"Serotonergic psychedelics" is apparently a sub-class of psychedelics. Now, I believed that the pharmacological definition of psychedelics is that they all agonise 5HT receptors, especially the 2A subtype. However, the existence of this serotonergic sub-class implies that perhaps some psychedelics don't operate on serotonin receptors. Unless, something else is meant by "serotonergic".

Does serotonergic in this case refer to what receptors they agonise, or, what chemical the substances imitate. If the latter, that means that some psychedelic substances are able to agonise 5HT receptors without imitating serotonin, whereas the serotonergic psychedelics do this while imitating serotonin.

If the former, then that means that not all psychedelics agonise the 5HT receptors, meaning that "agonises the 5HT serotonin receptors, especially the 2A subtype", is not the definition of psychedelics.


1 Answer 1


Short answer
It's messy.

The classical psychedelics (mescaline, DMT etc.) are derived from plants (peyote, ayahuasca) and have a long history of use by shamans and originally often mainly served religious purposes, before being exploited by the New World peoples for recreational (and occasionally scientific) purposes. LSD is also considered to be classic yet it is a synthetic derivative, but readily made from lysergic acid derivatives extracted from the mold Claviceps purpurea. These classic psychedelics are indeed all, primarily, 5HT2A agonists.

Having sad that, 'psychedelic' is a classical term meaning 'mind opening', and was first coined back in the 1950's. It's a broad, ill-defined term often associated with illicit drugs, hippies and alternative rock. The term serotinergic drug is more specific, while the term '5HT2A agonist' is yet even more specific. The former also includes MDMA, which is imo mind-opening, yet (generally) not hallucinogenic. The latter includes those drugs that produce profound hallucinations, i.e., the classic psychedelics.

This is the reason I tend to move away from 'psychedelic' as often soft drugs like THC are also termed 'psychedelic'. Hallucinogenics are a more specific class of drugs and is the one I think you are referring to, i.e., those compounds producing hallucinations, i.e., sensations that are not there (a hallucination being 'a perception in the absence of external stimulus that has qualities of real perceptions').

Now what about non-serotinergic hallucinogens? Well, there are particularly potent hallucinogens that are primarily not serotinergic, but glutaminergic, particularly the dissociative anesthetics. These include PCP and ketamine that are hallucinogenic as they

can produce visual and auditory distortions and a sense of floating and dissociation (feeling detached from reality)

However, here again it comes down to a matter of definition; a 'true' hallucination is a percept in the absence of a stimulus; a distortion is more akin to an illusion, namely

an instance of a wrong or misinterpreted perception of a sensory experience

In addition, most and perhaps all hallucinogens are 'dirty' drugs, in that they affect multiple neurotransmitter systems and therefore have broad effects. MDMA for instance is psychedelic because of its 5HT effects but definitely has stimulant, dopaminergic properties too (having the methamphetamine backbone this isn't surprising of course).

In all, not only is the scientific terminology messy, also the science behind it is messy, as 5HT2A agonists may still have effects on other neurotransmitter systems too. This can explain why every 5HT2A drug has slightly, or even grossly different actions than structurally related ones.

  • $\begingroup$ I see. So, if I get you right, there are three definition: The definition where psychedelics are a category substances that primarily agonise the 5HT2A receptors, then the definition where psychedelics are substances that agonise any of the 5HT receptors, and then the definition where psychedelics is just a synonym to hallucinogens? And then one can say that some substances are semi-psychedelic, because they agonise the 5HT, even the 5HT2A receptors, but also agonise other systems in the brain, giving other, non-psychedelic effects? $\endgroup$
    – A. Kvåle
    Feb 26, 2021 at 23:48
  • $\begingroup$ @A.Kvåle - well, yeah, as I start off with; it's messy $\endgroup$
    – AliceD
    Feb 27, 2021 at 13:22
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    $\begingroup$ Okay thanks, I see it was a good idea to start of the "What are psychedelics?" chapter of my treatise with: "The category of psychedelics is ill-defined". $\endgroup$
    – A. Kvåle
    Feb 27, 2021 at 13:44
  • $\begingroup$ I have a few more questions: Do all true hallucinogens (those who create true hallucinations) agonise 5HT receptors? Those hallucinogens that primarily agonise the 5HT2A receptors, are they compromised solely of the classic psychedelics, or are there other substances within this category? $\endgroup$
    – A. Kvåle
    Feb 27, 2021 at 17:25
  • $\begingroup$ According to this article:ncbi.nlm.nih.gov/pmc/articles/PMC5756147 , chapter 3, "...it has been evidenced in both humans and experimental animals that the activation of 5-HT2A receptors is necessary to generate hallucinogenesis...". Given this, it seems that the categorization looks a little like this: Hallucinogens can be substances that induce any visual distortion, like illusions. "True hallucinogens" must agonise 5HT2A receptors, in order to create true hallucinations. [Continued in next comment] $\endgroup$
    – A. Kvåle
    Feb 27, 2021 at 17:43

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