Serotonin, the fraudulent anti-depressant

Depression makes you feel like: “Life is a “beach”.

Life just sucks, or so it feels.

Major depressive disorder (MDD) is one of the oldest well-recognized medical disorders, having been clearly described in medical texts dating back to ancient Greece.

Depression is a stress-related disorder that includes abnormalities of affect and mood, neurogenerative functions (such as appetite and sleep disturbances), cognition (such as inappropriate guilt and feelings of worthlessness), and psychomotor activity (such as agitation or retardation).

There are actually a few different types of depression, ranging from mild to severe major depression, uncoping depression and dysthymic depression (persistent depressive disorder)

Although they have some similarities, they also have quite a few differences. For example, both dysthymic and major depression has hyperactivation of the parasympathetic nervous system, whereas uncoping depression is the opposite. Where people with uncoping depression have too little neural noradrenaline levels in the brain and overactivation of the dorsal raphe nucleus, people with major depression have the opposite. That’s why people don’t react the same to meds, or specifically SSRI drugs.

For this article I want to specifically focus on the involvement of serotonin in depression. Mostly because it’s been thought (hypothesized: yep, it’s not even proved) that serotonin is low in depression and that we should boost it. Serotonin is the “happy hormone”, the “feel-good hormone”, right? That’s what everyone has been regurgitating the last couple of decades.

However, research shows that it’s not the boost in serotonin that’s beneficial, because the SSRI drugs only become effective after a few weeks, which casts dought on if serotonin is really the missing link here. The main hypothesis for why SSRI drugs only start to work after a few weeks is because SSRI drugs, such as Prozac, increase neurosteroids in the brain (such as allopregnanolone), that has pro-GABA effects. And it’s actually the GABA that has anti-depressant properties. So it takes a while for the SSRI drugs to increase allopregnanolone and when it gets high enough, the anti-depressant effect kicks in.

Additionally, it’s not only due to the increase in allopregnanolone, but also because some of these anti-depressant “SSRI” drugs also increase noradrenaline, dopamine and BDNF, antagonize and downregulate certain serotonin receptors, block adrenergic receptors, block the effect of cortisol, modulate acetylcholine, etc.

Naturally, the origin or cause of depression is never single factorial, but often, if not always, is multi-factorial. Stress and excess cortisol is one of the major persistant themes we see in depression, and it’s stress and cortisol that increases the serotoninergic system and damages the dopaminergic system.

Evidence against serotonin as the happy hormone

Elevated serotonin synthesis in depression

Stress has been shown to increase tryptophan hydroxylase type 2 (TPH2) expression, the enzyme that synthesizes serotonin in the brain, specifically in the dorsal and median raphe nucleus of the brain (R, R).

Several studies have also found increases in neuronal TPH2 mRNA and protein expression within the dorsal raphe nucleus in human depressed suicides (R).

This points to increased serotonin synthesis in certain areas of the brain, which then contributes to depression.

Reduced serotonin breakdown in depression

The enzyme monoamine oxidase-A (MAO-A) predominantly breaks down serotonin, so blocking or inhibiting it significantly increases serotonin. That’s how many SSRI drugs work, by inhibiting serotonin breakdown.

Low-expression of MAO-A (which leads to elevated serotonin) has been shown to be associated with antisocial and anxious-depressive traits in alcoholic males (R).

Most importantly, the MAOA-L allelic variation (slow MAO-A activity) is associated with an increased risk of violent behavior, aggression as well as aberrant emotional regulation (R).

Mice lacking MAO-A and catechol methyltransferase (COMT) (an enzyme that also breaks serotonin down), or mice lacking the serotonin transporter (5-HTT) display among
other alterations, anxiety-like and depression-like behaviors (R).

Elevated cortisol, due to stress, inhibits MAO-A and B in the liver, thus inhibiting serotonin and dopamine breakdown (R), which can worsen depression and anxiety.

Serotonin transporter

Reduced function of the serotonin transporter (SERT) is associated with increased susceptibility to anxiety and depression and with type-2 diabetes (R). Low SERT means that more serotonin is left in the synaptic cleft which amplifies the action of serotonin. Increasing SERT lowers synaptic/free serotonin and this reduces the action of serotonin.

Sodium, zinc, Bacopa, forskolin and berberine can increase SERT and reduce free serotonin. Tianeptine is also a very effective serotonin reuptake promoter and has been shown to have anti-depressant effects.

Also, individuals heterozygous for the SERT gene (low transporter activity) showed exacerbated ACTH response to stress (exaggerated adrenal response to stress). Additionally, low SERT in combination with a MAOA-L variation (low MAO-A activity), results in elevated ACTH response to psychological stress (R). More serotonin = greater reaction to stress = not being stress-resilient.

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This dopaminergic diet is the best thing ever in a highly serotonergic Western environment.

Serotonin receptors

There are 14 known serotonin receptors, 7 main types and some of them with subtypes.

5-HT1 class

5-HT1A is the autoreceptor at the dorsal raphe (DR) nucleus in the brain, and binding to it specifically lowers DR serotonin.

5-HT1B/D are also autoreceptors, but they’re mainly expressed at the median raphe (MR) nucleus. Activating them lowers MR serotonin, but not DR serotonin.

Overactivation of the MR in the midline of the brain stem is involved in depression and anxiety (R). It’s promoted by noradrenaline (very mildly), acetylcholine, glutamate, restrained stress and certain visual and auditory stimuli and lowering it has anti-depressant effects. Symptoms of overactive MR include aggression, violence, muricidal tendencies, short fuse, apathy, “laziness”, anhedonia, suicidal tendencies, etc.

Certain SSRI drugs (e.g. Prozac) can enhance aggression, suicidal tendencies, inactivity, etc., because it promotes MR serotonin activity.

On the other hand, SSRI drugs can also induce anxiety, fear, restlessness, panic, etc. (R), if it over-activates the DR system. The DR serotonin stimulates the release of corticotropin-releasing hormone (CRH), which fuels fear. 3α, 5α-THP (of which 5α-DHP is the precursor) stops the CRH-mediated fear (R).

DR serotonin release is activated by social defeat (embarrassment and shame), 5-HT1A and 2A antagonist, noradrenaline and adrenaline (through α1-adrenoceptor signaling), amphetamine, cocaine and modafinil (also through α1-adrenoceptor signaling) (R).

So 5-HT1A agonists will lower DR, but not MR serotonin. 5-HT1A agonists have been shown to lower anxiety (R), but on the contrary, it can make depression worse. 5-HT1A agonists can worsen symptoms such as apathy, anhedonia, aggression, etc. because it leaves MR serotonin unopposed. DR serotonin inhibits MR serotonin release.

Cortisol is a 5-HT1A antagonist (which can potentiate fear), so over time it increases 5-HT1A expression and lowers DR activity, which is seen in depression. On the other hand, prenatal stress can lead to a reduction in 5-HT1A receptor expression and this increases DR activity which leads to fear and anxiety later in life (R).

5-HT1B/D agonists lower MR serotonin, but not DR serotonin, and this helps to reduce aggression, muricidal thoughts and behaviors, violence, irritation, suicidal idealizations, etc.

5-HT2 and 3 class

Next on the relevant list, we have the 5-HT2A and 2C receptors. Blocking 5-HT2A and 2C has anti-depressant and anti-anhedonic effects (R). Overactivity of 5-HT2C receptors may contribute to the etiology of depression and anxiety as some suicide victims have abnormally high expression of 5-HT2C in the prefrontal cortex (R).

The raphe obscurus (RO), another part of the brain that creates and secretes serotonin activates the vagus complex. Too much RO activation leads to overactivation of the vagal complex (VC), which in turn inhibits the C1 medullary nucleus (which creates adrenaline) via GABA. This contributes to fatigue (because of a reduction in adrenaline), which is very common in depression. RO can be inhibited by 5-HT2A and 3 antagonists and the vagal complex can be inhibited with the 5-HT3 antagonist (ginger anyone?).

Other 5-HT3 antagonists, such Ondansetron, have been shown to have anti-depressant effects (R, R, R, R)


“No in vivo studies of the cerebral 5-HT4 receptor binding in depressed patients or at-risk populations have been published so far, but a postmortem study of 19 depressed suicide victims showed increased 5-HT4 receptor density in the frontal cortex and caudate nucleus.” (R)


If you have major depression with symptoms such as:

  • Aggression
  • Violent behavior
  • Anger
  • Short fuse
  • Suicidal tendencies
  • Overeating
  • Hypoactivity/laziness
  • Impulsiveness
  • Anhedonia

…then you might benefit from antagonizing the MR nucleus with 5-HT2A antagonists (e.g. ginseng, Ginkgo Biloba, Bacopa, feverfew) and by lowering estrogen and inflammation. If you’re feeling restrained, then it would also be a good idea to get out more to reduce MR activation.

People with major depression (without anxiety) also do well on magnesium, but could do bad on zinc, methylene blue, clonidine and agmatine.

If you have symptoms such as:

  • Anxiety
  • Low appetite
  • Fear
  • Panic
  • Overly emotional
  • Hyperactive

…then you might do best on a 5-HT1A agonist (e.g. zinc, methylene blue (product: oxidal)), GABA promotors (5a-DHP, taurine, valerian root), glutamate antagonists, (magnesium, theanine, zinc) and agmatine.

People with anxiety tend to do worse on NMDA agonists (e.g. glycine) and 5-HT2A antagonists.

As always, thanks so much for reading my article. Let me know in the comments below if you have any questions. And if you found this article to be insightful and helpful please like and share so this information can help others as well.

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2 Replies to “Serotonin, the fraudulent anti-depressant”

  1. You have the most amazing post. Often times I will see something that doesn’t seem quite right in peoples beliefs on certain health issues. You lay everything out showing how a lot of health related beliefs are in error. Keep up the good work.

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