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The Serotonin 5HT1A receptor is more important than you think.  Even if you don’t have your genetic data from 23andme, you should still read this post and if you do have your genetic data you can unlock its many secrets using SelfDecode.


Is Serotonin a Cause of Depression?

It’s pretty accepted in the literature that low serotonin can contribute to depression. But it’s not likely necessary or sufficient.

The best current evidence suggests that the 5HT1A receptor (and therefore serotonin as well) plays a role in depression.

Just to bring down one study:

In the prefrontal cortex (DLPFC) and hippocampus, there is a significant decrease in 5-HT1A receptor production in people with major depression and a significant decrease in 5-HT2A receptor production in people with Bipolar (R).

5-HT1A Receptor: Autoreceptors vs Postsynaptic Receptors

You can get easily confused about a specific point regarding these receptors, so I will clarify this first.

5HT1A receptors are often found on the same neuron that is releasing serotonin (called autoreceptors).  The reason the serotonin releasing neuron has the receptor is because it acts as a negative feedback system.  When there’s too much serotonin in the gap between neurons, the releasing neuron needs to know so that it can stop releasing more serotonin.

5HT1A receptors are also found on the serotonin receiving neuron (called postsynaptic receptors), where serotonin acts as the key and the 5HT1A receptor acts as the lock.  These postsynaptic receptors and their activation cause a chain of events that lead to all the good stuff that serotonin does.

In order to increase serotonin function, we want less activation of the receptors on the releasing neuron (auto-receptors) and more activation on the receiving neuron (postsynaptic receptors).

To overly simplify it…Auto receptors=BAD, Postsynaptic receptors=GOOD. 

The goal then is to make the autoreceptors that inhibit serotonin secretion to become less sensitive to serotonin and we want to activate or make more sensitive the postsynaptic receptors.

This mechanism has been shown to be the major mediator in the therapeutic benefits of most mainstream antidepressant supplements and pharmaceuticals, including serotonin precursors like L-tryptophan and 5-HTP, SSRIs, SNRIs, MAOIs, tricyclic antidepressants (TCAs) and tetracyclic antidepressants (TeCAs) (R).

The Difference Between SSRIs and MDMA (R)

If SSRIs and MDMA (a pure form of ecstasy) both cause increased levels of serotonin, why do you feel very different on MDMA and SSRIs?

This is because, in low doses, the 5HT1A receptor activators actually tend to decrease serotonin release (by also binding to the autoreceptors) and decrease activation of postsynaptic 5-HT1A receptors… and they further decrease serotonin release but increase postsynaptic 5-HT1A receptor activity at higher doses by directly stimulating the receptors in place of serotonin.

The autoreceptors must first become less sensitive (by chronic SSRI stimulation) before the concentration of serotonin in the synapse can increase significantly.

This is theorized to be a major factor in the therapeutic lag that is seen with SSRIs.  

Though the responsiveness of the autoreceptors is somewhat reduced with chronic treatment, they still remain effective at constraining large increases in serotonin concentrations.

MDMA, on the other hand, is what’s called an “SRA” or a serotonin releasing agent.

MDMA directly acts on the release mechanisms of serotonin neurons and forces the release to occur regardless of autoreceptor-mediated inhibition.  

The downside to that is you’d have to tightly control the dosage or else you’ll be getting too much serotonin because your neurons are not regulating serotonin levels well anymore.

Again, in contrast to SRAs like MDMA, SSRIs actually decrease serotonin levels initially and require several weeks of chronic dosing before serotonin concentrations reach their maximal elevation and full clinical benefits for conditions such as depression and anxiety

There are drugs in the pipeline to increase serotonin levels more quickly than SSRIs….

Sometimes, 5-HT1A autoreceptors are located on neurons that are meant to inhibit mainly dopamine or glutamate instead of serotonin.  So SSRIs can work differently than SRAs, which don’t activate the autoreceptors and involve other neurotransmitters (R).

Summary of Effects of 5HT1A Activation

The following are some effects of 5-HT1A activation: (R)

The Good:

  • Stimulates vagus nerve
  • Reduces fatigue. People with CFS were found to have fewer 5HT1A receptors (R).
  • Increases sociability – partly from oxytocin and endorphins maybe
  • Increases sex drive and arousal
  • Improves some kinds of learning – improves cognitive functions associated with the prefrontal cortex, possibly via inducing prefrontal cortex dopamine and acetylcholine release.
  • Increases dopamine– in the medial prefrontal cortex, striatum, and hippocampus, which could be beneficial for Schizophrenia and Parkinson’s.
  • Decreases aggression
  • Decreases food intake
  • Decreases blood pressure and heart rate via by stimulating the vagus nerve (rostral ventrolateral medulla).
  • Decreases impulsivity
  • Decreases nausea
  • Decreases body temperature/Cools you…Vasodilation of the blood vessels in the skin increases heat loss…
  • Decreases pain perception (R) and substance P (cause of pain, inflammatory) – mediated by 5-HT1A receptors in the dorsal raphe nucleus…..Experiments in rodents suggest that 5-HT1A activation (specifically in the brainstem’s raphe nuclei) causes a perception of relatively less pain with a mild pain stimulus, but relatively more pain when exposed to a more intense pain-stimulus.  These animal studies are supported by genetic studies. (R5HT1A receptors combine with mu-opioid receptors to cause a numbing of pain, and activating the 5HT1A receptor should cause pain relief (R). There is a substantial connection between depressive disorders and chronic pain and serotonin dysregulation is one such mechanism likely to be shared by both disorders (R). (Think fibromyalgia…)
  • Decreases drug-seeking
  • Reverses opioid-induced respiratory depression.

The Bad:

  • Inhibition of penile erection
  • Takes longer to get to REM sleep 
  • Impairs certain aspects of memory and learning –  due to interference with memory-encoding mechanisms and by inhibiting the release of glutamate and acetylcholine in various areas of the brain.
  • In the raphe nucleus, 5HT1A autoreceptor activation causes rats to be less active (R).


  • Causes pupils to get smaller or contract

5HT1A and Hormones

5-HT1A receptor activation induces the secretion of the following hormones (R):

  • Cortisolone reason why people might have low cortisol isn’t because adrenal fatigue, but because the 5HT1A receptors aren’t being activated.
  • ACTH
  • Oxytocin – contributes to the prosocial, anti-aggressive, and anti-anxiety properties
  • Prolactin
  • Growth hormone
  • Endorphins (beta) – contributes to anti-depressant, anti-anxiety, and anti-pain effects

5HT1A and Spirituality

In people, PET scans have found that the more 5-HT1A was sensitive to serotonin in the raphe nuclei, hippocampus, and neocortex , the less they self-reported a tendency to have spiritual experiences (R).

This would indicate that people who are overly spiritual might be lacking in serotonin or more precisely, they have less activation of the 5HT1A postsynaptic receptors.

5HT1A and The Circadian Rhythm

5HT1A receptors have less of a powerful response, depending on the time of the day.  In rats, peak responses were observed in what would be our daytime while the weakest responses were observed in their what would be our nighttime (R).

The 5HT1A receptor might help you set your circadian rhythm as well.

In hamsters, 5HT1A activators induce a significant phase advance (make you wake up earlier) under constant light conditions (R).

The 5HT1A activators accelerated the rate of entrainment to the hamsters that had a shifted circadian rhythm (R).

So if you’re traveling across time zones, activating these receptors is a good idea.

Another study found 5HT1A activators had an inhibitory effect on Per1 and Per2 mRNA levels in the SCN (which is induced by light), which occurred only during the hamster’s mid-subjective day, but not during the early subjective day or subjective night (R).

5HT1A Genes/SNPs

If you want to interpret your genes, you can use SelfDecode.

You need to buy your 23andme in order to see what genes you have.

SNPs in the 5HT1A gene:

  1. RS1364043 (5-HT1A) GT
  2. RS6295 (5-HT1A) GG

SelfDecode is the best gene analyzer around and helps you interpret your genetics from 23andme and ancestry.

What Decreases 5HT1A Autoreceptors or Increases Postsynaptic Receptors

  • CBD activates 5HT1A receptors (R)
  • T3 is effective in both augmenting and accelerating the therapeutic response to antidepressant drugs. When given to animals, it reduced the sensitivity of 5-HT1A (and 5HT1B) auto-receptors (and postsynaptic) in the hypothalamus (R).  I do notice an anti-depressant effect when I up my thyroid hormone production with ICES/LLLT.
  • Estradiol accelerates the effects of fluoxetine (SSRI) on these receptors, presumably by blunting the increase in 5HT1A autoreceptors from SSRIs in the hypothalamus (PVN) (R).
  • Cortisol. Chronic exposure to cortisol desensitizes 5-HT1A autoreceptors receptors (R).
  • Lithium increases 5HT1A postsynaptic sensitivity, while not changing the autoreceptors and it’s thought that this is in part responsible for its anti-depressant activity (R).
  • St John’s Wort increases the number of postsynaptic 5-HT1A (and 5-HT2A) receptors (R).
  • Ashwagandha decreases 5-HT1A signaling (R).
  • Zinc acts as a blocker of the 5HT1A receptor and prevents the binding of this receptor (R).  However, it also helps block the combining of the 5HT1A receptor and another receptor (galanin 1), which results in an anti-depressive effect (R).
  • Fish Oil …When animals were fed diets low in Omega-3’s (ALA), 5-HT1A receptors decreased, causing the SSRI not to work properly (R).

What Modulates the 5HT1A Receptor

  • Exercise (aerobic) increases 5HT1A receptors in the dorsal raphe when they were reduced in an animal stress model (R).
  • Melatonin potentiates the 5-HT1A receptor in the hypothalamus, which results in its cooling effects (R).
  • DHA prevented negative effects of a high-fat diet on the 5-HT1A receptor (R).
  • Magnesium and Calcium  (divalent cations) increase the binding of serotonin to the 5HT1A receptors in the cortex (Purkinje cells) (R). Manganese also helps 5HT1A activators bind better (R).
  • Butyrate  increases 5-HT1A receptors in the hypothalamus (R).
  • Rhodiola increases the number of 5HT1A receptors (R).



  • Buspirone (R),
  • Shrooms/Psilocybin (R),
  • MDMA or the pure version of ecstasy increases feelings of love, empathy, and connection to others by stimulating oxytocin activity primarily via activation of the 5-HT1A receptors (R).
  • Quetiapine (R),
  • Amphetamines (R),
  • LSD (R)
  • DMT (R)

Chronic intake of SSRIs induces less sensitivity of the auto- and post-synaptic 5-HT1A receptors in the hypothalamus, so it’s both good and bad, but better than not for some people (R).

Chronic Transcranial Magnetic Stimulation (rTMS) reduces the sensitivity of post-synaptic 5-HT1A receptors in the hypothalamus, and the study says that “this may be significant in relation to the therapeutic mechanism of rTMS.” (R)

Berberine decreases the serotonergic system by activation of  5-HT1A autoreceptors and inhibition of postsynaptic 5-HT1A and 5-HT2 receptors. Since serotonin is mainly an excitatory neurotransmitter, this effect decreased anxiety in animals (R).

Health Tools I Wish I Had When I Was Sick

At SelfHacked, it’s our goal to offer our readers all the tools possible to get optimally healthy. When I was struggling with chronic health issues I felt stuck because I didn’t have any tools to help me get better. I had to spend literally thousands of hours trying to read through studies on pubmed to figure out how the body worked and how to fix it.

That’s why I decided to create tools that will help others cut down the guesswork:

  • Lab Test Analyzer – a software tool that will analyze your labs and tell you what the optimal values are for each marker — as well as provide you with actionable tips and personalized health and lifestyle recommendations to help you get there.
  • SelfDecode – a software tool that will help you analyze your genetic data from companies such as 23andme and ancestry. You will learn how your health is being impacted by your genes, and how to use this knowledge to your advantage.
  • SelfHacked Secrets – an ebook where we examine and explain the biggest overlooked environmental factors that cause disease. This ebook is a great place to start your journey if you want to learn the essential steps to optimizing your health.
  • SelfHacked Elimination Diet course – a video course that will help you figure out which diet works best for you
  • Selfhacked Inflammation course – a video course on inflammation and how to bring it down
  • Biohacking insomnia – an ebook on how to get great sleep
  • Lectin Avoidance Cookbook – an e-cookbook for people with food sensitivities
  • BrainGauge – a device that detects subtle brain changes and allows you to test what’s working for you
  • SelfHacked VIP – an area where you can ask me (Joe) questions about health topics

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1 Star2 Stars3 Stars4 Stars5 Stars (6 votes, average: 5.00 out of 5)


  • ed

    I read the ashwaghanda study. It says that Ash lowers presynaptic 5ht1a and increases 5ht2a. Isnt this bad?

  • davefx

    *bursting (instead of brusting)

  • davefx

    Just like the headline, probably one of the worst and most meaningless articles on this site (which is already dubious to begin with). Some of the reactions are telling enough. Measures and counter-measures jumbled together in one without clear recommendation, even layout, and often wishy-washy terminology.

    It also ignores such fundamental matters that not only does this at the heart seem to be the most orthodox, indoctrinated view serotonine and anti-depressants (you’d never guess with this presentation…), but also that the internet is brusting with people with lasting side-effects from this bone-headed course of treatmeant, like anhedonia, PSSD, akathisia etc. etc. Of course this is wrapped up in this like everything else bad in psychiatry, of which in fact can’t be told anything good, save that cheesy, clichéd, kind of sordid apocryphal sh*t that is sold as the “science” basis of it, and that is directly at the cost of respectful treatment of people’s feelings and issues, which would solve 95% and prevent all (100%) of the 70% of atrocious, life-quality decreasing side-effects within those same 95%.

  • Amyl

    HI – Just a note that the reference you cited for “chronic SSRI administration etc” points to a paper that is not the primary source. The paper you cite here merely states that Chronic intake of SSRIs induces less sensitivity of the auto- and post-synaptic 5-HT1A receptors, and then goes on to tests something else.

  • jtg1

    Where are you reading the 5-HT1A activation results in dopamine release? This needs references.

  • Andy V

    I’m not understanding the ashwagandha study, if you could elaborate…

    Decreasing 5-ht1a autoreceptor / Increasing postsynaptic receptor sensitivity = Good

    The ashwagandha study states in the discussion: 4 weeks Asvagandha treatment resulted in a significant diminution in the functional sensitivity of the 5HT1A postsynaptic receptors, as indicated by the reduced expression of ‘5HT syndrome’.

    So could ashwagandha supplementation be a negative as it relates to 5-ht1a agonism?

  • charles mitchell

    How about Creatine? I feel a substantial calming effect from taking it

  • Ed

    So, what could be better for premature ejactulation? According to the studies done in dapoxetine, 5-ht2c hypofunction and/or 5-ht1a hyperfunction is neurobiological cause of PE.

    Some anti-depressant produces delayed ejaculation however the problem is that at the same time produces weaker erections and less pleasurable orgasm. So the idea is to only reduce the activity of post-synaptic 5-ht1a only?

  • Denis Varvanets

    Joseph – please write about angiotensin 2type 1 receptor and how to downregulate it. also – interesting about the way to decrease the level of antibodies to AT II receptors

  • Judd Crane

    Decreased signaling from Aswhagandha:

    1. Joseph M. Cohen

      Thanks 🙂

  • Lynn D

    Well, tried to scan thru yesterday and again today. Time to go out and chase butterflies or something fun. Listed as GG , GG, TT. Think have higher serotonin and lower dopamine . In the past tried St Johns and felt really flat , Walking, gardening, bike riding… help best, being out and noticing all the amazing life. Will consider some of the other supplements but really rather just eat food! (anything help up appetite? or thirst?).
    Thank you for all this information

  • lordilol

    i have a question and i have no clue where to put it.

    i go to bed in 12 and get up at 6
    its too hot in the summer to sleep more but i noticed a strange pattern in myself, usually i feel
    not wanting to do anything but once darkness(sometimes) sets in i feel alive and i want to do things
    and i become more DARING, and focused? i feel less stress too
    what the heck is going on? why do i feel like this? i
    have no idea but i cant really replicate this shit to other time zones, and or other circumstances.
    i only noticed 3 days like this in the past month. i am super curious. its reminds of what i read about cereblysin .

  • Dana

    Interesting stuff! I remember using Butyrate to help with methylation at one was one of the very few things I’ve tried over time that caused an immediate reaction–red, hot ears (looked very strange), and a rash on my arm. Went away in about 20 minutes, and overall there was a positive effect-a little more clarity, more energy. I didn’t know its relationship to this gene…

    …and sounds like a lucky girl 🙂

    1. Joseph M. Cohen

      Interesting….Lol 🙂

  • Deltrus

    CC here, for once I lucked out. Not planning on being in a relationship for a long time though. Too many health issues.

  • Guin

    I’m GG and I respond positively to melatonin, NDT, fish oil, magnesium, and zinc–looking forward to trying butyrate, SJW, and lithium.

    My husband should apply for Sainthood. Good luck.

    1. Joseph M. Cohen


  • forgotmypreviousnick

    There is no decent source of lithium available in my beloved country of miracles. I know, some plants have higher lithium accumulation than others. Could it be good enough?

    1. Maija Haavisto

      San Pellegrino mineral water supposedly has a lot of lithium.

      Re: the article, Albizzia julibrissin may also be a 5-HT1A agonist.

  • Ole

    Top notch info as usual!

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