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When you think of antihistamines, you're probably only thinking about getting rid of a runny nose, but we're learning that antihistamines can be used for nausea, insomnia, and even depression!

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If you’re allergic to cats, or pollen, or dogs, or dust mites, or all of the above, you probably have antihistamines on hand. And when you take a dose, you may not be thinking of anything but stopping the sneezing, watery eyes, and general inflamed itchy irritation.

But scientists are learning that antihistamines are a pharmaceutical jack of many trades. Turns out, they don’t just work to relieve typical allergy symptoms that flare up when exposed to, say, ragweed. We’re learning that different types of antihistamines can fight insomnia, nausea, even depression.

And none of those things are allergies, so how can antihistamines do that? It’s down to the widespread presence of these molecules, and the receptors that bind to them, throughout our bodies. So let’s look at how we first discovered these molecules and how we’re still figuring out what they can do for us.

Thanks to scientists studying the compounds that cause them, the receptors in our bodies that modulate them, and the drugs that provide sweet relief, we have figured out the basics of what causes allergic reactions. Individuals with an allergy to, say, ragweed, release excess amounts of specific antibodies when they’re exposed to it. These antibodies bind to cells that store a substance known as histamine, triggering them to release some of it.

Then the histamine attaches to receptors, or binding points, in the affected tissues and, achoo! The receptors kick into action, increasing the permeability of blood vessels and inflaming surrounding tissues. Drugs called antihistamines can stop this by binding to the receptors instead, snuffing out the cascade of symptoms.

But the way we figured all that out was not straightforward -- and it is still ongoing. Learning about the natural and human-made roles of histamine and its receptors has helped us learn to treat allergies, but there’s potential for way more. And that’s because histamine, and histamine receptors, are actually.

They’re a pretty big deal. The first descriptions of human allergies were recorded in ancient China, Egypt, and Greece. These ancient scientists chronicled the misery of dripping noses, sneezing fits, and hives.

They also noted that exposure to certain substances triggered these symptoms, but not in everyone. Throughout the 19th century, researchers conducted experiments that laid the foundation for the study of these reactions. And in 1902, a pair of French scientists described experiments in which they injected animals like dogs and pigeons with toxins from jellyfish and sea anemone.

Those substances were known to cause severe reactions in humans. Now the first injections didn’t result in reactions, and the researchers hypothesized that these initial exposures might inoculate the animals against the toxic proteins. But instead, they found that a second dose triggered a violent, often fatal reaction.

The phenomenon was named anaphylaxis, in contrast to prophylaxis, or protective effects. So that’s where the word anaphylaxis came from! Which I did not know until now.

At this point, though, people still believed that allergies were caused by poisons. In 1904, however, researchers realized that the allergens causing the reactions were basically harmless, until something happened to cause an individual to react to them. Then by 1906, the observation that hay fever was linked to pollen helped connect the dots between experiments and allergies in the real world.

Symptoms only appeared after years of contact with a particular pollen. When sensitivity to pollen reached a critical threshold, bam, the next pollen season would be a sneezy one. For those unfortunate enough to experience an anaphylactic reaction, it would be way worse.

The role of histamine would be uncovered in experiments around the same time. Researchers were studying a fungus called ergot that grows on rye and wheat. Ergot was known to cause shooting pains, burning sensations, and even hallucinations in people who eat contaminated grain.

In 1907, chemists had synthesized histamine, and in 1910, they isolated histamine from ergot. In time, researchers demonstrated that histamine had a stimulant effect on smooth muscle from the gut, affecting acid secretion and digestion. They also found histamine working in the respiratory tract, lowering blood pressure, and inducing a shock-like condition when injected into animals.

But it wasn’t until 1927, when histamine was isolated from healthy liver and lung samples, that scientists realized that histamine is a normal part of the human body. When they’re not turning us into sneeze machines, histamines play a role in a lot of important biological functions. They work as signaling molecules, meaning they send messages between cells.

They help mobilize white blood cells to kill disease-causing agents, and they keep our brains awake when we have things to do. But experiments also showed that histamine in the lung increased dramatically after anaphylaxis, implicating it in allergic reactions. Researchers assumed that there must be some sort of substance that would have the opposite effect, and took up the quest for these anti-histamines.

The first antihistamine, described in 1937, blocked histamine in the guinea pig gut, as well as in the respiratory system. The finding provided a lot of evidence for the idea that histamines do a lot more than trigger our immune systems to freak out in the presence of harmless allergens. The same year, researchers reported a related antihistamine that protected the guinea pig from the lethal effects of anaphylaxis.

The first antihistamine for humans went on the market in 1944. The next component in histamine and antihistamine research was the search for whatever it is in the body that they both act on. Now based on the fact that antihistamines worked against allergies, the evidence was strong for the existence of at least one histamine receptor.

The idea was that antihistamines attach to these structures and physically block the action of histamine. We now know that there are, in fact, several histamine receptors, and they’re involved in a lot more than allergies, and in a lot more places than just our faces and skin. And while scientists are still figuring out what exactly they’re doing all over our bodies, it’s clear that they are important.

As early as the 1940s, researchers were proposing that there must be multiple types of histamine receptors, because the antihistamines at the time didn’t seem to block every known histamine response. The first receptor, the one that antihistamines did work on, was eventually dubbed H1. We now know H1 is the most ubiquitous histamine receptor and it is found throughout the body.

The second receptor, H2, was actually identified starting in 1972, when researchers developed an antihistamine that did block histamine, but not via the H1 receptor. The development of additional antihistamines that worked on H2 was a big step in the treatment of acid reflux disease and stomach ulcers. It soon became clear that histamine calls a lot of the shots when it comes to the secretion of stomach acid, especially via H2.

Since then, H2 receptors have also been found in heart and immune cells, among other tissues. Now in the 1970s and 80s, researchers were also on the trail of a potential third type of histamine receptor. Experiments had suggested that histamines seemed to be doing something in the central nervous system, and the available anti-H1 and H2 antihistamines didn’t seem to touch them.

The H3 receptor was officially named in 1983 when researchers proposed that another type of antihistamine was somehow modulating neural activity in tissue samples from rat brains. Since then, H3 has also been found in the human brain. Now.

The H4 receptor is the most recent to be proposed, around the turn of the 21st century. Unlike the receptors discovered earlier, it was identified through a search of human genome data. See, now that we know the sequence of the human genome, we can search it for sequences that are similar to ones we already know.

In this case, researchers spotted a fourth sequence that looked similar, but not identical, to the three histamine receptors we already knew about. They’ve also found compounds that act against what seems to be this fourth kind of histamine receptor, and the research is ongoing. It is also clear that different combinations of histamine receptors seem to play a role in different conditions.

Understanding what histamine and its receptors are doing throughout our bodies has really gone hand-in-hand with the development of drugs that act on them. And because there are so many kinds of histamine receptors, active in so many different parts of our bodies, well, that means antihistamines can potentially do a lot. Some of the so-called first generation antihistamines are still in use today.

Like diphenhydramine, which is the active ingredient in Benadryl. That acts on the H1 receptor and provides relief from sneezing, watery eyes, and itchy skin from allergies, and it’s also an active ingredient in some cold and motion-sickness medicines. These drugs tend to work really well to block those symptoms, in part because they pass from the blood into the nervous system and work not only in the nose but in the brain.

Studies have suggested that histamine binding to H1 in the brain increases arousal and wakefulness. And since antihistamines stop that from happening, they can make you really drowsy. And that might be why that same active ingredient is also sold as a sleep aid.

So-called second generation antihistamines don’t cross the blood-brain barrier as easily. These include loratadine, which blocks H1 and works to stop hives and dampen sneezing from allergies, but not from colds. So it’s marketed as a non-drowsy treatment for allergies.

Another well-known second generation antihistamine is ranitidine, which blocks H2 and works against stomach acid and heartburn. Unfortunately for those who found relief from it, it was pulled from the market due to a contaminant and it isn’t likely to return to pharmacy shelves. But there’s also famotidine, which is very similar.

With everything scientists have learned, histamines are still a very hot area of research. They still haven’t ruled out that there may be even more variations on histamine receptors, with slight differences in location and function. And since the discovery of H3 and H4 receptors is so recent, researchers are still looking into synthesizing new molecules that act on them to control the symptoms of all kinds of diseases.

Scientists are also tapping into histamine and its receptors to unlock new insights into psychiatric conditions, like depression, obsessive-compulsive disorder, schizophrenia and more. In fact, some already approved antidepressants interact with the H1 receptor. But recent experiments in mice have revealed that histamine-related inflammation can mess with mood-stabilizing neurotransmitters like serotonin.

So researchers believe further study of how they all work together could improve serotonin-based treatments for depression in humans. Now it’s also worth noting that it’s not always dialing down the activity of histamine receptors that can treat what ails us. Some researchers are looking into all the different ways antihistamines and histamine receptors can interact.

Like with the H3 receptors in the brain. In a study published in 2019, a group of Japanese researchers looked at the effect of histamine on H3 in long-term memory in mice and humans. And they hypothesized that increasing histamine in the brain might improve memory.

In their experiments, lab mice treated with high doses of compounds that releases histamine from H3 receptors showed improvements in memory after treatment. And a human trial they conducted found that participants who didn’t do well on memory tests were better able to recognize images after high doses of a drug similar to histamine. However, people who performed well on the tests to begin with actually got worse.

On top of all of the above, scientists are also looking at the role of histamine in everything from exercise benefits to cancer treatments to Tourette’s syndrome. And this is an abridged list of the future of histamine research. So as you can see, histamine isn’t just the culprit in sneezing, itchy eyes, and hives.

With its role in the brain, stomach, and so much more, there’s still a lot of pioneering to do in the world of histamines. And for all the intrepid researchers studying it who are allergic to their lab animals or something in the air, we will raise a cheer to non-drowsy antihistamines to help your science go a little smoother. Thanks for watching this episode of SciShow, and thank you as always to our patrons for helping to make it possible.

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