Histamine: Psychiatry’s Neglected Monoamine

Psychiatric TimesVol 41, Issue 5

Understanding the heterogeneity and complexities of the histamine monoamine system.




Would you be interested in a medication that increases your wakefulness, attention, and cognition? This medication would also help you lose weight, and it would not be scheduled by the US Drug Enforcement Administration.

However, we would have to inject this molecule directly into your brain because of its other effects on the body, which would include itching, hives, activated inflammatory response, increased permeability of capillaries to allow white blood cells to pass through, increased gastric acid secretion, bronchoconstriction, and vasodilation.

This molecule is already ubiquitous throughout the human body, and it is one that we in psychiatry rarely talk about unless we are describing the activities of drugs that block it: antihistamines.

Histamine is a monoamine, although in my experience, many psychiatrists do not realize this. During presentations on psychiatric medications, I often ask the audience to name the monoamines. Not surprisingly, the 3 that are always reported are serotonin, norepinephrine, and dopamine.

When I ask for more, the common replies include acetylcholine, glutamate, and GABAs—none of which are monoamines. The actual full list of classic monoamines includes histamine, melatonin, and epinephrine. There is also a rather large list of trace amines, but a discussion of these is for another time.

The Histamine System

One unique and rather curious habit we have developed regarding histamine is to use the term antihistamine when we discuss how our drugs interact with the histamine system. I rarely hear of drugs that are called antiserotonin, antidopamine, antimelatonin, or antinorepinephrine. So to be fair, let’s define the histamine system.

Histamine was initially discovered in 1910 and initially was thought to be a localized hormone-like molecule in the periphery associated with inflammatory responses, itching, and gastric secretion. Subsequently, it was found to be an important neurotransmitter in the brain and spinal cord, which will be the focus of this article.

The neurons that produce central histamine are located in the tuberomammillary nucleus in the posterior hypothalamus, which then project to a wide range of brain structures in which the histamine is released and diffuses across the synapses to agonize histamine receptors.

Four distinct G protein–coupled receptors have been extensively characterized, appropriately named H1, H2, H3, and H4. H1 and H2 receptors are prevalent both in the central nervous system (CNS) and the periphery, whereas H3 autoreceptors are primarily in the CNS and H4 receptors are primarily in the periphery on basophils and in bone marrow.

The 2 best characterized consequences of CNS postsynaptic H1 agonism by histamine are wakefulness and decreased appetite. Like other monoamines, histamine is synthesized in the presynaptic histamine neuron’s cytoplasm and then concentrated in vesicles by VMAT-2 pumps. These histamine-filled vesicles will merge with the presynaptic membrane and release the histamine into the synapse when the neuron is excited.1

H1 Antagonists for Insomnia

The first clinically used H1 antagonist was phenbenzamine (Antergan) in 1942, primarily for the treatment of allergic reactions. Other H1 antagonists quickly followed, including diphenhydramine (Benadryl) and promethazine (Phenergan). In 1957, the US Food and Drug Administration (FDA) approved hydroxyzine (Atarax, Vistaril) for anxiety, sedation, and pruritis. These are now classified as first-generation H1 antagonists, as they are lipophilic and readily cross the blood-brain barrier, with the associated effect of sedation.

Although some are approved for insomnia, they are approved only for short-term use due to there being no long-term studies and concerns about chronic anticholinergic effect, which is a common accompanying receptor activity.

In 1973, the FDA approved terfenadine (Seldane) as the first second-generation H1 antagonist due to minimal sedation as a consequence of decreased crossing of the blood-brain barrier. Terfenadine and astemizole (Hismanal) were both withdrawn from the US market in 1998 and 1999, respectively, due to their risk of QTc prolongation. There are many second-generation H1 antagonists currently available.

Understanding that histamine is a monoamine provides a possible clue to the FDA’s class warning of somnolence and sedation in all VMAT-2 inhibitors. Histamine binds more tightly to the VMAT-2 pumps than to the VMAT-1 pumps—hence the VMAT-2 inhibitors tetrabenazine (Xenazine), deutetrabenazine (Austedo, Austedo XR), and valbenazine (Ingrezza) are likely to deplete presynaptic histaminergic vesicles of histamine by inhibiting these VMAT-2 pumps.

This would create a decrease in the amount of histamine released into the synapse from the presynaptic histamine neurons, which hypothetically would have the same effect on postsynaptic H1 as an H1 antagonist would. Putatively, this could explain the somnolence and sedation observed by some patients with the VMAT-2 inhibitors.2

Associated Weight Gain

It is well established in psychiatry that antidepressant and antipsychotic medications with strong CNS H1 receptor antagonism increase weight gain in both short-term and long-term use.3-6 A remarkable amount of elegant scientific research has mapped out a compelling hypothesis as to why H1 antagonists disrupt appetite regulation and contribute to weight gain, in some cases quite dramatically.

An iconic study by Kim et al integrates a wide range of research on how H1 antagonism, which is orexigenic, and the peptide hormone leptin, which is anorexigenic, both ultimately converge on the same enzyme in the hypothalamus—albeit with oppositional effects on this enzyme—to increase or decrease food intake and satiety. In the hypothalamus, when the enzyme AMP protein kinase (AMP-kinase) is phosphorylated secondary to H1 antagonism, food intake increases with associated weight gain.

In contrast, the presence of leptin dephosphorylates AMP-kinase, which suppresses food intake and increases metabolic processes, leading to weight loss. Kim et al repeated these experiments on mice whose gene for the H1 receptor was deleted (knockout mice), and neither H1 antagonism nor leptin affected food intake or metabolic processes.7-10

H3 Autoreceptor Effects

Remarkably, the third histamine receptor was not discovered until 1983. Data from well-designed basic scientific research ultimately demonstrated that a new receptor, H3, functioned as a presynaptic autoreceptor, which responded to increasing histamine concentration in the synapse by shutting down further histamine synthesis and release into the synapse. This was a major advance, as it provided a hypothetical histamine circuitry, which further experiments confirmed as accurate.

The presynaptic histamine neuron would release histamine into the synapse, which would diffuse by entropy to the postsynaptic neuron, where it would agonize the H1 receptor. This H1 agonism began a cascade resulting in wakefulness, cognitive improvement, attention, and decreased appetite.11

Some of the synaptic histamine would also diffuse in a retrograde manner and bind to the presynaptic H3 receptors. When a certain threshold of histamine release is achieved, the histamine agonizing the H3 receptor shuts down further synthesis and release of histamine, hence reducing additional histamine release into the synapse and achieving the appropriate histamine synaptic equilibrium. This prevents the system from enacting too much wakefulness and appetite suppression.

Effects Promoting Wakefulness

The research that characterized the function of the H3 autoreceptor paved the way for new drug development of molecules that were functional antagonists of H3 to prevent histamine from decreasing further histamine presynaptic release, hence clinically resulting in increased wakefulness and possibly weight loss and cognitive benefits.

Pitolisant (Wakix), the first successful candidate drug, achieved FDA approval in 2019 “for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy.” Its mechanism of action is defined as “a histamine-3 (H3) receptor antagonist/inverse agonist.”12

ALTO-203, a novel molecule whose mechanism of action is an H3 receptor inverse agonist, has recently reported positive cognitive and emotional effects in healthy participants after a single dose. Alto Neuroscience has just announced the initiation of a phase 2 study to evaluate the efficacy, safety, and tolerability of ALTO-203 in patients with major depressive disorder and significant anhedonia.13

Antihistamine Medication Concerns

As always, the prescriber must weigh the risks with the benefits when prescribing or recommending any medication. An additional concern regarding the antihistamines is that many of them are available in over-the-counter preparations.

Hence, we should proactively educate our patients about these risks. Diphenhydramine is often listed as one of the most commonly used over-the-counter medications for insomnia, and it is an ingredient in many combination medications.

Although the FDA has approved some H1 antagonists as sedatives or for insomnia, the labels clearly state that they should be used for short periods of time. No long-term studies have been done with any of the commonly used antihistamines. Two significant concerns stand out:

  • H1 antagonists are associated with weight gain; chronic use may contribute to progressive weight gain, which may be further exacerbated by decreased activity related to the H1 sedating effects.
  • Many H1 antagonists also have anticholinergic activity. Chronic anticholinergic activity creates significant potential long-term risks, including cognitive impairment, blurred vision, dry mouth with increased dental issues, tachycardia, urinary retention, and constipation. It can also contribute to the onset of delirium.

Concluding Thoughts

It is important to understand the heterogeneity and complexities of the histamine monoamine system. In psychiatric practice, many of our antidepressants and antipsychotics contain some degree of H1 antagonism, and with some drugs, it is the most potent mechanism in play.

Choosing a medication with histaminergic properties for short-term symptom benefits may not be worth the long-term risks if the medication will be used chronically.

The common accompaniment of anticholinergic activity adds significantly to the long-term risks. As we progress in our understanding of the histaminergic system, novel drug targets are emerging that have the potential to further diversify our pharmacological armamentarium.

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times; Staff Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.


1. Panula P. Histamine receptors, agonists, and antagonists in health and diseaseHandb Clin Neurol. 2021;180:377-387.

2. Yadav R, Gati C. Packaging monoamine neurotransmittersCell Res. 2024;34(3):185-186.

3. Gill H, Gill B, El-Halabi S, et al. Antidepressant medications and weight change: a narrative reviewObesity (Silver Spring). 2020;28(11):2064-2072.

4. Mazereel V, Detraux J, Vancampfort D, et al. Impact of psychotropic medication effects on obesity and the metabolic syndrome in people with serious mental illnessFront Endocrinol (Lausanne). 2020;11:573479.

5. Kroeze WK, Hufeisen SJ, Popadak BA, et al. H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugsNeuropsychopharmacology. 2003;28(3):519-526.

6. Deng C, Weston-Green K, Huang XF. The role of histaminergic H1 and H3 receptors in food intake: a mechanism for atypical antipsychotic-induced weight gain? Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(1):1-4.

7. Kim SF, Huang AS, Snowman AM, et al. From the cover: antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinaseProc Natl Acad Sci U S A. 2007;104(9):3456-3459.

8. Obradovic M, Sudar-Milovanovic E, Soskic S, et al. Leptin and obesity: role and clinical implicationFront Endocrinol (Lausanne). 2021;12:585887.

9. Minokoshi Y, Shiuchi T, Lee S, et al. Role of hypothalamic AMP-kinase in food intake regulationNutrition. 2008;24(9):786-790.

10. Kola B. Role of AMP-activated protein kinase in the control of appetiteJ Neuroendocrinol. 2008;20(7):942-951.

11. Schwartz JC. The histamine H3 receptor: from discovery to clinical trials with pitolisantBr J Pharmacol. 2011;163(4):713-721.

12. Wakix. Package insert. Harmony Biosciences LLC; 2022.

13. Kuntz L. ALTO-203 for major depressive disorder and anhedonia: phase 2 study initiated. Psychiatric Times. April 3, 2024. Accessed April 14, 2024. https://www.psychiatrictimes.com/view/alto-203-for-major-depressive-disorder-and-anhedonia-phase-2-study-initiated.

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