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The literature online about this practice is very poor. The theory goes like this:

  • A mix of amino acids that does not include tryptophan will lower the proportion of tryptophan in the bloodstream.
  • Transporter molecules will have a harder time finding free tryptophan and thus not bring it back to the brain for synthesis into serotonin.
  • Serotonergic neurotransmission will drop acutely.

That last part is what does not make sense to me. Even if insufficient tryptophan is coming into the brain, don't the neurons already have plenty of serotonin stored in the axon vesicles from which the neurotransmission happens? Thus, reducing the amount of serotonin synthesis should only cause a decrease in neurotransmission when the reserves in the vesicles are depleted.

So what gives? Astonishingly this is not explained in the literature I have found.

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don't the neurons already have plenty of serotonin stored in the axon vesicles from which the neurotransmission happens

Sure, but neurotransmission is happening all the time. It's not uncommon for a neuron to fire several times a second, and though not nearly every vesicle is released per action potential, over minutes to hours you should be thinking about hundreds to tens of thousands of possible release events.

Of course, neurotransmitters aren't simply released and then gone; monoamine transporters are particularly famous drug targets; these transporters facilitate reuse of neurotransmitters as well as their degradation.

I had a bit of trouble finding a solid estimate of brain half-life/turnover of serotonin in papers I have access to, though this paper used an indirect method by using an inhibitor of subsequent serotonin metabolism:

Udenfriend, S., & Weissbach, H. (1958). Turnover of 5-hydroxytryptamine (serotonin) in tissues. Proceedings of the Society for Experimental Biology and Medicine, 97(4), 748-751.

Such estimates indicate a half-life in brain of the order of minutes

Other papers like this one:

Diaz, P. M., Ngai, S. H., & Costa, E. (1968). Factors modulating brain serotonin turnover. In Advances in pharmacology (Vol. 6, pp. 75-92). Academic Press.

refer to

Reports in the literature show that the turnover time of brain NE stores is 5.8 hours and that of brain 5-HT stores is 1.2 hours

but I don't have access to the full-text to find what reference they refer to. However this seems consistent with the timeline of tryptophan depletion (over several hours, or days) referred to in papers like this one:

Nutt, D. J., Forshall, S., Bell, C., Rich, A., Sandford, J., Nash, J., & Argyropoulos, S. (1999). Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders. European neuropsychopharmacology, 9, S81-S86.

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  • $\begingroup$ Very interesting. The question, then is, why does it seem that stuff like 5-HTP can cause clearly elevated levels of serotonin in the brain for extended periods of time, on the order of months? I have heard from one doctor that it can take 3 months to reach neurotransmitter homeostasis, and in my experience possibly even longer. $\endgroup$
    – JClaussFTW
    May 20, 2022 at 6:16
  • $\begingroup$ @JClaussFTW Are you talking about in the context of SSRIs? $\endgroup$
    – Bryan Krause
    May 20, 2022 at 13:16
  • $\begingroup$ @JClaussFTW Also I'd be curious to see a reference that suggests acute administration of 5-HTP causes elevated 5-HT over months. $\endgroup$
    – Bryan Krause
    May 20, 2022 at 15:32
  • $\begingroup$ No, definitely not in the context of SSRIs. I can attest that tryptophan and 5-HTP both cause effects for me that can last weeks to months after the initial dosing. The extended effects are roughly the same as the acute effects meaning it's not just the body's reaction to the drug being withdrawn, as that would produce opposite effects. PM me if you'd like to hear more because I'm not going to put it on this public forum. $\endgroup$
    – JClaussFTW
    May 21, 2022 at 8:03
  • $\begingroup$ @JClaussFTW Well, explicitly we can't discuss more because personal medical advice is off topic here. 5-HTP is generally considered a poor therapeutic option specifically because it has such a short half life, though. $\endgroup$
    – Bryan Krause
    May 21, 2022 at 14:31

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