Have I missed something or did that 35-compound receptor affinity study not look at TAAR activity? It strikes me that that would be another place to look. The mention that excess overall amine load could lead to purging made me think of this. Amines, ergo, trace amine activated receptor.

Have I missed something or did that 35-compound receptor affinity study not look at TAAR activity? It strikes me that that would be another place to look. The mention that excess overall amine load could lead to purging made me think of this. Amines, ergo, trace amine activated receptor.

The controversy continues to this day: Check this out: http://dx.doi.org/10.1016/j.jep.2009.10.030

The authors report both MAO-A and MAO-B inhibition for harmine and harmaline, although MAOAI is stronger...

..administration of MAO-B inhibitors, which increased β-PEA levels above their physiological range...

Studies with heterologous expression systems and brain synaptosomes have revealed a complex tripartite relationship between TAAR1, monoamine transporters, and monoamine autoreceptors in vitro.

i would like to understand more clearly ShamensStamen how Moclobemide and Harmalas differ in their specific functioning..and types of MAOI variance

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.

http://psychotropical.in...ty-and-5-ht3-antagonists

i do also note, though, that one of ayahuasca's names in the Amazon is 'la Purga' - that's what it 'does'.

We know that DMT has some affinity for 5HT3.

Receptor affinity profiles of psychedelic drugs, ordered by decreasing affinity...

DMT: 4.00 5ht7, 3.97 5ht1d, 3.91 5ht2b, 3.53 Alpha2B, 3.53 Alpha2C, 3.51 D1, 3.42 5ht2c, 3.28 5ht1e, 3.25 5ht6, 3.16 5ht5a, 3.13 Imidazoline1, 2.95 Alpha1B, 2.75 Alpha2A, 2.70 Alpha1A, 2.58 5ht2a, 2.37 SERT, 2.23 Sigma1; 0.00: 5ht1a, D4, D5, Beta1, D2, D3, DAT, NET, 5ht1b, Beta2, Sigma2, CB2, KOR, Ca+Channel, M1, M2, M3, M4, M5, H2, CB1; ND: H1, DOR, MOR, NMDA

The second section displays seven sites at which most compounds were assayed, but at which there were no hits: 5ht3 (serotonin-3 receptor), H3 (histamine-3 receptor), H4 (histamine-4 receptor), V1 (vasopressin-1 receptor), V2 (vasopressin-2 receptor), V3 (vasopressin-3 receptor), GabaA (GABA-A receptor).

That may indeed be something to look into. But that still wouldn't explain why there's no nausea/vomiting with the Harmala reverse tolerance, or when using Moclobemide.

A metabolic study on DMT showed this alkaloid to be rapidly metabolized in the blood to dimethylkynuramine by an unknown enzymatic reaction (Hryhorczuk et al., 1986).

And the other study sited with a Ki value of >10,000 eliminates any relevance as an antagonist.

Activity Assays

For the twenty-five compounds of Fig. 1, the NIMH-PDSP also performed activity assays at 5-HT2A and 5-HT2C. The Emax values (maximal activity) are relative to 5-HT (serotonin), measuring Ca++ mobilization. Ca++ flux assays were performed using a FLIPRTETRA. The activity assays were conducted with cell lines which have very high receptor expression levels (e.g. plenty of ‘spare receptors’). Under such conditions partial agonists will have considerable agonist activity. The data represent the mean ± variance of computer-derived estimates from single experiments done in quadruplicate. Thus, the four observations are averaged and a single estimate with error is provided.

http://journals.plos.org...371/journal.pone.0009019

Well, if harmala reverse tolerance was regulated through modulation of TAAR then it would explain something. E.g., increased amine levels -> initial nausea response; continued elevated amine level -> compensatory response (down regulation of TAAR?) = "harmala reverse tolerance"?

Of course, I've seen no evidence that TAAR mediates a nausea response (although it would perhaps make sense). Research may (already) show that this occurs. TAAR is a relatively newly discovered receptor type.