Before I begin, I've got most of my understanding on this topic from a fascinating, albeit very simple, metaphor I read on an article here: The Last Psychiatrist - "The Most Important Article On Psychiatry You Will Ever Read"

I want to know if this is a helpful and accurate way to think about drugs that have affinities to multiple receptors, such as LSD-25, and many other of our favourites. I also have a question regarding drug receptor preferences and probabilities at the end of the post.

I understand that few, if any drugs, are absolutely specific for one receptor; that most drugs have relative selectivity. Selectivity being the degree to which a drug acts on a given site relative to other sites.

A drug’s ability to affect a given receptor is related to the drug’s affinity (probability of the drug occupying a receptor at any given instant) and intrinsic efficacy (intrinsic activity—degree to which a ligand activates receptors and leads to cellular response).

My understanding of drugs that have affinities to multiple receptor sites is that they do not bind to all receptors simultaneously; that it depends on the dose.

As you increase the dose of a drug, from say 'no effect' to 'threshold effect', the drug will be able to increase the amount of receptor sites it can bind with.

As one increases the dosage, for all intents and purposes it is very much like you are doing different drugs - as receptor sites that were previously untouched, are now being hit.

Higher doses aren’t just necessarily stronger — they are completely different. The behavior of LSD-25 at 20ug is completely different than the behavior and effects at say 40ug, 150ug, 350ug or 500ug. It is binding with receptor sites at the higher doses, that aren't even touched at the low doses.

Instead of thinking that the drug binds to all receptors simultaneously, a simplistic but good visual analogy is to imagine it like a 'fountain' that has multiple tiers or 'levels' - and each level representing different receptor sites. This picture is a little misleading, as each tier is a different size - just imagine that each tier is the same size.



Water - or in this case LSD-25 - fills the top level, overflows into the second level, then that overflows into the third, etc. You can't get anything into level 3 until you fill levels 1 and 2. And, once you've filled level 1, you can't put anything more into it. Each level can only hold a certain amount, before moving on to the next level.

Level 1 is 5-HT1A, level two is 5-HT5B, level 3 is 5-HT6 - and so on, and so forth. [See Note1 below for a chart of LSD's affinities]

So you can imagine that as you increase the dosage, you will 'fill up' Level 1 - the 5-HT1A receptor site. As you increase the dosage a little bit further (for the sake of argument, imagine this is weeks later and not within the same day, to take into account of tolerance etc) the 5-HT5B, and 5-HT6 receptors will become affected (these receptors have very close levels of affinity with LSD-25, I'm not sure which would be affected first) - but the LSD-25's affects on 5-HT1A, and its effects on you, will not have increased; 5-HT1A is already at 'capacity'. [See Note2 below for clarification]

So if I take 20ug of LSD-25 one day, and take 500ug some other day, it is not 25X more of the original effect, but really it is an increase of the original effect, with the addition of more and more effects from different receptor sites.

Of course, the reverse is also true; if you use a drug to do a certain thing at a certain regular dose, then reducing the dose -by say, half- puts you into a different "level". It's not not half as good as it was at your regular dose - it's completely different.

Which receptors will be hit first?

Should we consider affinities with different receptors as 'preferences'? - ie, the higher the affinity with a receptor site, the higher probability that these receptor sites will be the first the molecule binds with? [This is of course taking into account, that everyone has different constitutions, and what may be the median affinity for the general population, will be slightly different for each person.]

Note1: Chart of LSD affinities

Important to note when using this graph: Ki Values are reported in such a way that the lower the number is, the higher affinity the structure has for the receptor. This means that the low values on the graph are the relevant information, not the taller bars.

The graph was from public source data at http://pdsp.cwru.edu/pdsp.php - which unfortunately, is now a dead link.

The black horizontal line on the graph, represents the plasma level of LSD in humans during recreational use and hence receptors which LSD has an affinity for above the line are unlikely to be affected by recreational LSD doses.

(Aghajanian GK, Bing OHL. (1964). "Persistence of lysergic acid diethylamide in the plasma of human subjects" (PDF). Clinical Pharmacology and Therapeutics 5: 611–14. PMID 14209776.)



Note2: Clarification This is just a metaphor, receptor systems don’t 'fill up' (i.e. become saturated) before the next system is impacted, more accurately, there exists a certain level of binding at one receptor such that it then becomes equally likely that it goes elsewhere. In other words, it goes onto the next receptor site not when the receptor site is at total 'capacity', but when the receptor site reaches a certain level of binding, which is likely to be different for all people, i.e each person's 5-HT1A receptor site (for example) is going to have different amounts of maximum binding, or 'capacities'.
The effects “max out” even if the receptor site, is not 'full'.

A drug’s maximal effect on a site can occur well before 100% saturation of a system; for example, a 10% affect on the 5-HT1A receptor may be all that is necessary to get maximal effect (whatever the effect 5-HT1A has on a person), such that increasing binding to 20% doesn’t get you any more of that effect. Nor might a drug be able to bind to more than 10%. So while binding saturation is used here interchangeably with maximal effect, it is not the same.]

It just moved to: http://pdsp.med.unc.edu/pdsp.php

Btw, do you know: ?

The levels analogy is flawed, although in the broadest sense, you're right.

Different drugs have different affinities for different receptors, the affinities are how statistically likely a ligand is to bind to a receptor, based, in part, on the amount of intermolecular force between them. LSD-25 is MORE likely to bind to the 5-HT2Ar than it is to the D5r, which means that at any given time, a large percentage of the drug will be bound to the 5-HT2Ar and a very small percentage will be bound to the D5.

When you increase the dose, you are increasing the number (in moles) of molecules available to bind to all receptors, so the number of LSD-25 molecules bound to the 5-HT2Ar goes up, but so does the number bound to the D5. The ratio, generally remains the same. The important thing to remember is that, in pharmacokinetics, ligand distribution and binding is treated like it behaves as an ideal gas, because the number of individual molecules and receptors is so high.

Most neurotransmitter systems need a certain level of activation or depression before effects on consciousness are felt (this is called the effective dose), which means that, just because you aren't feeling the effects of D5 agonism occurring doesn't mean that the ligand isn't bonding to the receptor, just that not many are. Eventually you will reach a point where you've saturated the receptors with the highest affinity, and you can keep pushing the envelope, by continuing to up the dose to get more effects from other receptor systems, but there are no 'levels,' it's all about statistics and distribution of ligands.

As for the thing about taking varying doses one day, you need to account of the fact that exposure to many drugs causes down-regulation of the target receptor, which means that any day-after effects are more to do with the body's attempt to restore homeostasis than anything really to do with the drugs receptor affinities.

Remember: drugs are just bundles of carbon and a few other elements, just like most receptors. They don't "know" things about their environment or make choices, they just behave according to simple rules. That's all they can do.

Blessings
~ND

I'll admit that at the moment a lot of this is beyond my comprehension - in the video Ufostrahlen posted, I didn't know what Nichols was talking about until 18:00 mins or so.

That being said, I appreciate both your responses - I'm no professional or academic, and I have a lot to learn.

Nathaniel.Dread:

I get the feeling that you are suggesting that what I've been talking about has far more to do with the distribution of ligands to receptors based on probability of affinities than it does work like in the metaphor I found - ie, it's not a rational distribution of ligands to receptors in the linear sense.

I certainly at this point feel as though I may be out of my depth (for now!) - but I do feel that a simple metaphor is desperately needed in terms of how we think about how psychoactive drugs actually work. The technicalities of this subject can definitely be alienating, hence why such simple metaphors - like the fountain - are so seductive; not necessarily technically true, but definitely a step in right direction.

I'm going to keep pushing at this, and hopefully I can develop some sort of metaphor that is easy to understand by all.

Right on. There's a a lot of written material on the various aspects of the psychedelic, but there are many gaps in the discourse too. The technical material is fascinating, but much of the papers are over my head or are just to dry for my reading taste. Discussion coming from a more popular science delivery would be a great contribution. Do it!

I worry about relying too much on metaphors and analogies, because people have a tendency to extend them beyond what is appropriate, and then you end up with misinformation and folks who think they know how a system works, when in fact, they're just leaning too heavily on a useful analogy they heard once.

That's not to say that you shouldn't keep working on this (you totally should, I think this is awesome stuff), I just want to bring up the limitations of analogy.

Blessings
~ND

I am just thinking if technically speaking, a kind of osmosis is at play here. I know of no research being done on this. So it's just a suggestion for Osmosis; The concentration of chemicals in a given synapse could provide us with a ligand affinity that changes over time? If we have 80% serotonin in 5hta and 30% in 5htB. A flood of serotonin in the brain prefers the 5htb over the nearly-saturated 5ht2a receptor? An illustration of the result is something like 85% serotonin in 5hta and 70% in 5htb.

Taking into account that other factors will still prefer high-affinity receptors but it gets increasingly harder to prefer it when you increase the concentration of molecules already present in the synapses.

The challange with distilling these mechanisms into an easy to digest metaphor is that these mechanical systems are built out from metaphors. We think we understand how electricity works and from this understanding we can manipulate and control it but.... what is electricty, i mean really what is it, anyways.

No, there is no way to change the affinity of a ligand to a receptor without structurally altering one or the other.

Blessings
~ND

I think you are right. I figured that synapses are closed spaces but actually my theory doesn't make much sense.

Fascinating subject. I'd like to go back to the original article that served as a source of both metaphor and understanding. My issue with the article from the getgo is its lack of what I might call distinct or revealed regions of ignorance.

Specifically, seroquel or quietipine does indeed bind to multiple receptor sites, but that does not make it less of an antipsychotic. It depends. It also offers a more gentle and less side effect prone way to target psychotic manifestations. Quietipine is close to the other atypical antipsychotics.

I would go about my description in a completely different way than that last psychiatrist. I'd highlight the ignorance and say that quietipine is one of a group of related atypical antipsychotics that have affinities for 5HT-2A/D2 and that that in combination is something of its merit and not simply D2. More here: https://books.google.com...nepage&q&f=false

I don't like how the last psychiatrist says simply D2=Psychosis. In fact, it seems that much of the D2 = psychosis understanding came from studying the action and efficacy of the earlier antipsychotics and studying what they do to the brain after they had shown some clinical efficacy. It is not wrong per se but probably too simplistic

There is also a study of the Fos protein and cFos-mRNA expression and its role in the efficacy of antipsychotics.

Seroquel looks to hit a sweet spot for chronic administration where it alleviates chronic psychosis in some individuals whilst minimizing EPS and anti-cholinergic issues. So for example, not so foggy and clouded.

One takeaway may be that each specific drug has its own efficacies and the study of efficacy works as much back from its effects on individuals as visible and as reported as it does from combined study of the neurology.

Yes. Yes. Yes. Probabilities and affinities. The Last Psychiatrist's hyperbole is a poor substitute for boring probabilistic language.

"if one molecule of Seroquel goes to H1, and not to D2, then can it have any antipsychotic effect? No. One molecule binds to H1, so it isn't an antipsychotic, it's an antihistamine."

If this poor psychiatrist were on the Nexus, he'd get a whallup for saying this! I'll pretend like he is here and gently tell him, no. In reality we only have many numbers of molecules and many receptor sites and we have relative affinities or propensities to bind. And yes, at all doses, Quietipine is itself, what we sometimes call an atypical antipsychotic.

Does it have efficacy? If so, what kind? There is no fixed answer to that and the fountain analogy is poor in the extreme. You don't have to favor large amounts of it for it to have the efficacy I would imagine it would have. Getting into that efficacy is bound to be a complicated story, something of which includes its propensity for D2 binding. But not all D2 binding is the same nor is that all of the story.

I also see no mention in his article on the chronic administration of Quietipine, a role in which apparently shines, with less side effects than other atypical antipsychotics. I should want to call it the least important article on psychiatry, but then I might fall into hyperbole. I found his article to bind somewhat to my humour sense and less so to my wisdom sense but the dose was low enough and the effect acute enough that I don't think I sustained too much damage from reading it!