Serotonin dubs thee sleepless

Serotonin is synonymous with sleep.

The misconception that serotonin promotes sleep is as strong as the dubious claim that serotonin is the “happiness” hormone.

Want to sleep better? Boost your serotonin.

But does it really help? What if it actually does the opposite?

What sleep looks like

There are typically four to six cycles of NREM and REM sleep during the night.

Almost 80% of total sleep time is represented by stages of NREM sleep, which consists of three stages that differ by sleep depth. N1 demonstrates the shallowest one and N3 reflects the deepest stage.

The physiological sleep architecture is defined by generalized slowing of EEG activity that reflects the progress from sleepiness to shallow sleep (N1), the presence of sleep spindles and K-complex waveforms that occur with the onset of deeper sleep (N2), and synchronized delta waves (N3) (R).

The periods of slow-wave sleep (SWS; synonymous to N3 and delta waves) occur principally in the first half of the night.

Stages of REM sleep are physiologically noticeable in the second half of the night and they lengthen with each following cycle of sleep (R).

REM sleep has been associated with dreaming, synaptic function, the regulation of emotions and mood, and learning and memory consolidation (R).

Point being, we need both NREM and REM sleep.

Sleep dysregulation and SSRI use

Approximately 60–90% of patients with major depression suffer from insomnia (problems with falling asleep or waking too early in the morning) and report difficulties in initiating and maintaining sleep, as well as early morning awakening and remaining awake. So they spend more time in N1 and N2 than N3. Certain SSRI drugs can reduce REM, but it doesn’t increase NREM or more specifically N3.

So sleep remains fragmented (R).

Serotonin has initially been thought to promote sleep, but after follow-up studies, researchers saw that serotonin was actually highest during day and dropped during the night (R). So this showed that serotonin is actually involved in wakefulness, and not sleep. However, serotonin does have both inhibitory and stimulatory effects, so it can make you feel drowsy, but it can also prevent proper sleep quality.

And that’s exactly what studies found on serotonin and sleep.

SSRIs are alerting both for volunteers and depressed patients. Sleep onset latency increases, thus making sleep initiation more difficult. Sleep continuity is disrupted; light (stage 1) sleep increases, and so do the number of arousal from sleep and the time spent awake at night” (R).

Fluoxetine use in depressive children and adolescents was associated with increased N1 sleep, number of arousals, and REM density but there was no change in ROL (rapid eye movement onset latency).” (R)

Many antidepressants with so-called activating effects (e.g. fluoxetine, venlafaxine) may disrupt sleep, while others with sedative properties (e.g., doxepin, mirtazapine, trazodone) rapidly improve sleep, but may cause problems in long-term treatment due to oversedation.

A few other sleep-related side effects of SSRI drug use is that it may worsen or induce primary sleep disorders like restless legs syndrome, sleep bruxism, REM sleep behavior disorder, nightmares, and sleep apnea, which may result from an antidepressant-induced weight gain (R).

Here are a list of a few anti-depressants and their effect on sleep.

As you can see from the top and second from the bottom, sedative anti-depressants improve deep sleep and sleep duration. And those drugs mentioned, all have anti-serotonin effects, blocking the 5-HT2A and/or 2C receptors. These drugs actually also have anti-histaminergic, anti-adrenergic and anticholinergic effects which can also help against overstimulation.

None of the other anti-depressants actually improve deep sleep or sleep continuity, because they’re not serotonin antagonists.

But I should add, not everyone gets sleep disorders from anti-depressants. The average prevalence of treatment-emergent insomnia in clinical trials with SSRI was 17% as compared to 9% out of patients randomized to the placebo arm. The average rate of treatment emergent somnolence in patients being treated with SSRI amounted to 16% as compared to 8% out of patients receiving placebo (R).

It’s still a big percentage of people!

What about tryptophan

But if serotonin is bad, why does tryptophan work?

First off it doesn’t work for everyone and also, tryptophan doesn’t just convert to serotonin.

Tryptophan is converted to melatonin and tryptophan metabolites in the gut, which can promote sleepiness in high doses.

One of the metabolites of tryptophan is kynurenic acid (produced through the kynurenine pathway), which is an NMDA antagonist (R, R). Magnesium and ketamine are also NMDA receptor antagonists and that’s one of their anti-depressant and sleep-promoting properties (R). Tryptophan can also be converted to quinolinic acid (through the kynurenine pathway), which is an NMDA receptor agonist. Quinolinic acid promotes wakefulness and is also neurotoxic in high doses.

However, creating more metabolites through the kynurenine pathway isn’t necessarily a good thing. Inflammation and stress are known to upregulate this pathway. Also, kynurenines (KYNs) and the kynurenine pathway (KP) enzymes, have been associated with a wide range of diseases including cancer, autoimmune diseases, inflammatory diseases, neurologic diseases, and psychiatric disorders (R).

A few other side effects of tryptophan, because it increases serotonin, is an increase in weight gain (R), deterioration of bone quality (serotonin contributes to osteoporosis) (R), liver problems (such as fatty liver, hepatic steatosis and liver fibrosis) (R), insulin resistance and much more.

Depending on the predisposition of each person, serotonin syndrome is a real threat with tryptophan supplementation. Symptoms include delirium, myoclonus, hyperthermia, and coma. In 1989 a new syndrome appeared, dubbed eosinophilia myalgia syndrome (EMS), and was quickly linked to supplemental tryptophan use. Key symptoms included debilitating myalgia (muscle pain) and a high peripheral eosinophil count (R).

Lastly, metabolites of tryptophan produced by colonic bacteria are reported to cause adverse effects in some species (R).

Why serotonin disrupts sleep

Serotonin:

  • Stimulates the adrenals to release cortisol and epinephrine, both of which are wake-promoting.
    • Precursors of serotonin (5-HT), including L-tryptophan and 5-hydroxytryptophan (5-HTP), have been shown to increase ACTH, CRH and cortisol levels. Some evidence suggests that 5-HT may even act directly on the adrenal glands to release cortisol (for reviews see Dinan 1996Porter 2004).” (R)
  • Activates the serotonin receptors 5-HT1A, 2A and 2C, all of which are wake-promoting (R).
  • Depletes glycogen, which is essential for an 8-9 hour fast which we call sleep (R, R).
    • Serotonin has been shown to induce liberation of histamine. 5-HTP, unlike exogenous serotonin, had virtually no effect on hepatic blood flow, although it induced glycogenolysis, hyperglycemia, and stimulation of hepatic phosphorylase activity to a degree similar to the exogenously administered amine.”
    • 5-HT, together with glucagon, markedly increases hepatic glucose output, a main driver of fasting euglycaemia, by increasing hepatic gluconeogenesis and glycogenolysis (29), while inhibiting glucose uptake and glycogen synthesis in the liver (30). In conjunction, 5-HT promotes lipolysis within white adipocytes to liberate free fatty acids (FFAs) and glycerol (30) as key substrates for hepatic gluconeogenesis, and further enhance hepatic glucose output. Moreover, gut-derived 5-HT promotes energy conservation and weight gain by reducing energy expenditure, via actions to attenuate thermogenesis in brown adipose tissue (31) and inhibit the browning of white adipose tissue (32).” (R)
  • Inhibits the cholinergic neurons in the pons which triggers REM sleep by activating the glutamatergic sublaterodorsal nucleus. “Then, the glutamatergic pathway activates glycinergic and GABAergic neurons, inhibiting motoneurons as well as brainstem serotonergic and noradrenergic neurons.9 Thus, the physiological reduction in serotonin release during REM sleep reinforces REM atonia by reducing motoneuron activation,10 while an abnormal increase in serotonergic tone (possibly due to SSRI) might induce REM sleep without atonia (RSWA)” (R).
    So although serotonin inhibits REM sleep duration, it actually causes REM sleep dysfunction.
    • Acute REM sleep behavior disorder (RBD) can be induced by the use of antidepressants, especially serotonin reuptake inhibitors (SSRI),17 suggesting a role of the serotonergic system in the pathogenesis of RBD. Overall, serotonin promotes the wake state and inhibits REM sleep.8” (R)
  • Causes vasoconstriction and increase body temps, thus preventing a drop in temperature which is necessary for going into sleep.

Conclusion

Using tryptophan, 5-HTP or other compounds to increase serotonin specifically will most likely not yield good results for sleep. On the other hand, blocking serotonin, specifically the 5-HT2A and 2C receptors, promote better sleep.

Interestingly, the more tryptophan reaches the brain to create serotonin, the worse mood effects people tend to get (R).

Also, serotonin is cleared from the synapsis via the serotonin transporter (SERT). The short (S) allele for SERT is associated with reduced expression and functioning of the transporter relative to the long (L) allele, meaning, less expression of SERT leads to higher serotonin. As a consequence, people with less SERT and higher serotonin are found to predispose to risk of stress-related and depression-related sleep disturbance as well as clinical insomnia (R).

GABAergics, anti-histamine, anti-serotonin, NMDA antagonist compounds will all be useful for sleep.

Theanine for example, which lowers serotonin in the brain, (together with GABA) promotes better sleep quality (faster sleep onset, more REM and NREM) (R).

If you want to learn how to optimize your sleep, check out this article:

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