I wrote here on how elevated blood histamine levels can manifest systemically. I wrote here on its potential association with motion sickness. But the neurotransmitter histamine can play several other roles as well.

Histamine Receptors

Any signaling molecule in the body accomplishes its task via receptors, which it fits into like a lock and key. Histamine has four of them, reflecting its different jobs.

The H1 receptor has a stimulating effect when bound to histamine. It’s best known for its role in allergies. This receptor also appears in two parts of the brain, the hypothalamus and the limbic system. The hypothalamus is the body’s master endocrine (hormone) gland, responsible for (among other things) the sleep/wake cycle. If you’ve ever taken a Benadryl for allergies, this is the reason why the regular version can cause drowsiness.

The H2 receptor is also stimulating, and it is found in the stomach, responsible for gastric (stomach) acid production. H2 blocking drugs like cimetidine are often prescribed for acid reflux, to lower stomach acid production. (It’s much better to address the root cause, though. See this article for more on acid reflux.) H2 receptors also appear in the CNS, in the hippocampus (best known for new memory formation), amygdala (best known for the fear response), and basal nuclei (best known for initiating or inhibiting movement).

H3 and H4 receptors are both inhibitory, meaning that histamine has a suppressive effect when bound to these. H3 tends to have a suppressive effect on the basal nuclei (countering H2’s stimulating effect), and H4 has a suppressive effect upon the NMDA receptors. Medications affecting these are far less common.

Histamine and Gastric (Stomach) Acid

As mentioned above, histamine is necessary for the formation of stomach acid—so high histamine levels, or histamine intolerance, can create excess stomach acid and reflux. Excess histamine levels is usually secondary to gut inflammation from another source. It can also occur due to undermethylation, often secondary to MTHFR genetic mutations. This is because methylation is one of the main pathways for histamine elimination.

On the flip side, adequate stomach acid is necessary to trigger the esophageal sphincter to close. Low histamine levels can thus also pose a problem, potentially leading to low stomach acid—and thus, to reflux. This may be due to a deficiency in the amino acid histidine, the precursor for histamine. Histidine is found in protein, such as meat, fish, poultry, soy, dairy, eggs, nuts, and seeds. Another possible cause of low histamine levels may be overmethylation, or taking excessive amounts of methyl donors as supplements. Again, this is because methylation is one of the main pathways for histamine elimination.

Histamine and Sleep

As mentioned above, antihistamines like Benadryl have sedative effects (unless it’s the non-drowsy variety). This is because antihistamines specifically antagonize, or work against, the stimulating H1 histamine receptors in the hypothalamus. This stimulates sleep.

One might therefore deduce that histamine stimulates wakefulness, which is in fact the case. Histamine (or histamine receptor stimulants) in the CNS decreases sleep. Those with sleep disorders like narcolepsy or hypersomnia (excessive sleep) often have low levels of histamine in the CNS.

High blood histamine levels won’t necessarily translate to high CNS histamine, though, as histamine does not readily cross the blood brain barrier (BBB). In the brain, histamine is made locally from histidine. Nevertheless, in sleep disorders, checking neurotransmitter histamine levels (via urine neurotransmitter testing) may be helpful.

Cognition, Learning, and Mood

As you might guess based upon the other CNS locations of H1 and H2, histamine has broader effects than just allergies and stomach acid production.

Given the receptor location in the hippocampus and the amygdala, it’s not surprising that histamine also plays a role in memory and learning. Histamine’s role in these functions are complex, though, since the H4 receptors inhibit NMDA receptors, which are also involved in learning and memory.

The limbic system, also a site of stimulating H1 histamine receptors, is made up of many brain structures associated with emotions. Since here, histamine plays an excitatory role, high levels have been associated with anxiety and even mania (perhaps why psychosis and hallucinations are potential severe reactions associated with H2 blockers: when those are blocked, more histamine is available to flood the H1 receptors instead). Again, methylation can also play a role here: undermethylation can lead to high histamine levels, which can also lead to anxiety.

Low histamine levels, on the other hand, can lead to understimulation of the limbic system, and thus, depression.

Histamine imbalance certainly isn’t the most common neurotransmitter associated with mood disorder symptoms, but it’s one worth checking on urinary neurotransmitter testing if other treatments don’t appear to improve symptoms.

The Upshot

Histamine mediates a lot more than just allergic responses. As with nearly anything else, blocking its effects in one place can have unintended consequences elsewhere. High or low levels are clues to a deeper problem, and not the problem in and of themselves.

The Many Faces of Histamine