I wrote here on the health benefits of sleep, and on practical solutions to insomnia. This is great, if the issue is one structuring your time to prioritize sleep, or minor changes to your routine.

But for more extreme cases of chronic insomnia, we’ll need to delve into neurotransmitters (and related hormones.) First, let’s investigate the physiology of sleep.

The Circadian Rhythm (Process C) and Exhausting Yourself (Process S)

Two processes govern sleep. The first is the circadian rhythm, governed by cortisol, serotonin and melatonin production, and dependent on the day/night cycle. The circadian rhythm is called Process C in the literature. The second process is how much you use your brain in a given day. The “exhaustion” process, called Process S, is the reason why you tend to sleep well when you wear yourself out, physically and/or mentally.

More specifically, your body’s energy currency is ATP (Adenosine Triphosphate). When you burn energy, you free adenosine, which then accumulates in the brain throughout the day. As it settles into the adenosine receptors, it sends your brain the signal, “it’s been a long day. Time to rest and recover.” Once you do sleep, the body reassembles the adenosine into ATP again, so you’re ready for the subsequent day. (Caffeine keeps you awake by antagonizing these receptors so that adenosine can’t get to them, by the way–I wrote more about this process here). Neurons that receive this signal also receive signals from GABA, the primary inhibitory neurotransmitter in the brain. More on this below.

Glutamate and GABA

The primary inhibitory and the primary excitatory neurotransmitters in the brain happen to share the same receptor, called NMDA. (This is the same receptor responsible for excitotoxicity in cases of primarily chemical toxicity or chronic infection.)

Glutamate is the excitatory neurotransmitter, and it’s the other side of the coin from GABA. GABA is posited to be the most important neurotransmitter associated with onset of sleep, as it antagonizes (blocks the action of) all of the other stimulating neurotransmitters in the “amine” family, including serotonin, epinephrine and norepinephrine (adrenaline), dopamine, and histamine, as well as glutamate of course. It doesn’t directly lower them though.

As mentioned above, GABA also works on the neurons with adenosine receptors, so it likewise contributes to Process S. This is the reason why the most popular sleep medications, including Ambien and benzodiazepines, work on the GABA system.

Probably because it blocks the effects of adrenaline, GABA also tends to lower cortisol. Cortisol, the stress hormone, is the other half of Process C, and therefore suppresses melatonin.

Interestingly, in people with chronic insomnia, GABA levels actually are higher than in those without sleep issues. I suspect this is a compensatory mechanism: the body is attempting to correct the problem.

Serotonin and Sleep

Serotonin plays both sides of the fence. On one hand, serotonin is the direct precursor to melatonin, so too little will likely mean melatonin deficiency and therefore insomnia. This is the reason why serotonin precursors such as tryptophan and 5HTP can sometimes be helpful for insomnia. Women who struggle with insomnia during PMS as well as during perimenopause and menopause likely have low serotonin, since estrogen promotes serotonin. (The other main issue is that in both cases, progesterone also tends to be low, and progesterone stimulates GABA receptors.)

On the other hand, serotonin production is a sun-dependent process, and is in that sense the opposite of melatonin, which rises at nightfall. So too much serotonin also can trigger insomnia. This is the reason why antidepressants such as SSRIs are so often associated with insomnia.

Taking SSRIs is the most common cause of too-high serotonin, but taking serotonin-producing supplements like 5HTP or tryptophan can do it too. Other possible causes include diet too high in carbs and too low in protein (which, by the way, is part of the reason why you crave sugar when you’re depressed. You’re self-medicating with serotonin). A speed-up MTHFR mutation can also raise serotonin levels. In these cases, the best treatment involves a dietary adjustment, and/or MTHFR support, respectively.

Adrenaline and Sleep

It’s pretty obvious that the “fight-or-flight” condition of the sympathetic nervous system is incompatible with sleep. High catecholamines such as norepinephrine and epinephrine tend to rise with chronic stress, as well as hyper-focus during the daytime.

Perhaps paradoxically, a lot of the patients I’ve tested turn out to be low in catecholamines, which has a similar effect to high levels. This, I suspect, has to do with the body’s compensatory mechanisms, which I wrote about in more detail here.

Because GABA antagonizes norepi and epi, supporting GABA is still one of the best short-term solutions to this issue. This can be done with GABA supplementation directly, with herbs that stimulate GABA receptors, or with taurine, which I wrote more about here.

Peptide Hormones and Sleep

Finally, I wrote here on how hypoglycemia can trigger insomnia by stimulating adrenaline and then cortisol, but the two peptide hormones associated with hunger and satiety, leptin and ghrelin, can also play a role. This study shows that low leptin and high ghrelin is associated with shorter sleep duration.

The best way to address this is to regulate glucose with a healthy diet.

The Upshot

If you suffer from chronic insomnia, both salivary cortisol testing and urinary neurotransmitter testing can help to elucidate the underlying cause.