STRUGGLING with DEPRESSION, ANXIETY, or BIPOLARITY? LEARNING can really HELP. Start with ARTICLES above or Topics below. Ty! Bill

5-HT1A receptor agonists relieve depression and anxiety. Great! What are they?

“I’ve heard Viibryd is a 5-HT1A receptor partial agonist. That’s supposed to be a good thing, but I have no clue what it means. Help!”

The arrival of Viibryd, an SSRI and 5-HT1A receptor partial agonist, has caused all sorts of hub-bub here on chipur. Most readers are all good with the SSRI piece; however, the 5-HT1A biz throws many for a loop.

It’s actually important to know, so we need to discuss it. And the only sane way to handle it is in pieces. Ready?


5-HT (5-hydroxytryptamine) is the chemical designation for the neurotransmitter serotonin. It’s role in the mood and anxiety disorders is huge.

5-HT1A Receptor

Receptors & Agonists

For the purposes of our discussion, receptor refers to a neurotransmitter receptor. You’ll see one on the receiving neuron (bottom) to the right.

Receptors are present on both postsynaptic and presynaptic neurons – the former being used to receive neurotransmitters, the latter for the purpose of preventing further release of a given neurotransmitter.

Each neurotransmitter has its own receptors. And it’s all about efficient electrical signaling.

An agonist is any chemical that binds to a receptor and triggers a response by that cell. A chemical with the opposite action is known as an antagonist.

Oh, partial agonist. Let’s not sweat that detail this go-round.

5-HT1A Receptor

A 5-HT1A receptor is a subtype of a 5-HT (serotonin) receptor. In fact, it’s the most widespread of the 5-HT receptors.

Amongst other locations, 5-HT1A receptors are found in high densities in the cerebral cortex, hippocampus, and amygdala – all heavily involved in the mood and anxiety disorders.

Activation of 5-HT1A receptors decreases blood pressure and heart rate, and lowers body temperature. Other activation effects include decreased aggression or an increase in calm behavior, increased sociability, inhibition of addictive behavior, and the facilitation of sexual behavior and arousal.

On the other side of the coin, activation of 5-HT1A receptors generates increased impulsivity, inhibition of penile erection, and the impairment of cognition, learning, and memory.

5-HT1A Receptor Agonists

So let’s put the pieces together. You may already be familiar with 5-HT1A receptor agonists and not even know it. How ’bout these?

aripiprazole (Abilify), buspirone (BuSpar), clozapine (Clozaril), LSD, nefazodone (Serzone), psilocybin, trazodone (Desyrel), vilazodone (Viibryd), yohimbine, ziprasidone (Geodon)

5-HT1A receptor agonists have traditionally been used in the treatment of mood and anxiety woes.

For example, buspirone (BuSpar) has been a popular anxiety med for a long time.

Just today, Doctor Z. shared in a comment, “Buspirone (Buspar) has been available for years and is a 5HT1A partial agonist. Very inexpensive in generic form. If you’re really interested in trying Viibryd, any conventional SSRI combined with Buspirone might be a reasonable and cheap alternative.” Click here to head to his website.

Atypical Antipsychotics

You’ll notice two atypical antipsychotics (Abilify and Geodon) in our list of 5-HT1A receptor agonists. Don’t know about you, but I’ve seen advertisements for Abilify as an augmentation agent for antidepressants for several years now.

Heavily involved here is overcoming a characteristic of serotonin-impacting antidepressants (like the SSRIs). It’s called therapeutic lag. Simply, it can take some time for them to work.

So an antidepressant regimen that can somehow pick-up 5-HT1A receptor agonistic properties brings faster relief and greater overall efficacy.

That’ll Do It

Alrighty, then. A nice thumbnail on 5-HT1A receptor partial agonists. The info may come off like so much bio-babble, but it’s really important to have in your back pocket. I mean, why wouldn’t you want to know the action of a med you paid for – and aim to swallow?

Yes! chipur’s responsibility is to protect and serve…

To check-out all of the chipur articles on the biology of the mood and anxiety disorders, just click here.

  • As I mentioned on your Abilify post, what you’re not saying is that the 5HT1A receptor slows the release of serotonin. And not talking about what a partial agonist actually is, is in fact ruining your whole argument, since that’s likely the key to how these drugs work.

    An antagonist does not cause “the reverse action.” A ligand (any internal or external chemical that binds a receptor) that reverses action of a receptor’s agonist is called in fact an “inverse agonist.” An antagonist PREVENTS activation. 

    A partial agonist in fact behaves as a COMPETITIVE ANTAGONIST when in the presence of the ligand, in this case, serotonin.  So, yes, you really should be discussing this in this go-around! Since agonists of the 5HT1A receptor SLOW serotonin release when stimulated by serotonin in the synapse, you can see why you’d want some antagonism.

    When a partial agonist binds to the receptor, it competes with other chemicals that could also bind. Partial agonists also produce WEAKER stimulation that the actual agonist. That is, Abilify will bind to this receptor, and stimulate it more weakly than serotonin, and it will also prevent serotonin from binding.

    So when you have a bunch of serotonin in the synapse, plus at 5HT1A partial agonist, the net effect is a REDUCTION (but NOT a blockage, and NOT a reversal) of stimulation of this receptor. Which is a good thing, since this receptor slows serotonin release.

    • I’m curious, Sonja – what’s your background? Your information is impressive, and you express it well.

      • Graduate student in molecular pharmacology. Just finished my general exam so all this stuff is fresh in my mind. Former tech writer. :)

      • You are one smart woman, Sonya. I sure appreciate your contribution and may stick my neck out and ask if I can tap your knowledge down the road (hint, hint). In fact, I’ll tell you what – whenever you’d like to put 600 or so words together on a mood/anxiety related pharm topic I’ll publish it on chipur. If you’d like to chat, my email is Thanks again…

    • Michael Meyer, M.D.

      Sonya, only the pre-synaptic auto-receptors of 5HT1a slow the release of serotonin. Post-synaptic 5HT1A receptors do not have this ability. So, a partial agonist (AKA mixed agonist-antagonist) theoretically would increase serotonin transmission in the situation of a deficiency of endogenous serotonin, and decrease it in the presence of an “excess”, but only post-synaptically. The whole picture when you add the auto-receptors then gets even more confusing… at least to me.

      • Ian

        Buspirone is more selective towards the pre-synaptic 5-ht1a autoreceptor. Paradoxically, heightened anxiety states can be associated with elevated serotonin activity in certain brain regions (i.e. dorsal raphe nucleus). The original ads for buspirone’s action as an anxiolytic, pointed to its ability to lower serotonin as part of its mechanism of action. In fact, many serotonin antagonists (blockers) (ketanserin, mirtazapine, atypical antipsychotics etc.) exhibit anti-anxiety effects. As a partial presynaptic agonist, buspirone probably works more as a stabilizer of serotonin than anything else. Drugs with post synaptic 5-ht1a receptor agonism can acutely increase anxiety. However, the hippocampus responds to 5-ht1a agonists by increasing the generation of new brain cells. The delayed anxiolytic effects of 5-ht1a agonist (and SSRIs for that matter) may involve a combination of enhanced neurogenesis / learning (cognitive adaptation), and control of anxiogenic serotonin firing in the dorsal raphe nucleus (through presynaptic mechanisms). Originally, it was thought that prolonged administration of presynaptic agonists would eventually desensitize the autorepceptor, leading to enhanced serotonin firing. However, in many studies, SSRIs and bupsirone don’t actually desensitize the autoreceptor (at least in humans – at therapeutic concentrations). Many studies of anxiety in humans show that the serotonin autoreceptor is already desensitized.

      • Thank you, Ian. Incredibly detailed and important information, and I’m pleased to have it here for those who’ll stop-by in the future. And I really like the fact that Dr. Meyer can comment five years ago and you significantly supplement it in the immediate. Very nice…


  • HI Sonja and Bill,

    There has been only one time in my life when I felt normal, happy and the most me. I have spent the rest of my life trying to get back there and that search has led me to the elusive 5-HT2C  agonists.

    I was prescribed Redux (like fenphen) for weight loss before it was pulled and although the effortless weight loss was exhilarating in and of itself, it was also very much about the emotional stability, the missing puzzle piece sense of “Finally.” I was never more stable and happy in completely natural way.

    It was my experience w/ Redux that has convinced me that my depression and anxiety is not so much in my “head” but in my body. Waiting on Locarsin! Wishing and hoping!


  • Brilliant concept. You guys can express the impression about Dopamine exactly what I wish for. Anyway it’s all important questions. Keep it up though!

  • dummy_profile821

    Hey! I really appreciate this! No one else is explaining all this in laymen’s terms on the internet.

    I am new to Buspar, and found this explanation.Thanks!

  • Gilda Sanchez

    Bill, I’m fascinated about this 5HT receptor. The 5-HT1a receptor may be implicated in developmental disorders such as autism spectrum disorder. A study here found low densities of 5-HT1a along with NMDA and benzodiazepine receptors. This might explain the “synaptic connectivity disturbances” as said in the article.

    • Read the article and found it interesting, Gilda. It’s a good read, Chipur folk. Thanks for sharing. Dang, we know so little now. But just think what the future holds – the mysteries to be explained/resolved. And the misery removed. Hmmm. Hey, thanks for the visit and contribution, Gilda…

  • Stevo1035

    I have a question. I’ve taken buspar in the past and it worked very well, especially all the years I was also taking paxil. In fact the only way I could tolerate paxil was with buspar, as it eliminated many of the bad side effects. However I could only tolerate so much buspar too. The main reason is that it made my joints very painful and also made my muscles hard and rigid, even though I was also much stronger and much more muscular. But it was also quite painful physically, even though I felt better in my head. My questions is then if buspar caused these painful muscle and joint side effects can I expect the same side effects from Viibryd? Since they both agonize 5ht1a. Thank you.

    • Hi Stevo! Stay tuned – will answer shortly…


    • Okay, Stevo, let’s take a look. I’ll begin with usual disclaimer. I’m not a medical doc, pharmacist, or world-class biochemist – just a humble counselor and writer.

      First of all, in terms of predicting what similar acting psychotropics will do in/for an individual is a crap-shoot. Just the nature of the beast. That said, musculoskeletal pain is listed as a common side effect of buspirone, muscle rigidity is listed as rare for vilazodone.

      Yes, both act as serotonin 5HT1A receptor partial agonists; however, buspirone acts as a presynaptic dopamine antagonist at three receptors. It’s also a partial alpha-1 adrenergic receptor agonist. Vilazodone has negligible inhibitory activity at norepinephrine and dopamine transporters. Perhaps that’s why you may not get the same muscle/joint effects from vilazodone.

      Appreciate your visit and participation, Stevo.


      • Stevo1035

        Thank you so much for looking into this for me. I actually had to stop the paxil/buspar combo because out of the blue after about 7 years on this my legs started getting real weak, numb, and wobbly, mainly in my thighs and hips. I’m wondering if the dopamine action of buspar as you noted above caused any drug induced Parkinsonism like I’ve been reading about. I could tolerate the sore muscles and joints like I mentioned which were always side effects but once my legs started giving out on me I had to stop. It’s been about 7 months and I have only slightly recovered. I’m seeing a neurologist but my emg, brain MRI, and bloodwork are all normal, however she can see the twitching in my thigh muscles on physical exam. The problem is I suffer from such bad anxiety that I really need an antidepressant bad, so I’d like to give Viibryd a try, I’m just scared I’ll get worse again. I’ve tried lyrica off label for anxiety with mixed results, it can make depression much worse on some days. I don’t know what to do and the doctors don’t seem to know what to tell me.

      • You may have already given it a go; however, the antihistamine hydroxyzine (Vistaril) is reported to be effective for anxiety Hang in there, Stevo…


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