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According to this article, agonism of the 5-HT$_{2A}$ is necessary for hallucinogenesis. Now, not all hallucinogens are primarily serotonergic, but does there exist hallucinogens that aren't at all serotonergic? If so, that means there are hallucinogens that don't agonise the necessary receptors for hallucinogenesis.

Would that mean that these non-serotonergic hallucinogens only produce visual distortions (illusions), and not "proper" hallucinations? And do all serotonergic hallucinogens activate the 5-HT$_{2A}$ receptors, or are there serotonergic hallucinogens that don't activate exactly this receptor, but still primarily or partially operates on all the other serotonergic receptors?

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    $\begingroup$ The article does not say that 5-HT2a agonism is necessary for hallucinogenesis; it says that it's necessary for this class of drugs. The evidence for this is that if you use an antagonist at 5-HT2a receptors you block the psychedelic effect when administered with these drugs, and that similar molecules in the same class that have little or no activity at the 2a receptor are not psychedelic. You asked a very similar question already here: psychology.stackexchange.com/questions/26710 and got answers about ketamine and PCP. $\endgroup$
    – Bryan Krause
    Feb 27, 2021 at 19:55
  • $\begingroup$ @BryanKrause So 5-HT2a agonism is only necessary for hallucinogens to produce hallucinations, but drugs within another class may produce hallucinations without 5-HT2a agonism? Also, would it be correct to say that hallucinogens are drugs that induce hallucinations and/or visual distortions (illusions), whereas serotonergic hallucinogens are drugs that necessarily produces hallucinations (and potentially perceptual distortions). Psychedelics can be used as a synonym for hallucinogens, serotonergic hallucinogens or hallucinogens primarily acting on the 5-HT2a receptors (classic psychedelics). $\endgroup$
    – A. Kvåle
    Feb 27, 2021 at 20:44
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    $\begingroup$ Psychedelic and hallucinogen are not necessarily interchangeable. I believe all psychedelics have hallucinogenic properties but not vice versa. Especially if you mean psychedelic in the narrow sense of classic psychedelics. $\endgroup$
    – Bryan Krause
    Feb 27, 2021 at 20:45
  • $\begingroup$ @BryanKrause Yes, I too see psychedelics as simply a category within hallucinogens, but I do feel an obligation to point at the different uses of the word. I do state in my "Classification" chapter that in my treatise, that I will almost solely be talking about the classic psychedelics, referring only to said classics when employing the word. Before that though, I just want to clear up what the word means, so that if they read it in different contexts, they understand it may not be used completely identically in that case as in my treatise. [Continued in next comment]. This is no. 1. $\endgroup$
    – A. Kvåle
    Feb 27, 2021 at 23:12
  • $\begingroup$ @BryanKrause For example, if I say "psychedelics yada-yada", and it holds true for the classic psychedelics, it may not hold true for a different definition of psychedelics. The readers may read a scientific text using a broader defintion of psychedelics that contains exceptions to whatever I stated in my text, which may prompt the reader to discredit my text. Therefore, I state clearly what I mean when I say "psychedelics", but I also intend to give some info on how the word is used in other contexts, hence my queries about hallucinogen classifications and whatnot. This is no. 2. $\endgroup$
    – A. Kvåle
    Feb 27, 2021 at 23:15

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I am not a scientist, just an ordinary person who has done a lot of reading on this subject. I will state what I believe to be true based on this reading. Please note that I am totally blind and using a speech to text dictation function on my phone to write this comment, so apologies in advance for any grammatical and spelling errors. I have tried to correct what I can and I hope you enjoy reading this and benefit from it. The term psychedelic has Greek origin and means mind manifesting. Psychedelic most properly refers to classical psychedelics otherwise known as serotonergic hallucinogens. These drugs strongly activate the 5HT2A receptor and this action is both necessary and sufficient for these drugs to generate the majority of their effects. As mentioned in a previous comment, classical psychedelics should be considered as a distinct category within the class of hallucinogens but I want to add that they should be separated more on the basis of their unique effects rather than simply their receptor pharmacology. To put it simply, 5Ht2A receptor activation is absolutely necessary for classical psychedelics to generate The whole range of their well-known and common effects. However, there are many other classes of hallucinogens that act on different receptor targets and have no detectable effects on any type of serotonin receptor including 5HT2A. NMDA antagonist (PCP and ketamine), anticholinergics(Scopolamine and diphenhydramine) and The kappa opioid agonist including the notoriously powerful naturally occurring atypical disassociative hallucinogen Salvinorin A. These hallucinogens act on receptors that have nothing to do with serotonin and I think this has some interesting outcomes in terms of user experiences. Unfortunately I only managed to find very little information on the subject of the link between receptor pharmacology and types of hallucinations generated. However, the overall idea I got from reading user experiences was The following. Classical psychedelics are by far the most potent in altering human consciousness. Whilst they create visual effects and may produce many types of hallucinations that range in intensity I think the most profound effects are on a persons sense of identity, perhaps they generate hallucinations of emotion in addition to those affecting the traditional five senses. Therefore, whilst you may hear, see, smell and even taste things that are not really there, on psychedelics, most of your attention will probably be focused on questioning your identity and life choices or reflecting on the nature of the universe and your place within it. Similar in some respects to the classical psychedelics, The kappa opioid agonist Salvinorin A as well as synthetic kappa opioid agonist ligands, produce a range of hallucinatory experiences, perceptual alterations and emotional changes which increase in intensity in a dose dependent manner. These drugs also share a strong emphasis on consciousness and identity/ego with the classical serotonergic psychedelics. Nevertheless, they carry a strong disassociative and often dysphoric component and are much more likely to cause out of body experiences and derealisation. The NMDA receptor antagonists are in my opinion One of the most interesting hallucinogens because they have the most recreational value. Often referred to as “disassociative anaesthetics“, they are capable of producing true hallucinations but these usually occur in a strange State of altered consciousness known as disassociative anaesthesia. Some people have theorised that this might involve a disconnect between the body and sensory input coming from it and the brain/mind making it a form of chemically induced sensory deprivation. However, I think the more correct opinion is that blockade of NMDA receptors on inhibitory interneurons leads to excessive glutamate release in other parts of the brain and resulting in an excitatory/inhibitory imbalance with the consequence of deranged information-processing in the brain. NMDA antagonists are renowned for their ability to frequently induce severe perceptual distortions, vivid dream like hallucinations, and even out of body experiences along with derealisation. I’m not sure as to why NMDA antagonists have greater recreational value than most other hallucinogens, but some interesting suggestions include a propensity to produce euphoria due to significantly high dopamine release, The numbing effect of the disassociative/anaesthetic effects on negative emotions especially in people liable to use drugs to escape their current reality and finally a possible antidepressant effect that may produce a mild mood lift known as an afterglow once the experience has worn off. Finally, the anticholinergics A.k.a. delirients are the drugs most likely to produce true/highly realistic hallucinations that are in most cases completely indistinguishable from reality. Even more worryingly, many of these hallucinations are reportedly reflections of what may happen in real life. For example, whilst in some cases you may see and feel spiders/other insects crawling all over you, in other cases users have invited friends into the house, eat with them and conversed with them for a very long period of time only to later discover that no one was actually there. Anticholinergics also come with a range of incredibly unpleasant side-effects including high body temperature, severely dry mouth, constipation, urinary retention, high blood pressure, rapid heartbeat, severe memory loss, dizziness, unconsciousness and possibly death.

I’ve never tried a hallucinogen in my life and I don’t ever intend to try one. However, out of all hallucinogens the class I would stay the furthest away from and would not even touch with a 10 foot pole are the classical serotonergic psychedelics. Whilst this might surprise you given that classical psychedelics are ranked amongst the safest drugs in terms of social and physical harm and given that they lack addictive qualities, I feel that their ability to profoundly alter human consciousness and shatter one’s identity with possible permanent consequences far outweighs their physical safety profile. Whilst there are many things about myself I wish to change or improve, I don’t believe the correct way is to take a sledgehammer and smash my identity to pieces through a chemically induced and uncontrollable mind-bending experience that could leave me traumatised and suffering with anxiety and depression that I never had before. I’ve seen this reported many times before, but psychedelic enthusiasts seem to shove it under the carpet and blame The user for failing to surrender to the experience or learn from it and understand its message correctly.

Now I will leave you with something that is confusing yet equally interesting. As I have mentioned above, I am blind so I can’t post links to Scientific studies but you could probably find them easily on the Internet. Basically I have read contradicting articles that examined the role of certain receptors in hallucinations. Whilst many of them supported what I have stated above, others have suggested that whilst 5HT2A receptor activation is necessary for the effects of classical psychedelics but not directly for the effects of other hallucinogens, blocking 5HT2A receptors with potent antagonist could suppress hallucinogen associated behaviours in animals injected with kappa opioid agonists. I don’t know what to make of this finding, however it might well be that large-scale and potent blockade of 5HT2A receptors might have a general calming/antipsychotic affect on the brain that intern suppresses hallucinations. If this is the case, then there’s really not much contradiction but it’s very interesting nonetheless. I also read a study in the journal frontiers which explained that the mild disassociative component of The Serotonergic empathogen MDMA was not at all dependent on the 5HT2A receptor as previously suspected. I’m going to read that study again because I can’t remember whether they pointed out a different target and what the implications could be but I would be happy to post what I have learnt if any of you are interested.

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