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Why am I Flushing from Niacin? Histamine and Two Other Causes

Niacin, also known as Vitamin B3, is the name given to a family of nutrients. While some less common forms (such as NADH) exist, most supplements come in the form of nicotinic acid, inositol hexaniacinate and niacinamide.

It is nicotinic acid that we are talking about when it comes to the infamous ‘niacin flush’. Nicotinic acid has some important therapeutic effects, especially its calming effect (mediated by ‘mopping up’ methyl groups to block formation of adrenaline, but potentially mediated by supporting modest increases in serotonin and interactions with the benzodiazepine receptor). In this form, Niacin is regularly used for individuals who are experiencing ‘over-methylation’ symptoms (something that is very common in individuals who have polymorphisms/genetic mutations at the COMT enzyme (this deactivates adrenaline and other catecholamines). Although there is no evidence yet that Niacin actually enhances the COMT enzymes, it’s anti-adrenaline effects make it an effective addition for those with slow activity here. I have recommended it when I want to support better sleep in those who have been particularly stressed (or who have recently started a methylation protocol and seen their sleep disrupted). However, nicotinic acid is also a vasodilator. This means that it relaxes the walls of blood vessels across the body. This induces a significant increase in blood flow to many areas, especially the skin.

For this reason, many practitioners have made use of Niacin in order to help with detoxification procedures (the idea being more blood flow to the skin = more waste products ejected through these channels). These ideas are valid; the ‘niacin flush’ has no negative health effects and, in these circumstances, we can expect to exploit such reactions for health benefits. However, it is not very popular; it seems the idea of hot, itchy, blotchy-red skin does not hold universal appeal.

It’s fair to say that most people want to elicit the beneficial effects of Niacin without getting the unpleasant flush. So what causes this flush?

Niacin, Mast Cells and Prostaglandins

Your immune system is made up of many different types of cells that work together like an army, each with a specialized task in protecting you from invasion. They communicate through the release of various chemical messengers. Some of these chemicals recruit other cells for the fight; others change the local environment to improve chance of victory.

One group of mediators are called prostaglandins. Made from fatty acids, these are expressed by many immune cells and can exhibit a number of effects; this includes increased pain, heat and redness. They also increase blood flow in the local area (to aid in the delivery of immune cells to the frontline, and the removal of waste products). Prostaglandins D2 and E2 have particularly powerful effects in this regard. They can be found in a whole host of immune cells but are released liberally from immune cells of the skin (called Langerhans cells) when stimulated by danger/infection signals… or nicotinamide, the circulating form of Niacin.

NSAIDs like aspirin work by inhibiting an enzyme that allows the prostaglandins to form in the first place. It is through this mechanism that these drugs work as painkillers. Aspirin also inhibits the Niacin flush. However, concerns about long-term use of aspirin makes it unappealing as a daily strategy.

So what else can we do to avoid the flush?

It’s clear that most people don’t get Niacin flushes until they start to take really big doses (like 500mg or more). Thus, there has to be something going on if their colour changes so spectacularly at doses of just 50mg or so… So why do some people seem so sensitive? And what does this tell us about treatment strategies?

The starting point is to look at the common patterns I see in clinic:

  • 1. “Bedding in”. It is quite common to see individuals get the flush on the first couple of nights of taking Niacin. What has been interesting is that individuals who show low niacin on testing (eg. blood test for Red Blood Cell NAD activation) are the ones most likely to notice this. This tends to go away quickly, leaving behind just the desired responses, but it still raises the question of whether there is any increased prostaglandin activity as a result of the low Niacin or simply a sensitivity to the effects of Niacin when it is actually added in. This may be explained by the fact that Niacin shows some interesting anti-inflammatory effects in animal studies; it has reduced nitric oxide synthase in animal models and potently reduces cytokines levels in test tube studies. We cannot be certain that these are the mechanisms, as Niacin is so active elsewhere. To this end, its feasible that there are downstream effects of Niacin’s other functions; perhaps more inflammation occurs when we miss out on Niacin support of mitochondrial function, neurotransmitter balance (and therefore vagus nerve transmission to macrophages), repair of damaged tissues (via NAD-dependent function of PARP enzymes that repair the cell), or cholesterol management (and therefore movement of fat-soluble chemicals, including inflammatory mediators). The truth is we’re not sure, but this almost always stops happening within a few days.
  • Summary: it appears that a lack of Niacin leaves individuals more susceptible to inflammation, which means that they are more likely to experience an inflammation-mediated flush in the first few days of taking Niacin.
  • Action: just observe, to make sure it does indeed pass.

 

  • 2. Reduced methylation activity. I have periodically spoken with clients who have accidentally missed their morning supplements and noticed that, should they take Niacin that evening, they will flush. As mentioned above, Niacin acts as a ‘methyl sponge’. It does this at the liver, where enzymes convert the circulating niacin into N1-methyl-nicotinamide and further downstream metabolites. This reaction uses up SAMe in the process, leaving less methyl groups in circulation. The two substrates for this enzyme are Niacin and SAMe, the universal ‘methyl donor’. This means that the more Niacin there is and the the more SAMe there is, the more this reaction can occur. What’s the implication here? If you have less methyl donors available, we’d expect there to be more ‘active’ Niacin left floating around in the bloodstream. This means more Niacin to activate receptors on immune cells, leading to the release of prostaglandins and therefore the flush. Methyl groups are provided from the diet, but also from supplements like methylfolate, methylB12, TMG, Choline, etc.
  • Summary: methyl donors ‘use up’ Niacin at the liver. Removing these means that Niacin levels can build, and thus there is more to
  • Action: Ask the individual if they forgot to take their methyfolate (etc) that morning. Or, if deliberately removing such items from the protocol, amend the Niacin dosage accordingly.

 

  • 3. Inflammation. This is by far the most common cause whenever someone gets an ‘unexplained’ flush to Niacin. Histamine is a chemical the body releases to aid in the inflammatory process. Like Niacin, histamine is a potent vasodilator. It also sensitizes the affected areas and can result in itching. Burn your finger on stove, and you will get an acute release of histamine in this area (this dilates blood vessels, in order to allow more healing nutrients into the damaged area and more waste products out. It makes the area sensitive to touch, so you protect it from further damage). Catch a cold and you will also get a release of histamine, although this will me spread out across the body. The problem with histamine and niacin together is that you now have two vasodilation agents in play at the same time. Niacin does not induce the flushing via histamine, but histamine enhance the amount of vasodilation in blood vessels that ultimately drives flushing symptoms. In other words, it appears histamine itself will not cause flushing but make it easier for the flush to occur. This is exactly what I see in clinic, with individuals often finding relief from the flush through the use of an anti-histamine and some finding that it does not stop the flush but alters it (from being highly itchy and unpleasant to being a ‘relatively pleasant, warming sensation’). Sometimes, people notice nothing. The way I’d describe the relationship is that ‘histamine puts you at the edge of the cliff, Niacin kicks you over the edge’. Histamine isn’t the only inflammatory mediator that increases vasodilation; nitric oxide (iNOS) is also released by immune cells when they encounter a threat and this both dilates blood vessels and primes mast cells. Mast cells are a potent source of the same prostaglandins that induce flushing.
  • Summary: there are a number of inflammatory messengers that put our immune cells on alert. They may not cause the flush directly but put the body ‘on the edge’, to such an extent that even a tiny amount of Niacin can cause flushing.
  • Action: ask the individual about any immune symptoms (have they also noticed sniffing/sneezing? changes in digestive function or stools? any rashes or headaches, etc?). Often this will show a correlation between the flushing and the transient cold symptoms. If there is no such connection, then I will begin investigation into other causes of inflammation (chronic infection, oxalate/lectin issues, mould exposure, allergies, dysregulated immune response, etc) as well as poor histamine processing (histamine is only detoxified by DAO, an enzyme that depends on Vitamin C, copper and magnesium, and via HNMT, which requires methylation).

Conclusion and Action Points

There are ways to block this histamine-induced flush, such as taking aspirin (reliable) or taking anti-histamines (hit and miss). While this may make sense if the individual is subject to a cold (a temporary inflammatory event), these methods have some drawbacks when used long-term. Therefore, should individuals experience regular flushing, it makes sense to address the underlying causes of excessive inflammation (and therefore the chemical cocktail of prostaglandins, histamine and nitric oxide). This generally relates to:

  • excessive reactions to food chemicals (mould exposure and lectins/oxalates reactions remain the most common, but food intolerances and microbials infections also feature highly)
  • poor methylation (a complex subject in its own right)
  • insufficient DAO expression
  • dysregulation of immune response (especially factors that promote production of the ‘tolerance’ cytokine, IL-10)

It may also be worthwhile increasing intake of radicchio in the diet. What makes this leafy vegetable, a staple of Italian salads, so special? Its luteolin content. Scientists studying the effects of this polyphenol founds that it entirely abolished skin flushing (and entirely abolished the rise in serum Prostaglandin D2) in humans taking Niacin. However, this used particularly high doses (1000mg), so responses at a more ‘normal’ servings may not be so pronounced. There is only one excellent source of luteolin in the diet, which is radiccio (which provides 38mg for every 100g).

In any cases, using the niacin flush as a flag of underlying immune activity remains the most sensible course of action. Dealing with these underlying causes will not guarantee that you will never get a flush, but it will significantly raise your threshold and, importantly, mean that any flushes will be much more pleasant.

So the take-home message is that, while the itchy flush is no concern, it may prove an useful metric for inflammation in the body (and for subsequent progress, as and when it disappears).

(article revised on 13/10/2019).

Leave a comment

  1. Hi Marek
    Could you elaborate more on the last questions by Ian, “My question is does niacin exhaust histamine through releasing it on flusing or does it increase boy histamine levels”? I too wonder that myself, as I am taking high doses of niacin and appear to have trouble with histamine. Thanks

    1. I’m interested in the answer as well. It truly feels like a highetened histamine level caused by niacin.
      In addition, I wonder if the rapid heart rate caused by histamine or another side effect, not mentioned in the great article.

  2. There are plenty of causes that can result in an increased heart rate but, should this reliably in response to taking Niacin, then we can be satisfied that Niacin is the ‘independent variable’ and thus causing this symptom.

    There is no way mechanism through which Niacin could ‘exhaust’ histamine, as the mechanism is conducted through prostaglandins (rather than directly through histamine)… the easiest way to summarize it is that higher baseline levels of histamine put you at the edge of the cliff, and then Niacin kicks you over (see https://www.ncbi.nlm.nih.gov/pubmed/18784348).

    1. Excellent study. If that’s correct, then the vasodilation is due to prostaglandin D2 and not nitric oxide. Are you aware of direct influence on NO mechanism?

      Speculation: Maybe prostaglandin D2 increases blood flow to the skin since that is where we usually get injured (the skin hurts first) as part of an inflammatory response.

      Speculation 2: if no NO direct mechanism is involved, then the increased blood flow isn’t systematic, just to the skin or areas relevant to inflammation.

      1. When it comes to flushing, I am interested in the synergy of the prostaglandin and histamine (the additive effect). If individuals take steps to reduce the activity in either one, we tend to see the flushing issue disappear… although inflammatory cascades that involve nitric oxide are highly relevant, I would not expect this to contribute to the flush (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1906415/).

  3. I took 25 mg of nicotinic acid (1/4 of a 100 mg tab). I developed sneezing and nasal congestion about 30 – 45 mins after and it lasted for approx. 1-2 hrs. I have asthma but there was no dyspnea. Only symptoms of allergic rhinitis (I’m very familiar with that). I had no rash or skin symptoms. Can you advise whether the (most likely) symptom related to mast cells or an inflammatory response would resolve with continued titration of nicotinic acid?
    My husband takes it all of the time for cholesterol lowering and he is currently titrating at 1000 mg od with goal to increase to 3,000 mg.
    Because of the many health benefits for B3 I really wanted to be able to take it too (in this formation vs. Niacinimide). But I do tend to be an allergic type person and I am allergic to ASA, NSAIDs, Salicylates (even in Foods but only bothered with higher contents) and Sulfites. Could you please advise?

    1. Whenever I see these types of responses following a low dose (by supplementary standards), then we’re not so much looking at the nicotinic acid as ‘the cause’, but something that is instead taking you over the edge. In other words, that there is baseline inflammation that are almost enough to result in symptoms but itself, but requires just that little bit more in order to cross the threshold. So this is where the focus would always be on what is driving this (see my other article on mast cells for potential causes). If the use of nicotinic acid makes a difference to to something fundamental (eg. sleep), which can have downstream effects on baseline inflammation, then we can expect the individual to settle on this dose. If the nicotonic acid doesn’t have impact on fundamentals for you, then I’d expect to continue to see the same reactions.

    2. I think researching about molybdenum would help you, i supplement it for help processing sulfa based foods, and helping to increase glutathione

  4. I’ve been taking Niacin for months and I still get a crazy flush. It’s not uncomfortable particularly just looks scary. I have histamine intolerance, is this why? Should I stop taking it and stuck with Nicotinamide? Am I putting myself at risk?

    1. In my experience, most individuals with histamine issues will notice flushing from small amounts and this remains the case until the root cause of histamine issues are addressed. However, the only consequence of these reactions is the discomfort involved (I’ve never seen this affect an individual’s long-term progress).

  5. I was taking 1g instant release niacin 1x a day intermittently and had to discontinue due to a delayed fire ant stinging sensation after the main flush. It was nearly intolerable, made me flinch and scratch endlessly despite many interventions. Did not have this issue for the first weeks. Thanks for the insights, really trying to sort this out.

  6. Hi, I would like to know if hay fever symptoms can be diminished by de use of niacin. Is histamine release being inhibit each time I consume niacin or somehow being depleted? Thanks

    1. The flushes are not actually mediated by histamine (they are actually mediated by prostaglandins). However, if histamine is higher, then this makes the flushes more pronounced/itchy. But Niacin will not deplete histamine.

  7. I flush intensely at 30 MG. Full body flush. Ive been told to take it with melatonin. Mel 20 minutes prior to niacin as part of a protocol. Apparently the melatonin allows the niacin to enter the cells easier. It definitely cancels out the flushing.
    But still, I cannot get over 100mg niacin without 50 MG melatonin. I’m not sure these Mel dosages are safe?

    1. So the research indicates that melatonin is non-toxic in mega doses (much higher than those you describe), but that doesn’t mean that it is a good idea and I think we should always think very carefully before introducing anything at 100x the naturally-produced levels. Melatonin stabilizes mast cells, which are responsible for producing PGD2 (the main offender in flushing), so the relationship makes sense. However, I’d first question why the mast cells are overactive in the first place… my article on mast cells is here: https://www.marekdoyle.com/mast-cell-activation-messenger/

  8. I’ve been taking Niacin while doing breathing exercises and I noticed I was able to hold my breath 20% longer during the flush. I was astounded. My dose was 300 mg. I haven’t been able to find any research on this. The breathing exercise also “enhanced” the effects of the flush so that it was much stronger.

    1. Niacin has a vasodilation effect, which can see more oxygen arrive at cells. If this happens at the chemoreceptors that regulate your respiratory rate, then you can expect to see an improved breath hold. It’s also worth considering the way that Niacin promotes the release of fatty acids from the fat cells; when your cells metabolize more fats, they produce less carbon dioxide, reducing the need to breath it out (and thus, longer breath holds). This impact is highly variable based on dietary composition, mitochondrial performance, etc, but this is why many freedivers use the ketogenic diet to enhance performance.

  9. I have chronic nasal stuffiness which I’m sure is connected to allergies and/or food sensitivities.
    Tonight I took 250 mgs of niacin, got the flush but it also decreased the stuffiness and I was able to breathe more freely. I also take a High B Complex but never flush.
    Surprised that it cleared nasal stuffiness.

  10. I experimented with trampoline for lymph activation + 500mg Niacin + intense Sauna afterwards for increased detoxification. Was very healthy but soon after developed a constantly stuffed nose and a strong histamine intolerance. I haven’t been able to get rid of this and it been two months now. Could the Niacin and developed histamine tolerance / blocked nose be related and what could be done to reverse this? Any hint appreciated!

    1. Hi Marty, there is nothing about trampolining, niacin or saunas that I’d expect to trigger histamine issues. Therefore, I would not look at any of these factors as a potential ’cause’, but consider what role they may have played in unmasking imbalances that were previously not visible. To that end, there can be a number of downstream effects when Niacin is introduced (due to the vasodilation effects and, subsequently, increased blood flow to areas that may have been receiving suboptimal oxygen delivery) or after saunas (which influence vagal nerve, cellular detoxification, endoplasmic reticulum activity and also blood flow, especially to the gut). However, to connect this up, we’d need to know the full case history, current metabolic patterns and context (eg. Organic Acids test results) otherwise its guesswork… and, as always, we should also consider the role of coincidence (as many people with nasal congestion will see a dramatic shift in the histamine issues across the body).

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