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).