Training adaptation: the histamine connection

Inflammation and training adaptation

How is that post-training cold water immersion and ice baths could harm training adaptation? The most likely explanation in plain English is that intense workouts produce micro-damage to muscles, inducing repair processes that leave them slightly better adapted than they were before. But inflammation is an important part of this recovery process, and if you damp down inflammation by using ice/cold (a common approach when athletes sustain an injury), you are interfering with adaptation.

There’s long been good evidence for this effect; back in 2002, research found that anti-inflammatory medication such as ibuprofen and acetaminophen (tylenol/paracetamol) inhibits protein synthesis in muscles after high-intensity exercise⁽⁵⁾.And just four years later, another study found that ibuprofen inhibited muscle strengthening in rats⁽⁶⁾. In a nutshell, while anti-inflammatory drugs like ibuprofen might reduce pain, they can retard the repair of tissues (and therefore adaptation) by blocking the inflammatory damage/repair cycle.

Digging a bit deeper, more recent research has established that oxidative damage to muscle tissue by chemical species that are produced naturally during intense exercise (eg hydrogen peroxide, superoxides and other reactive oxygen species) are part and parcel of training adaptation. In particular, these reactive oxygen species act as intracellular messengers mediating skeletal muscle adaptations following exercise⁽⁷⁾. This is why elevated levels of oxidative stress markers have been associated with greater training adaptations after 6-weeks of exercise training in humans⁽⁸⁾. It also explains why trying to dampen down oxidative stress and associated inflammation using supplementation of high doses of certain antioxidant nutrients such as N-acetyl cysteine (NAC) and vitamin C can blunt training adaptations in the longer term (see this article)^(9,10).

Histamine and training adaptation

Just as training adaptation can be enhanced or impaired by the factors listed above, very recent research is providing evidence about the role of a signalling molecule that you are probably already familiar with in a different context - histamine. Histamine is a signalling chemical released by the immune system to communicate information between different cells of the immune system. If you are a hay fever sufferer or have allergies, you will already understand some of the actions of histamine in the body – ie its role in causing allergic and anaphylactic symptoms. In an allergic reaction – for example pollen in hay fever – the body’s immune system overreacts to a harmless foreign protein. This leads to a cascade of immune reactions and a release of histamine, which causes allergy symptoms.

However, there’s more to histamine than its role in immune function and allergies. It also regulates countless bodily functions and plays a key role in the body’s inflammatory response. More importantly for athletes, there’s growing evidence for the role of histamine in the day-to-day responses to regular training. It turns out that endurance exercise turns on pathways that stimulate the production and the release of histamine from special cells known as ‘mast cells’ in skeletal muscle tissue^(11,12). In turn, the released histamine appears to upregulate more than 750 genes involved in protein production following exercise – genes that play an important role in processes such as inflammation, vascular function, metabolism and cellular maintenance^(13,14). In short, histamine release during exercise seems to be a play a vital role in helping to switch on various training adaptation processes that take place following exercise⁽¹⁵⁾!

Testing the histamine theory

Although there is good theoretical evidence for the role of histamine in facilitating proper training adaptation, is this actually true in practice? In other words, are there studies comparing training adaptation in humans who train with normal histamine release or with histamine release blocked? The sharp-eyed and hay fever sufferers reading this will of course know that blocking histamine release is exactly what antihistamines do – a medication taken by millions of hay fever sufferers every spring and summer. This then is a very important question to answer, as athletes using antihistamines could be losing out on training adaptation potential following their workouts!

New research

To try and answer this question, a new study by US researches has investigated the link between histamine release and training adaptation⁽¹⁶⁾. Published in the ‘Journal of Applied Physiology’, this study set out to determine the effect of normal histamine release vs. blocked histamine release (using anti-histamines) on the improvements in fitness, aerobic capacity, oxidative metabolism and measures of vascular function, following six weeks of endurance exercise training in young healthy, active men and women.

What they did

Sixteen (6 males, 10 females) active and healthy individuals participated in the study, which was a randomized double-blind placebo-controlled exercise training study. This meant that the participants were randomly allocated to either a control or intervention group and that neither the researchers, nor the participants knew which participants were given a placebo and which were given the intervention (histamine blockers), thus making the study more rigorous.

To provide a training stimulus, all the participants underwent a 6-week supervised endurance exercise training intervention, exercising 3-4 times per week, and totalling 21 sessions in total. These sessions consisted mainly of continuous moderate-intensity exercise conducted around (60% of each participant’s VO2max) – an intensity that is known to elicit a robust histamine-mediated vascular response during recovery from exercise⁽¹⁷⁾. In addition, high intensity intervals were included, as some individuals do not show, or have blunted, adaptations to continuous moderate-intensity exercise alone⁽¹⁸⁾. However, prior to all training sessions, the participants received one of the following:

·       Histamine blocked group - (taking anti-histamines): 540 mg of fexofenadine and 300 mg of ranitidine.

·       Control group – inert placebo capsules that looked exactly the same but contained no anti-histamines.

The dosage of anti-histamines given to the experimental group is known to result in more than 90% inhibition of histamine release, lasting for six hours after administration. Fexofenadine and ranitidine were chosen because they do not have sedative effects, nor do they impact resting blood flow, heart rate, blood pressure, or smooth muscle tone. To monitor the participants’ fitness progression, incremental cycle exercise testing to exhaustion was conducted every two weeks, along with peak aerobic power testing. In addition, a number of metabolic and biochemical tests were carried out using blood sampling and muscle biopsies to see how the participants’ vascular and oxidative capacity changed over the 6-week intervention.

What they found

The key finding was that while both the control and anti-histamine group experienced gains in fitness, the participants taking anti-histamines suffered a significantly poorer (blunted) training response. In particular, the rate of improvement in peak power output over the period of the exercise training intervention was 3.05% per week in the placebo group taking no histamine blockers, but just 1.62% per week (ie only around a half) in the histamine blocked (anti-histamine) group (see figure 2).

Figure 2: VO2max and peak power changes with and without anti-histamines

There was similar trend for VO2max, where the participants taking the placebo fared better than those taking anti-histamines, gaining an average of 0.31L/min over the six weeks compared with 0.20L/min in the anti-histamine group. While this difference was not quite large enough to show statistical significance, a study with a larger number of subjects would likely have shown this. When the researchers compared the vascular and oxidative capacity changes of the two groups, they found that the poorer training adaptations in the anti-histamine group were paralleled by blunted adaptations in vascular function and oxidative enzyme capacity, providing further evidence that histamine release plays a key role in training adaptation, and that blocking it can blunt training adaptations.

Implications for athletes

What do these findings mean for athletes, who may be using anti-histamine medication – for example, hay fever sufferers who use it during the late spring and summer months when pollen levels start to climb? For a good analysis, we can turn the study authors’ own conclusions where they state the following:

“Histamine appears to be intimately involved in the adaptive processes that occur within skeletal muscle in response to aerobic or endurance exercise. Blocking histamine’s actions during endurance exercise training using common over-the-counter antihistamines, results in diminished gains in fitness, which are linked to specific deficits in training adaptation. However, these findings are yet to be translated into appropriate guidance for routine users of antihistamines, who may be taking only one type of anti-histamine at lower doses than used in this study and not always prior to training.”

In a nutshell, the authors commented that while they can’t be certain that their findings will always be replicated in athletes taking anti-histamines, there’s solid evidence that under certain circumstances, using anti-histamine medications can blunt your training adaptation response – a very undesirable outcome.

For athletes who are hay fever sufferers or who regularly use anti-histamines for other reasons, what’s the best advice? Given their negative effects on training adaptation, it might make sense for athletes who suffer from hay fever only mildly to exercise caution when considering their regular use. For example, it might be preferable (if possible) to restrict anti-histamine use to days where the pollen count is high and symptoms are particularly prevalent rather than using it every day in the summer out of habit. This will of course depend on the severity of hay fever symptoms you experience; if you are severely affected, undertaking high quality training might be difficult without anti-histamine use!

Another option is to try and separate your ingestion of anti-histamine medication and your training sessions by six or more hours. So for example if you take an anti-histamine tablet in the morning, you could try and schedule your training sessions for late afternoon or early evening, by which time the bulk of the histamine blocking effect following exercise will be reduced. Also, bearing in mind that the biggest impact of anti-histamine use seems to be on peak power, it might be especially worthwhile trying to schedule intense workouts well away from prior ingestion of medication.

Bear in mind too that pollen levels fluctuate wildly with weather. In particularly, heavy rain helps to lower pollen levels considerably by ‘washing it out’ of the air. Therefore, if you live in a wet or changeable climate, you could schedule high-quality workouts for wet days where you can get away with no or reduced medication. A final option to consider for those with access to decent home training equipment such as treadmills and stationary bikes is to train without anti-histamine medication but to compensate by using an air purifier/pollen filter at home, both during exercise and afterwards!

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