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Tuesday, September 9, 2014

Natural 5-HT1A Receptor Antagonists / Agonists / Ligands.

In my thorough (and somewhat exhaustive) research, I have come upon some particularly beneficial information. I have seen many people trying to find information on this topic, and it wasn't easy sifting through tons of information & studies in effort to compile an active list that can't be found on Wiki's 5-HT1A entry.

However now I have found what I believe to be the keys to what many of you search for.

A brief overview.

  • Serotonin 5-HT1A presynaptic autoreceptors inhibit serotonin release, and noradrenaline release on sympathetic nerve terminals. (!) (!)
  • Serotonin 5-HT1A agonists may decrease serotonin release, and this can be beneficial or detrimental, depending on your situation and genetics.
  • Serotonin POST-SYNAPTIC 5-HT1A receptors are largely involved in neuroendocrine responses; it is deemed to be (generally) the POST-SYNAPTIC 5-HT1A receptors that release cortisol, ACTH and prolactin as well as growth hormone.  (!) (!) (!)
  • 5-HT1A receptors also have differential effects on memory, with some functions serving to improve short term memory, and yet decreasing long-term memory and some declarative memory functions. (!) (!)
  • 5-HT1A PRESNYPATIC activation inhibits GABA in the PVN (Paraventrical Nucleus) projecting to the Spinal Cord. (!)
  • 5-HT1A POSTYNAPTIC are located on GABAergic interneurons. The effects of modulating GABA through this pathway would depend on the ratio of presynaptic vs PostSynaptic densities.  (!) (!) (!) (!)
  • 5-HT1A activation inhibits Substance P. (!) (!)
  • 5-HT1A activation also inhibits NMDA-channels and activity. (!)
  • 5-HT1A POSTSYNAPTIC activation increases noradrenaline in the hypothalamus. (!)
  • 5-HT1A receptors correlate with glutamatergic tone (generally inhibitory) and are well expressed in the hypothalamus. (!)

Natural (Herbal) Agonists and Expression Modulators of 5-HT1A Receptors


:: GINKGO BILOBA :: Reverses aging related decrease of 5-HT1A receptors and can act as a 5-HT1A agonist - which can improve some aspects of memory and modulate serotonin activity.

Natural HERBAL (5-HT1A Receptor Modulator/Antagonist)

I find this one especially interesting, it acts at PreSynaptic 5-HT1A's as an agonist; decreasing serotonin levels, but yet at the 5-HT1A Post-Synaptics, it inhibits the activity and decreases serotonergic tone yet again. This is likely to contribute to the compounds anxiolytic effects as noted in the study. Also may account for it's positive effects on LH, Testosterone and Cortisol. (!) (!) (!)

Although it may raise serotonin through other mechanisms (like MAO-inhibition and effects on sigma and transporters) - this might be a valuable tool in modulating the serotonergic system when combined with other ingredients. If you are looking to treat PSSD (Post SSRI Sexual Dysfunction) Berberine is of additional use in another way; besides it's effects on 5-HT1A receptors. It inhibits and downregulates PDE-5 (the same enzyme Viagra,Cialis etc Target).

( Berberine effect on PDE-5 mRNA Expression )

Berberine also has notable nootropic effects. (!)

NOTE : Berberine has also been found to exert an effect on other serotonin receptors, namely it antagonizes 5-HT4 receptors as well. Making it a suitable remedy for treating PSSD yet again. 5-HT4 serotonin receptors are anxiogenic (anxiety provoking) and contractile (constricting) - thus berberine improves vasodilation by dual serotonin and PDE-5 antagonism.

Binding of STW 5 (Iberogast) and its components to intestinal 5-HT, muscarinic M3, and opioid receptors.


Clinical studies with the fixed herbal combination product STW 5 (Iberogast) have indicated an efficacy comparable to metoclopramide (5-HT(3) antagonist) and cisapride (5-HT(4) agonist) in functional gastro-intestinal diseases like functional dyspepsia (FD) and irritable bowel syndrome (IBS). Since serotonin (5-HT(3) and 5-HT(4)) and muscarinic M(3) receptors are known to play a central role in the etiology of FD and IBS, the extracts contained in STW 5 and several of their phytochemical components were studied in vitro for binding affinities to these receptors of the intestine. STW 5 inhibited the binding of (3)H-GR113808 and (3)H-4-DAMP to 5-HT(4) and M(3) receptors, respectively, about 10 times more potently than the binding of (3)H-GR65630 to 5-HT(3) receptors. IC(50) values for STW 5 did correspond to extract dilutions of 1:1000 (M(3) binding) and 1:2000 (5-HT(4) binding). In addition, STW 5 also potently inhibited the binding to opioid receptors with an IC(50) value of 1:2000. Of the nine herbal extracts contained in STW 5, the fresh plant extract of bitter candy tuft (Iberis amara) selectively inhibited binding to M(3) receptors, while ethanolic extracts of celandine herb and chamomile flower were selective to 5-HT(4), and liquorice root to 5-HT(3) receptors. Binding affinities to human recombinant 5-HT(3), 5-HT(4) and M(3) receptors were qualitatively similar to those of the corresponding intestinal receptors. The benzylisoquinoline alkaloid berberine had significant inhibitory action on 5-HT(4) and M(3) binding, showing IC(50) values of 40 ng/ml (100 nM) and 200 ng/ml (500 nM), respectively, but is present in the extract of celandine herb only in traces, so that also for the celandine extract a cooperative effect of several phytochemical constituents can be assumed. These in vitro data indicate that 5-HT(4) (to a lesser degree 5-HT(3)), muscarinic M(3), and opioid receptors represent target sites for the treatment of FD and IBS with STW 5 (Iberogast).


  1. Hey there,
    Ive tried ginkgo in the past, the first 2 days I felt cured, even had some hallucinations @ night time before when combined with ashwagandha, guess there must have been some 5ht1a/5ht2a manipulation going on.
    But the side effect which I had assumably due to ginkgo, was increased intraocular pressure, which stopped when I got rid of the ginkgo, but the new blood vessels in my eyes stayed!!!
    Was on it for like 5 days, first 2 days was amazing on it, then on day 3 a shift or so took place and I felt anxious (due to noradrenalin? - I know ginkgo affects this aswell).
    Could you tell me how to block the intraocular pressure from the ginkgo, I know it has been associated with brain bleeding and bleeding disorders :/ be a shame if I couldn't use this.

    1. It could be related to Ginkgo, it does boost circulation. However, if it is INCREASED intraocular pressure, and not muscle tension, then its probably related to Ginkgo's effects on nitric oxide, NOT norepinephrine, it could also have something to do with platelets.

      I would lower the dose of Ginkgo, how much were you taking?

      Do ensure you are getting enough macronutrients and Omega-3's in your diet.

  2. Would berberine work like Pindolol together with SSRI, to improve SSRI´s effect on both depression and PE?

    1. No, it wouldn't. The concept of Pindolol 'speeding' up the anti-depressant effects of SSRI's is that it acts as a ''Pre-Synaptic'' antagonist to the 5-HT(1)A somatodendritic 'autoreceptors'. Whereas Pindolol exhibits partial agonist properties of the post-synaptic receptor, Berberine displays weak-moderate antagonist actions...meaning Berberine and Pindolol are chemically opposite in regards to both their presynaptic and postsynaptic actions.

  3. Thanks. Do you know of a "natural" 5-ht1a antagonist/blocker? That would improve SSRI effect on depression/anxiety and PE. SSRI worked great in the beginning but kind of pooped out. Now on high dose Sertraline. Before Citralopram.

    1. Well if you are trying to enhance the effects of an SSRI you would be looking for an ''autoreceptor antagonist'', meaning something that blocks the PRESYNAPTIC 5-HT1A somatodendritic autoreceptors which are totally different than the post-synaptic 5-HT1A receptors which regulate endocrine activity, beta-endorphin etc. You might do well with something like Pindolol if you have high blood pressure since it also blocks 5-HT1A autoreceptors :

      As far as natural stuff goes, that's a tricky one, I haven't seen any specific herb or nutrient that blocks 5-HT1A-autoreceptors without affecting other receptors, but the thing is, if you've been on an SSRI for a while, you probably already have less 5-HT1A-autoreceptor activity [the one that ''regulates'' Serotonin in the brain]. So you may not 'need' an antagonist, instead, you should measure out Urine/Blood levels of neurotransmitters to see if you still need more serotonin, most people with Depression find they have an issue with Dopamine and / or NorAdrenaline in addition to a serotonin issue, its very rarely *ONLY* a Serotonin issue, and sometimes, serotonin isn't at all involved. Actually often. If you think that SSRI's help, then maybe they do, for You, but dysphoria and 'pooping out' happen more frequently with SSRI's than other anti-depressant medications.

      It's also worth noting that recent research has actually shown that Serotonin is not the reason, or rather, entire reason for SSRI's so-called benefits, in fact, they actually show that most SSRI's that are commonly used affect/increase neurosteroids like Allopregnenolone.


  4. Tremendous insight/knowledge you have. Thank you. In fact, recently I notised that upping my dose of l-tyrosine had great effect (dopamine etc) on mood, mental clearity and desire. Do you know of optimal usage/doses of that?
    I am still certain that my PE is related to hyperactive 5-ht1a receptors, that got "knocked down" in the beginning of taking SSRI, but later "reactivated" (very speculative, I know). So my thought was to add pindolol. Or do I got it the other way around? But I am not to keen on adding to much synthectic stuff - hard on the lever. Oh well. Thanks for answering.

  5. In found this: It has been proposed that the persistently short intravaginal ejaculation latency times (IELTs) in men with lifelong PE are associated with diminished 5-HT neurotransmission, a hyperfunction of 5-HT1A receptors, and/or a hypofunction of 5-HT2C receptors (Waldinger et al., 1998).