Speculations on an Implausible Mechanism
What about the necessary plausible mechanism by which this putative effect might be mediated? The answer to that is simple, there is no plausible mechanism.
That should be the end of the story. The fact that it is not is because the above-mentioned agencies have issued official ‘warnings’ which most doctors are unable to understand.
The proposed mechanism for this putative effect is the notion that increased levels of free serotonin are generated by ‘displacement’ of serotonin that is ‘free’ because it is unable to bind to 5-HT3 receptors which are already blocked (i.e. ‘occupied’) by ondansetron. At least, that is what I think they think they mean. But the text below indicates a lack of clarity and precision in the formulation of this idea, which was mooted in the penultimate paragraph (left-hand column at the bottom of page 20) of the WHO document (18 ), which says:
A mechanism for a suggested increased vulnerability to serotonin syndrome when concomitantly using 5-HT3 antagonists and other serotonergic drugs might be that blocking of the 5-HT3 receptor subtype, and at the same time increasing the levels of serotonin, results in excessive serotonin to other serotonin receptor subtypes, including 5-HT1A and 5-HT2A (25, 26).
In support of this wild speculation the WHO & FDA documents quote both Turkel (25) and Altman (26). Neither the Turkel nor the Altman report is by a researcher or expert in this field, they contain no original research data, nor any other referenced data (see below): they are merely musings that offer no science whatsoever to back up the WHO ‘claim’.
I mentioned above that the mis-citation of references can go beyond carelessness and become academic fraud. The references cited in science writing are supposed to substantiate the facts and arguments being put forward. If a paper is cited which does not in fact say what the authors claim or insinuate it says, or it is simply irrelevant in that particular context, then it is mis-cited. Obviously, that may represent occasional carelessness but it is a serious academic failing which can rapidly shade into deceit and fraud. This is a very serious issue that academics have difficulty facing up to.
So, this is what Turkel et al. (2001) actually state (so we can all be sure no mis-citation is involved):
“Multiple serotonin receptors may be involved in producing the symptoms of the syndrome. The serotonin syndrome implies both central and peripheral serotonin dysfunction. Perhaps blocking one type of serotonin receptor and functionally increasing systemic and CNS levels of serotonin simultaneously, hence presenting excessive serotonin to other receptors, increases the risk for serotonin syndrome …”
They offer no supporting evidence (and particularly, they offer no citation to substantiate this novel and imaginative idea), nor more detailed discussion about this speculation. In 2010 Altman et al. (26) cite Turkel without adding anything. Therefore to cite Altman as well is misleading because it gives a spurious impression that there is greater support for the idea than actually exists.
The FDA discussion states (it parrots the WHO, p. 12 under ‘Discussion’) “In order for Altman’s hypothesis to be true …”. There are two reasons why this statement represents the sort of sloppy thinking that characterises both these documents. Firstly, it was not Altman’s idea at all, it was propounded by Turkel. Secondly, it is quite wrong to describe it as a hypothesis, it was speculation, which is not the same thing. To be fair to Turkel it was introduced as speculation (“Perhaps blocking one type of serotonin receptor …”). Indeed, any good referee should have dis-allowed such speculation, unless it was substantiated by reliable references, which it was not.
It is onerous and tedious to have to dissect something as pedantically as this, but it is necessary to illustrate the point that much of what becomes accepted as part of the scientific literature about ST is poor science peppered with mis-reading and mis-interpretation of references.
Finally, a basic knowledge of neuro-anatomy and neuro-pharmacology gives us sound reasons for supposing that such a mechanism could not possibly exist or be relevant. Serotonin release from the pre-synaptic nerve diffuses across the tiny gap separating it from the receptors and only a minute proportion of the released serotonin binds (i.e. locks onto) receptors. It diffuses rapidly into the local extra-cellular fluid and a large proportion of it is taken back up into the pre-synaptic nerve for re-use. The amount that actually binds to the receptor is a small proportion of the total amount present. That fact alone would indicate that the amount taken out of this pool by binding to a particular type of receptor would have a small effect on that pool. The idea is made even less plausible because the different types of receptor are not physically juxtaposed, they are separated by much greater distances than the synaptic gap. Because diffusion involves an inverse square law the rate of decrease in concentration of the neurotransmitter drops rapidly with increasing distance from the release site. I hope this conveys convincingly what a simplistic and untenable idea this is.
An analogy may help to convey the picture. Imagine being at the back of a press gallery with a myriad of reporters thrusting their microphones in front the speaker. Do you suppose that the sound waves absorbed by all these microphones would make you significantly less able hear the speaker? Of course not. Nor, if they were all suddenly turned off would the speaker sound louder.
9. Serotonin Toxicity and 5-HT3 antagonists - PsychoTropical Research
