Is serotonin the happy brain chemical, and do depressed people just have too little of it?

* Scientific study references are indicated in (). These can be found at the bottom of the article, and can be clicked on to access the original reports.

Serotonin is somewhat of a media darling, often nicknamed ‘the happy brain chemical’. Articles such as ‘Hacking into your happy chemicals’ and ‘Chemicals that activate happiness, and how to gamify them’ (1,2) offer tips on ways to boost happiness by increasing serotonin levels, using anything from yoga to bananas.

This line of reasoning tends to underpin the claim that individuals with depression have a ‘chemical imbalance’ in their brains – a serotonin deficiency – and that their mood can get back on track with drugs that increase serotonin levels. While this story is quite convenient, it simply does not make sense.

Serotonin is fundamentally very much like the other 100+ neurochemicals that are found in the nervous system. It is a molecule that brain cells, or neurons, release in order to communicate with other cells by stimulating their receptor molecules. The ultimate purpose of any neurochemical signal is to carry some form of information. For instance, the amount of neurochemical released by photoreceptor cells in the retinas of our eyes tells the brain something about the lighting in our environment. In light of this, we might question the purpose of having a generic ‘feel-good chemical’ such as serotonin. Of course, you could argue that a neurochemical that makes us feel good when we have done something beneficial for survival is an extremely useful teaching signal. This point is valid enough, but there is no evidence that serotonin directly underpins happiness.

How we know that serotonin doesn’t make you happy

Many studies have explored whether rapidly lowering serotonin levels makes healthy individuals feel less happy, and have consistently found that this is not the case. One common method used for this purpose is acute tryptophan depletion (ATD), which effectively and temporarily lowers brain serotonin levels by 50-90% over the course of several hours. Participants of ATD studies are given a drink containing a variety of essential amino-acids except for tryptophan – an essential molecule which is processed in the central nervous system to produce serotonin. These consumed amino-acids compete with the relatively fewer tryptophan molecules to access the brain from the bloodstream, and naturally win. As a result of this, serotonin synthesis goes down and levels of the neurochemical drop dramatically within 5-7 hours. Using this method, researchers find that healthy individuals don’t actually report feeling any less happy when deprived of serotonin (9,20).

We also have no evidence that increasing brain serotonin levels actually improves people’s mood. Researchers have studied the effects of giving healthy individuals single doses of common anti-depressants, such as citalopram. This drug works by blocking the serotonin transporter, a tiny pump that rapidly takes serotonin back into the cell which originally released it, and thus shuts off the neurochemical signal. Ultimately, citalopram and other similar drugs called selective serotonin reuptake inhibitors (SSRIs), enable serotonin to float around in synapses (spaces between neurons) for longer periods of time.


One study using the SSRI citalopram found that temporarily raising individuals’ serotonin levels did not actually increase their reported level of happiness (11).  The evidence that anti-depressants don’t automatically make people feel happier might sound surprising – after all, that is on some level what we expect these drugs to do. But this finding lies at the root of the problem that most depressed individuals taking SSRIs don’t actually feel better until roughly six weeks after beginning treatment, while roughly 40% of individuals don’t improve at all (5). In essence, it’s clear that lower serotonin levels don’t necessarily make you sadder, while medications that increase serotonin levels don’t necessarily provide a ‘happy fix’. So what is serotonin doing in the brain, if not making you feel good?

An alternative view: serotonin regulates learning

Currently, we have some solid evidence that serotonin generally regulates how the brain learns about the environment. As an example, researchers have found that serotonin may be responsible for enabling animals that have lost one sense, such as due to blindness, to become more sensitive to information coming from another sense.

One brain region where this serotonin-driven effect has been found is the whisker cortex of rodents. The cortex is the folded external structure of the brain, composed of several layers of tightly packed cells, shown in the image below in a darker purple.

BrainsThe function of a particular bit of cortex depends on where its cells are getting their information. For example, neurons in the cortical region in the backs of our heads receive signals triggered by light activating cells in our retinas – thus, this cortex processes and allow us to experience visual information. As the name suggests, the whisker cortex of the rodent brain is a region that receives touch information from the whiskers as the animals explore their environment.

One study published several years ago found that when juvenile rats spent most of their time in the dark (where vision was of little use), their whisker cortex became more sensitive to touch information coming from the whiskers than when these rats also had plenty of visual information (13). In the dark, serotonin-producing neurons released more of the neurochemical onto cells in the whisker cortex, which ultimately made them more easily excited when information arrived from nerves attached to the whiskers. How did serotonin achieve this?

Let’s look closely at a synapse, or the connecting space, between a few neurons found in this region – in the picture below, we have one neuron arriving from the whiskers and another neuron receiving and passing on this information. Receiving cells typically contain a variety of receptors that respond to neurochemical molecules being released from communicating neurons. Most commonly, their membranes are peppered with receptors for the neurotransmitter glutamate (marked in yellow and brown in the image below), which makes cells become excited, and closer to passing on signals that they receive. They also house particular serotonin receptors (marked in red), which receive signals from serotonin-releasing neurons that find their way into the whisker cortex. Strong stimulation of these receptors when rats lived in the dark activated diverse molecules inside the cells, which transported and inserted more glutamate receptors into their membranes. Remember that glutamate is a neurochemical that excites cell membranes. The result of this mass insertion of glutamate receptors was that, in the future, the changed neurons became more sensitive to stimulation of the whiskers!


Essentially, serotonin encouraged the whisker cortex to learn that it was better for the rats to focus more strongly on touch when visual information was unavailable to help them explore their surroundings. This effect is quite unrelated to happiness, and reveals that serotonin has a much wider role in enabling brain cells to learn from the environment.

Serotonin might actually be helping us learn to be anxious 

One brain structure where learning is associated with depression and anxiety disorders is the amygdala – a collection of nuclei (cell clusters) buried deep in the brain. This is where serotonin plays its role in a fascinating way.


Researchers consider the amygdala as the primary storage site for memories about negative and dangerous events, since both animals and humans with amygdala damage show remarkable difficulties learning that particular stimuli are associated with upsetting consequences, such as electric shock, loud noise, or bad social encounters (10,14). We can thus view the feeling of anxiousness, which is linked to amygdala activity, as a useful emotional response that encourages us to avoid situations that we have learnt to be potentially threatening. Indeed, patients with amygdala damage generally fail to experience anxiety or discomfort about things that humans normally find uncomfortable or threatening – spiders, snakes, or confrontational situations. One particular patient from a case study published several years ago looked back at a previous experience of being held at knifepoint, and described feeling essentially no discomfort at the time (10).

Serotonin is known to have a powerful effect on fear learning in the amygdala.  Already decades ago, researchers observed that when rodents are trained that particular sounds predict unpleasant outcomes, certain amygdalar neurons begin responding more strongly to signals from nerves coming from the auditory system (18). In essence, these animals’ experiences teach them that auditory information can predict whether something threatening might occur, and thus amygdalar neurons become sensitive to such information when it arrives. Serotonin is known to be partially responsible for the physiological changes that underpin this learning effect (8,19), which means that it also influences how well the animal itself learns to expect and avoid the bad outcome.

Indeed, when it comes to the anxiety and avoidance that animals show when they have learnt to fear something, the impact of serotonin is quite profound. Studies found that increasing brain serotonin levels in rats by giving them single doses of SSRI anti-depressants such as citalopram or fluoxetine (aka Prozac) actually increases how intensely they express their fear (4). This doesn’t fit with serotonin’s reputation as the happy neurochemical, and instead shows that this neurochemical seems to teach us to feel anxious when in bad situations.

Depressed and anxious people might simply be too good at learning about bad outcomes

Over the past few decades, researchers have been discussing that mental health issues such as depression and anxiety might fundamentally be disorders of learning, rather than outcomes of a ‘chemical imbalance’ that requires correction by a serotonin boost. Specifically, certain individuals which have atypical function of the serotonin system (which might be caused by genetic factors or stressful lives) may be at risk of developing depression or anxiety because they are too good at learning about negative outcomes, and thus are more likely to feel that the world is a bad place if they experience negative life events. One of the most talked-about studies in the psychiatric literature supports this possibility (6). It found that individuals with a particular genotype affecting the serotonin system were more likely than others to develop depression or anxiety only if they had experienced stressful life events, such as child abuse, unemployment, or loss of a loved one. Clearly, having an atypical serotonin system alone wasn’t enough – it had to be combined with negative experiences.

This perspective might explain why treatment with SSRI anti-depressants doesn’t tend to increase happiness until weeks after depressed patients have begun taking medication. Serotonin changes produced by the drug, combined with appropriate therapy, might work by allowing patients to learn that the world is not such a bad place rather than simply making them happy. This might work by making negative emotional events less effective at exciting emotional brain regions such as the amygdala, and thus allowing individuals to learn less from and gradually take less notice of such negative events. Such learning takes time.

Similarly, the learning perspective on serotonin might go some way towards explaining why some depressed patients generally do not improve when undergoing SSRI treatment. Consuming pills in the absence of improvement in life conditions or appropriate therapy might in fact make it easier for already depressed individuals to ‘learn’ more about the negative events surrounding them, and consequently feel worse.

Finally, we are all still wondering – are these learning effects which likely contribute to depression and anxiety produced by low serotonin levels after all? Is there any truth to the serotonin deficit hypothesis? Alas, the evidence is unclear. Many studies indicate that depressed patients have lowered serotonin synthesis in their brains, so in this respect, there does seem to be reason to believe that such individuals have serotonin deficiencies. However, it has also been found that single doses of SSRI anti-depressants increase tissue serotonin levels primarily in the short-term, while chronic treatment ( >21 days) either has no effect on serotonin levels or might actually reduce them by 30-40% in multiple brain regions (12, 16). Given that improvements in depressive or anxious symptoms tend to take place weeks after an individual commences drug treatment, it appears that we are treating the supposedly serotonin-deprived depressive state by lowering serotonin levels.  Of course, this doesn’t quite make sense, which is something that researchers are currently well aware of. It goes to show that we are still far from figuring out the mystery of serotonin. However, we can say with some certainty that serotonin is not simply the happy neurochemical.



  3. Albright, M. J. et al. (2007). Increased thalamocortical synaptic response and decrease layer IV innervation in GAP-43 knockout mice. Journal of Neurophysiology 98, 1610-1625.
  4. Burghardt, N. S. et al. (2007). Acute selective serotonin reuptake inhibitors increase conditioned fear expression: blockade with a 5-HT(2C) receptor antagonist. Biological Psychiatry 62, 1111-1118.
  5. Carvalho, A. F. et al. (2007). Augmentation strategies for treatment-resistant depression: A literature review. Journal of Clinical Pharmacy and Therapeutics 32, 415–428.
  6. Caspi, A. et al. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386-389.
  7. Castren, E. (2005). Is mood chemistry? Nature Reviews Neuroscience 6, 241-246.
  8. Chen, A. et al. (2003). Serotonin type II receptor activation facilitates synaptic plasticity via N-methyl-D-aspartate-mediated mechanism in the rat basolateral amygdala. Neuroscience 119, 53-63.
  9. Evers, E. A. et al. (2005). Effects of a novel method of acute tryptophan depletion on plasma tryptophan and cognitive performance in healthy volunteers. Psychopharmacology 178, 92-99.
  10. Feinstein, J. S. et al. (2011). The human amygdala and the induction and experience of fear. Current Biology 21, 34-38.
  11. Harmer, C. J. et al. (2003). Acute SSRI administration affects the processing of social cues in healthy volunteers. Neuropsychopharmacology 28, 148-152.
  12. Muck-Seler et al. (2002). Influence of fluoxetine on regional serotonin synthesis in the rat brain. Journal of Neurochemistry 67, 2434-2442.
  13. Jitsuki, S. et al. (2011). Serotonin mediates cross-modal reorganization of cortical circuits. Neuron 69, 780-792.
  14. Kazama, A. M. et al. (2012). Effects of neonatal amygdala lesions on fear learning, conditioned inhibition, and extinction in adult macaques. Behavioral Neuroscience 126, 392-403.
  15. Lesch, K. and Waider, J. (2012). Serotonin in the modulation of neural plasticity and networks: implications for neurodevelopmental disorders. Neuron 76, 175-191.
  16. Nakayama, K. et al. (2003). Possible alteration of tryptophan metabolism following repeated administration of sertraline in the rat brain. Brain Research Bulletin 59, 293-297.
  17. Rakic, P. (2009). Evolution of the neocortex: a perspective from developmental biology. Nature Reviews Neuroscience 10, 724-735.
  18. Rogan, M. T. et al. (1997). Fear conditioning induces associative long-term potentiation in the amygdala. Nature 390, 604-607.
  19. Tran, L. et al. (2013). Depletion of serotonin in the basolateral amygdala elevates glutamate receptors and facilitates fear-potentiated startle. Translational Psychiatry 3: e298.
  20. Van der Veen, F. M. et al. (2007). Effects of acute tryptophan depletion on mood and facial emotion perception related brain activation and performance in healthy women with and without a family history of depression. Neuropsychopharmacology 32, 216-224.

35 thoughts on “Is serotonin the happy brain chemical, and do depressed people just have too little of it?

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  4. Welcome to the blogosphere – you have a lovely place here.
    You say “We also have no evidence that increasing brain serotonin levels actually improves people’s mood.” As a matter of fact, we have excellent evidence for this. The drug MDMA produces a massive release of 5-HT into the synapse and also strongly enhances aspects of mood. Check for example Fig. 2a in Liechti et al. Gender differences in the subjective effects of MDMA. Psychopharmacology. 2001;154(2):161–8. There is quite a bit of literature on the effects of MDMA in humans, just google it. Of course, this doesn’t make serotonin the ‘happy brain chemical’, I certainly agree with you on that.


  5. That increasing serotonin leads to improved mood seems to be a common misconception which, I agree, is important to be talked about. Although even the label “antidepressant” doesn’t promise positive mood but more the absence of negative mood, which is not at all the same thing. I’m a CBT therapist and find that most people describe feeling more “numbed” by SSRIs. Nobody has ever reported to me that they feel like it has raised their mood by itself. Some people don’t like feeling so forced into flatness. Often those who were really very down and so were, to them, excessively tearful daily and/or struggling to do anything and so make much meaningful progress towards recovery, are the ones who seem to me to report finding SSRIs helpful: they report that their experience of negative mood is numbed enough that they can motivate themselves to engage in something enough to achieve some sense of reward, which can begin to counter the downward mood spiral with an upward one. From your discussion it would follow that increasing the serotonin signal would enable the learning that must happen in therapy for the individual to find it helpful and make the necessary changes; that is assuming that SSRIs are actually increasingly serotonin levels of course, which, as you say, is in question!


  6. Hi! I am not aware of any videos that discuss the ideas and studies I have described in this article, so unfortunately I have nothing to recommend. But if you are interested in getting some more details on the function and effects of serotonin, I can advise you to google Catherine Harmer – a researcher based in Oxford whose work focuses on how serotonin might relate to emotional learning, and how this might allow us to better understand depression. You can find her publication list on the Oxford website and from there, you can google the titles of the papers she and her co-workers have written and try reading them for a deeper understanding. I’m not sure how accessible the writing is, but you can always give it a try if you have the time and are up for it! I think this particular review might be a great starting point for you:

    – Why do antidepressants take so long to work?

    I hope this helped.


  7. Thank you, I am very glad you enjoyed it! Yes, the plan is to keep writing every once in a while about a variety of topics relating to the brain, and discussions of other psychiatric disorders will occasionally surface!


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  14. I think I’ve heard similar arguments in the book, Anatomy of an Epidemic.

    If it only works in half of the cases, and (according to that book) long term outcomes are horrendously worse than not taking it at all, and we don’t know enough about the brain to understand how all of that fits together, it puts potential patients into a horrible dilemma of deciding what they will do when they get written a script for an SSRI.


  15. This is a tough question… I’m not sure there’s reason to believe that the consequences of taking SSRIs could be ‘horrendously worse’ compared to not taking them. In roughly half the cases, SSRIs aren’t effective, although in other cases, they do make it possible that patients feel worse over time if their lives continue to be difficult and the medication makes the brain more ‘plastic’ to learning about bad events. I suppose risks are inherent in most medications, and patients being treated for various problems, such as diabetes and alcoholism, are often expected to take some control over their lifestyles in order to maximise the effectiveness of their drugs. In that respect, maybe SSRIs aren’t so dramatically different from many other treatments. Rather than thinking of this as presenting a horrible dilemma, maybe it just highlights that we need to see pills as part of a solution rather than a miracle tonic. In this case, people become more likely to take treatment seriously, rather than expect to get better as soon as they begin popping pills. I see your point though… It’s hard to respond to.


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  17. Glad you enjoyed it! If you go to the ‘Article Archives’ page, you can scroll to the bottom, where it gives you the option to follow the blog via email. You will then begin receiving email notifications whenever I publish something new 🙂


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