenty-first century mast cell stabilizers [2013] See Table 1 “Naturally occurring mast cell stabilizers”
    • I have a page that links to what contain various flavonoids here, with the amount (and mast cell stabilizers labelled)
      • Often people work off “contains” only, ignoring the amount, for example
        • Apigenin: Kumquats has 21 mg/gram and mangos 0.01 mg/gram — a 2000x difference!
    • Example: Apigenin
  • PubMed reports nothing for probiotics that have this effect. Nor for bifidobacterium, nor lactobacillus
    • For Bacillus, we find evidence of histamine release [1975], exactly the wrong response

DAO Response

There are chemicals/vitamins that DAO and  Histamine N-methyltransferase (HNMT) ( the key natural histamine removers) need to act upon histamines. These include:

  • “Vitamin B6 is a collective term for all 3-hydroxy-2-methylpyridines which act as vitamins. Vitamin B6 substances like pyridoxine, pyridoxal, pyridoxamine, and their phosphorylated metabolites are all equally effective. Pyridoxal-5-phosphate and pyridoxamine-5-phosphate fulfill the functions of a coenzyme in the organism [for activation of DAO].” [2014]
  • Impact of oral vitamin C on histamine levels and seasickness [2014]
    Note: “Histamine (p < 0.01) and DAO levels were increased after the intake of vitamin C (p < 0.001)”
    • The p values suggests that DAO increased significantly more than histamine.
    • This may be the source of QAnon belief that citric fruits/vitamin C is bad.
  • “A cross-over study in former East-Germany on patients who had infection-related asthma found that 5 g/day vitamin C decreased the proportion of participants who had bronchial hypersensitivity to histamine by 52 percentage points (95% CI: 25 to 71).” [2013]
  • “copper …. did significantly increase two enzyme activities (SOD and DAO)” [1997]
  • “diamine oxidase (DAO) activity were both increased (linear, p = 0.0004, 0.001, respectively) with Defatted Rice Bran…” [2019]

Negative Impacts

Caution: DAO production seems to increase with gut permeability issues (GPI). Thus something that improves GPI may not actually decrease DAO production, the change of DAO may be a side effect.

  • “selenium-enriched yeast …significantly decreased the serum concentrations of diamine oxidase (DAO)” [2020] – unclear if the yeast or the selenium was the primary cause.
  • “Tannic acid … reduced diamine oxidase (DAO) activity”  [2020] ( Tea, coffee, wine, chocolate)
  • ” Antimalarial drugs that inhibit histamine N-methyltransferase also inhibit putrescine catabolism in vivo and DAO activity in vitro” [1981]
  • “putrescine supplement…. increase in putrescine at 1 h and in diamine oxidase (EC 1.4.3.6) activity within 3-6 h” [1986]
    • “putrescine is found in virtually all foods of plant origin, and is particularly abundant in fruits and vegetables, notably citrus fruits (1,554 nmol/g) and green peppers (794 nmol/g) (961). There are also high amounts of putrescine in wheat germ (705 nmol/g) and soybean sprouts (507 nmol/g) (3770).” [2019]
Drugs that inhibits DAO The structure and inhibition of human diamine oxidase [2009]

Histamine Production

Many probiotics produce histamines, for a list see our commercial probiotic list. For many probiotics, we could not find PubMed studies. Lactobacillus buchneri has been implicated in histamine-poisoning[1991].

See this post to see why strain is often not sufficient, L.Reuteri may or may not produce histamine depending on specific strain.

Foods

Fermented foods are usually uncertain for which bacteria are fermenting it. As we see above, many produce histamine. Studies of commercial Kefir have found that the listed bacteria and the actual are usually in disagreement. Bottom line: no fermented food. This includes sauerkraut, soy, miso, red wine and salami[2020] [1991] .This usually extends into no left-overs, most items left in the fridge (or out) indefinitely– get covered in furry green/black coats. This extends to many cheeses [2020][1995], with Feta Cheese being a possible exception [2020]. For cheese, the same cheese name (like Stilton and Camembert cited below), from one producer may be fine and from another bad — the difference is which strains (not species) of bacteria was used. This also applies to yogurts. For “wild Culture cheeses” it is Russian Roulette for histamines.

Very fresh fish can be safe, but they are prone to producing histamine quickly once skinned [2020].

This also applies to items like nuts and beans that are not fresh.

Citrus fruits are high in histamines” [Internet Legend?] – alas, I could not find any usable studies. I did find this

In this study, aqueous extracts of peels of best known citrus fruits namely grapefruit (Citrus paradisi), lemon (C. limon), lime (C. aurantifolia) and orange (C. sinensis) were used. Depending on polyphenols content, the extracts were graded as orange > lemon > lime > grapefruit. Effects of the extracts on the release of histamine from rat peritoneal exudate cells (PECs) was measured to know anti-allergic activity. All extracts inhibited the release of histamine from rat PECs induced by the calcium ionophore A23187

Anti-histamine release and anti-inflammatory activities of aqueous extracts of citrus fruits peels [2013]
  • “Nasal spray from lemon and quince (LQNS) is used to treat hay fever symptoms and has been shown to inhibit histamine release from mast cells ” [2016]

Other Histamine Producing Foods

In researching another possible internet myth, pineapples and banana. I found a summary of a study which could easily be misread to imply histamine issues. After some effort, I found the full text of the article and shows the results of their lab tests below. The summary statedHistamine, tyramine, noradrenaline, serotonin and other pressor amines occur in fruits and fermented foods such as bananas, pineapples, cheese and wine. ” It does not state that each is found in every fruit and fermented food

Naturally Occurring Toxic Factors in Plants and Animals Used as Food [1966]
Grasping for straws?

“Abnormal association between mast cells and nerve fibers, and increased release of tryptase and histamine have also been described in IBS patients [7],” [2017] has led to the not-demonstrated belief that what improves IBS also improves histamine. i.e. Beneficial effects of Saccharomyces boulardii CNCM I-745 on clinical disorders associated with intestinal barrier disruption [2019]

Highest Mast Stabilizer Foods

As mentioned above, we should not ignore the amount, fortunately the database behind Microbiome Prescription, allows us to compute across all natural mast cell stabilizers and get concrete numbers.

By amount of Mast Cell Stabilizers

Foodmg/gram
Spices, parsley, dried4523.25
Spices, celery seed841.05
Capers, canned303.89
Spices, saffron205.48
Dill weed, fresh68.48
Thyme, fresh47.75
Elderberries, raw27.35
Kumquats, raw21.87
Peppermint, fresh18.05
Cranberries, raw16.15
Cranberries, dried, sweetened12.83
Blueberries, cultivated (highbush), raw9.53
Blueberries, frozen, unsweetened7.55
Cranberry sauce, whole, canned, OCEAN SPRAY6.51
Pitanga, (surinam-cherry), raw6.2
Acerola, (west indian cherry), raw5.79
Figs, raw5.47
Currants, european black, raw5.16
Raisins, golden seedless5.11
Prickly pears, raw5.04
Apples, raw, with skin4.27
Apples, Red Delicious, raw. with skin3.87
Blackberries, raw3.85
Apples, Gala, raw, with skin3.8
Apples, Golden Delicious, raw, with skin3.69
Spices, marjoram, dried3.5
Lemons, raw, without peel3.07
Olives, ripe, canned (small-extra large) – May be high in histamine [2000]2.8
Rosemary, fresh2.55
Apples, Granny Smith, raw, with skin2.54
Cherries, sweet, raw2.53
Mulberries, raw2.47
Cranberry sauce, canned, sweetened2.44
Apples, Fuji, raw, with skin2.36
Apricots, raw2.26
Gooseberries, raw2.11
Applesauce, canned, unsweetened, without added ascorbic acid (includes USDA commodity)2
Juice, lemon, canned or bottled1.83
Plums, dried (prunes), uncooked1.82
Kiwifruit, green, raw1.81
Cherries, sour, red, raw1.71
Strawberries, raw1.61
Raspberries, raw1.48
Jujube, raw1.26
Raspberries, frozen, red, unsweetened1.14
Juice, pomegranate, bottled1.11
Apples, raw, without skin1.07
Strawberries, frozen, unsweetened0.98
Grapefruit, raw, pink and red, all areas0.94
Dates, deglet noor0.93
Sauce, pasta, spaghetti/marinara, ready-to-serve0.92
Watermelon, raw0.91
Oranges, raw, navels0.91
Plums, raw0.9
Peaches, raw0.88
Pears, raw0.84
Oranges, raw, all commercial varieties0.77
Juice, grape, canned or bottled, unsweetened, without added ascorbic acid0.75
Melons, cantaloupe, raw0.72
Nectarines, raw0.69
Juice, apple, canned or bottled, unsweetened, without added ascorbic acid0.58
Olives, pickled, canned or bottled, green May be high in histamine [2000]0.56
Juice, lime, raw0.51

By Number of different Mast Cell Stablizers

Different flavonoids may have different responses, hence the most varied should also be considered.

FoodFlavonoids Counts
Raspberries, raw6
Strawberries, frozen, unsweetened3
Oranges, raw, all commercial varieties3
Apples, raw, with skin3
Blueberries, cultivated (highbush), raw3
Blueberries, frozen, unsweetened3
Cranberries, raw3
Kiwifruit, green, raw3
Lemons, raw, without peel3
Mangos, raw2
Melons, cantaloupe, raw2
Oil, olive, salad or cooking2
Cranberry sauce, canned, sweetened2
Currants, european black, raw2
Dill weed, fresh2
Elderberries, raw2
Gooseberries, raw2
Grapefruit, raw, pink and red, all areas2
Capers, canned2
Cherries, sour, red, frozen, unsweetened2
Cherries, sour, red, raw2
Cherries, sweet, raw2
Cranberries, dried, sweetened2
Apricots, raw2
Bananas, raw2
Blackberries, raw2
Oranges, raw, navels2
Peaches, raw2
Peppermint, fresh2
Pitanga, (surinam-cherry), raw2
Prickly pears, raw2
Raisins, golden seedless (because of age, histamine risk)2
Raspberries, frozen, red, unsweetened2
Strawberries, raw2
Thyme, fresh2
Watermelon, raw2
Rosemary, fresh2
Spices, celery seed2
Spices, parsley, dried2
Acerola, (west indian cherry), raw2

Bottom Line

I will gladly take comments citing gold standard sources (PubMed with full test), please do not add comments about so-and-so saying something is bad. I dislike QAnon medicine.

The above should give a framework for diet and cooking, as points

  • Use items high in mast cell stabilizers
  • No fermented foods or left overs
  • No ‘old raw’ ingredients (i.e. nuts, beans, etc) – unfortunately, most of these do not have “Picked dates” on them. Bad storage (i.e. high humidity, temperature) is also a factor.
    • Dried fruit/vegetables have significant histamine risk
    • Canned food is unclear, but there are cases of problems from some manufacturers[2010].
  • Fresh frozen is usually fine. We buy blueberries originating at a far 4 miles away. We know that the temperature is cool when they are harvested and thus the risk of bacterial growth on them is low. Likely much lower than “fresh blueberries” at the market that was shipped from Chile and have been on display for 3 days.
    • Find out when fruit, vegetables etc are delivered to your market, you want to shop the next day — avoiding all old looking items
  • Peel fruits etc, immediately before consumption. Skins evolved to protect the contents from bacteria (i.e. histamine producing) growths

Whenever you hear an avoid (example list)— do your homework on it. Use PubMed exclusively. One of the best items for mast cell stabilization is Kumquats, which is on many avoid lists because it is in the citric family…. another QAnon recommendation.

IBS/Gut permeability appears to be a significant co-factor.

Evidence please! Studies, not the volume of people repeating rumors!