Monoamines: A Full House

When I ask an audience at the beginning of a presentation whether they can name the 5 basic monoamines functioning in the human brain, within a few seconds, the neurotransmitters serotonin, dopamine, and norepinephrine are shouted out. But then confusion about the other 2 fills the room. I often hear glutamate, γ-aminobutyric acid, and acetylcholine, but I rarely hear the correct answers. Spoiler alert: The other 2 are histamine and melatonin. However, as is usually the case in science, the story is not that simple. So let’s take a walk around the monoamine block.

Monoamines are molecules that contain 1 amino group (a nitrogen atom bound to 2 hydrogen atoms, with the formula NH₂) that is connected to an aromatic ring (a 6-membered carbon ring with 6 hydrogens bound in a shared circle [such as benzene, C₆H₆]) by a 2-carbon chain (eg, -CH₂-CH₂-). The Table lists the classifications of the 5 monoamines in humans, and Figure 1 displays their synthetic pathways.

Dopamine, Norepinephrine, and Serotonin

Clinicians are well acquainted with the monoamines dopamine, norepinephrine, and serotonin. These neurotransmitters and their accompanying brain circuitry are foundational to the practice of psychiatry. Epinephrine, a metabolite of norepinephrine, is also a monoamine, but it has little direct activity in the human brain. The vast majority of epinephrine is produced in the adrenal medulla and is released directly into the circulatory system. It is believed not to cross the blood-brain barrier. Epinephrine’s primary activity is related to peripheral endocrine and autonomic functions. A tiny number of neurons in the brain’s medulla oblongata, which resides in the brain stem, produce epinephrine. The medulla oblongata regulates autonomic functions, including cardiovascular, respiratory, and vasomotor activity. Strong evidence demonstrates that epinephrine improves memory consolidation during emotionally laden experiences. Supporting the difficulty for epinephrine to cross the blood-brain barrier, sotalol, a peripherally restricted drug that antagonizes β-adrenergic receptors, blocks the effects of epinephrine on memory consolidation.¹

So What About Histamine?

Histaminergic neurons originate primarily from the tuberomammillary nucleus of the hypothalamus. The effects of antihistamine properties of medications, including sedation and weight gain, are well known, but the important properties of histamine agonism are often forgotten. Unsurprisingly, its primary role in the brain is to facilitate wakefulness, enhance arousal, and suppress appetite. Increasing histamine agonism has informed drug development for the treatment of hypersomnia, narcolepsy, obesity, and cognitive impairment secondary to sedation.

There are 4 histamine receptors in humans, with the histamine H3 receptor (H3R) functioning as a presynaptic autoreceptor that inhibits further histamine release when activated by excessive histamine at the neuronal synapse. This puts the brakes on the increased wakefulness and hypervigilance that would occur with too much histamine agonism of the postsynaptic histamine H1 receptor. Pitolisant (Wakix), the first successful candidate drug for the treatment of excessive daytime sleepiness or cataplexy in adult patients with narcolepsy, achieved US FDA approval in 2019. Its mechanism of action is an H3R antagonist/inverse agonist. A previous editorial shared a more detailed review of histamine.²

Misunderstood, Neglected Melatonin

Despite its essential role in humans in managing circadian rhythms, including synchronizing the daily sleep-wake cycle and seasonal rhythms known as circannual cycles, melatonin remains the most misunderstood and neglected monoamine in psychiatry. It serves the additional important function as an antioxidant, thereby decreasing oxidative stress. Melatonin is primarily synthesized in the mitochondria of the pineal gland, a pea-sized endocrine gland in the center of the brain, but, interestingly, outside the blood-brain barrier.

Minuscule concentrations of melatonin are used to manage the circadian rhythms in humans. Approximately 80% of melatonin is synthesized during the night, with human plasma concentrations ranging from a low of 10 to 20 pg/ml during the day and a high of 80 to 120 pg/ml at night.³ To provide context, a common over-the-counter (OTC) dose of melatonin used to treat insomnia is 1 mg, which is 10 to 13 g. A picogram (pg) is 10 to 12 g.

The human brain adjusts melatonin production in response to exposure to visible light. Significantly, blue light inhibits the pineal gland’s synthesis of melatonin, whereas orange/red light has no impact on melatonin production. Sunlight enters the eye and activates the retinal photosensitive ganglion cells, which send a signal to the suprachiasmatic nuclei, which then instruct the pineal gland to suppress melatonin synthesis and to release hormones that increase wakefulness. In the absence of blue light, the circuit ramps up melatonin synthesis, promoting drowsiness and sleep onset (Figure 2).

Melatonin production decreases with aging, providing one hypothesis for why sleep duration often decreases with age. In contrast, during adolescence, the timing of melatonin release changes, delaying their sleep-wake cycle.⁴ This phenomenon has resulted in the common recommendation for a later start time for middle school and high school students.

Although melatonin is used ubiquitously in the US for the treatment of insomnia, there are no FDA-approved formulations, and the literature overall does not support its efficacy. Additionally, OTC doses are exceedingly high, and the immediate-release formulations lack strong evidence of efficacy. A 2023 guideline update on the diagnosis and treatment of insomnia concluded⁵:

“Prolonged-release melatonin can be used for up to 3 months in patients [aged] 55 years [or older]. Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon, and phytotherapeutics are not recommended for insomnia treatment.”

Not to Be Forgotten: Trace Amines

No discussion of monoamines would be complete without mentioning the trace amines, which exist in low concentrations compared with the 5 main monoamines. Although a large number exist, the 4 basic trace amine groups include octopamine, phenethylamine, tryptamine, and tyramine. Research in the trace amine arena is young, and much remains to be learned. Originally characterized in the 1970s, they are defined as endogenous monoamines present at physiological levels, at least 2 orders of magnitude lower than those of serotonin, dopamine, and norepinephrine.⁶

Trace amines were all but forgotten until 2001, when the trace amine–associated receptors (TAARs) were discovered. Intensive research ensued, and the emerging consensus is that trace amines fine-tune the 5 core monoamine circuits through a range of activities. Through their signaling at the 6 characterized TAARs, trace amines can modulate neurotransmitter presynaptic release, regulate monoamine transporter function, impact neuronal excitability, and likely play a significant role in brain-gut-metabolic functioning. They continue to be studied in wide-ranging clinical trials, including mood disorders, schizophrenia, generalized anxiety disorder, cognitive disorders, Parkinson disease, and brain-gut-microbiome signaling. In psychiatry, for example, the TAAR1/5-HT1A agonist ulotaront experienced a few setbacks in 2023 but is still in phase 2 and 3 clinical trials.^7-9

Concluding Thoughts

Monoamines have been front and center since the 1950s with the development of the first antipsychotic and antidepressants: chlorpromazine, iproniazid, and imipramine. Three of the 5 major brain monoamines are well known by clinicians in the psychiatric vernacular. Serotonin, dopamine, and norepinephrine are the “3 of a kind” in the full house of the psychiatrist’s molecular poker hand. Histamine and melatonin, the “2 of a kind” completing the full house, have far less recognition as monoamines. However, all 5 are necessary for the healthy and precise functioning of our brain and deserve equal awareness and understanding.

References

1. Roozendaal B, McGaugh JL. Memory modulation. Behav Neurosci. 2011;125(6):797-824.

2. Miller JJ. Histamine: psychiatry’s neglected monoamine. Psychiatric Times. May 17, 2024. https://www.psychiatrictimes.com/view/histamine-psychiatry-s-neglected-monoamine

3. Karasek M, Winczyk K. Melatonin in humans. J Physiol Pharmacol. 2006;57(suppl 5):19-39.

4. Hagenauer MH, Perryman JI, Lee TM, Carskadon MA. Adolescent changes in the homeostatic and circadian regulation of sleep. Dev Neurosci. 2009;31(4):276-284.

5. Riemann D, Espie CA, Altena E, et al. The European insomnia guideline: an update on the diagnosis and treatment of insomnia 2023. J Sleep Res. 2023;32(6):e14035.

6. Berry MD, Gainetdinov RR, Hoener MC, Shahid M. Pharmacology of human trace amine-associated receptors: therapeutic opportunities and challenges. Pharmacol Ther. 2017;180:161-180.

7. Koblan KS, Kent J, Hopkins SC, et al. A non–D2-receptor-binding drug for the treatment of schizophrenia. N Engl J Med. 2020;382(16):1497-1506.

8. Dedic N, Dworak H, Zeni C, et al. Therapeutic potential of TAAR1 agonists in schizophrenia: evidence from preclinical models and clinical studies. Int J Mol Sci. 2021;22(24):13185.

9. Kantrowitz JT. Trace amine-associated receptor 1 as a target for the development of new antipsychotics: current status of research and future directions. CNS Drugs. 2021;35(11):1153-1161.