The Serotonin Hypothesis of Psychosis
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- Опубликовано: 14 мар 2022
- Learn the essentials of psychopharmacology from Dr. Stephen Stahl! This clip from Stahl’s Essential Psychopharmacology, Video Edition covers the serotonin hypothesis of psychosis. Learn more: nei.global/epvideos
Although serotonin receptors and synapses are ubiquitous throughout the brain, the serotonin hyperfunction hypothesis of psychosis suggests that psychosis may be caused by an imbalance in excitatory 5HT2A receptor stimulation of those glutamate pyramidal neurons discussed above that directly innervate VTA/mesostriatal integrated hub dopamine neurons and visual cortex neurons. The hallucinogens LSD, mescaline, and psilocybin, which are all powerful 5HT2A agonists, have long been known to induce psychosis, dissociative experiences, and especially visual hallucinations by overstimulating prefrontal and visual cortex 5HT2A receptors. These symptoms can be blocked by 5HT2A antagonists, demonstrating that hallucinogens cause psychosis by 5HT2A stimulation.
About: In Stahl’s Essential Psychopharmacology: Video Edition, the newly published fifth edition of the landmark textbook comes to life as Dr. Stahl himself presents every chapter with fully animated illustrations. Learn more: nei.global/epvideos
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Made the explanation way easier to understand than the book does, and the key sentence of showing how all these hypotheses leads back to dopamine. Thank you.
Thank you for posting this 🙏
Thank you for the great info!
3:35 😂laughing out loud in a coffee shop damn it hahahhaha
This is just my opinion/Theory from the research I have done on 5HT2A receptors and their role in the brain. I am wondering if these receptors act naturally as some type of emotional amplifier, giving normal emotions a more sharp edge. this is something I’ve always suspected, but I have more reason to believe this after reading a study on The role of 5HT2A receptors in sleep paralysis hallucinations. The author also claimed that this receptor was involved in the attachment of normally meaningless environmental stimuli to strong emotions. I also read a paper claiming that 5HT2A antagonists could diminish the ability of human subjects to recognise fearful faces, indicating these receptors play a major role in fear. this makes sense since classical psychedelics produce the opposite effects, that is intensified fear and a strange sense of connection to inanimate objects. personally, I’ve never tried psychedelics and never will, and I have a strong dislike for them. this is because, the more I read about their emotional effects, the more disturbing they seem. Additionally, I’ve read stories of peoples lives being destroyed by some type of post traumatic stress disorder triggered by the psychedelic experience. it’s not only flashbacks to the trip that plagued these people, some don’t even have these flashbacks, but do experience severe depression, anxiety, panic attacks, and even psychosis. some say they could not stop questioning their everyday reality and the point of their existence and did not respond to therapy. what is even more unfortunate is that many of these people claim to have been highly motivated, successful or at least happy/laid-back individuals before their experience. I also want to give my rebuttal to the psychedelic enthusiasts Who directly or indirectly tried to claim that we are currently living in a regulated psychedelic state based on the fact that we have these receptors, and an extremely powerful agonist of them, DMT is naturally found in the brain. let’s start with DMT. Firstly, this compound is only present at very low levels in the brain. however, researchers studying its function have found it to be a strong agonist of the Sigma receptor which is not hallucinogenic under normal circumstances. in fact, they found that DMT was synthesised and released very close to these receptors before being rapidly destroyed by monoamine oxidase enzymes before it could reach the serotonergic receptors. therefore, DMT is believed to play a Neuromodulatory and neuroprotective role via Sigma receptor activation. whilst I’m not aware of any studies knocking out DMT production in the brain, we already know that 5HT2A antagonists do not significantly affect the human perception of reality. so what about serotonin and fiveHT2A receptors which are much more abundant than DMT? well, serotonin does not cause us to hallucinate under normal circumstances, even when its levels are strongly elevated. The reason for this is that 5HT2A receptors can activate two different downstream intracellular signalling pathways depending on how an agonist binds to them. basically, unlike its methylated tryptamine metabolites, serotonin activates both pathways in a balanced manner and modulates neuronal function. This binding is possibly involved in emotional amplification to some degree and this receptor is involved in the side-effects of SSRI antidepressants, such as anxiety and initial worsening of depression. however, the methylated tryptamines preferentially activate one pathway and in doing so cause the receptor to form a complex known as a heterodimer with a metabatropic glutamate receptor called MGLU2. MGLU2 serves many protective functions in neurons, but one of its main Rolls is to restrain glutamate release by neurons. When the psychedelic bound 5HT2A receptor forms a complex with MGLU2, The function of MGLU2 is inhibited and a huge amount of glutamate is released. This not only screws up information-processing in the brain, but could also amplify the effects of other neurotransmitters as well as emotions in general associated with those neurotransmitters. despite the so-called benefits of micro dosing, psychedelics, even at low doses, have been found to strongly impaire memory in animals. in an article published in the Guardian, A woman microdoseing LSD for depression noted that she became extremely paranoid that her supplier was an informant for the police. this is whilst she defended the drug and stated that it helped her, but she still acknowledged that it might have been behind her paranoia. I am convinced that it was the microdoses of LSD due to its inappropriate enhancement of glutamate function in certain areas of the brain.
Very informative comment
If what you say is true-and I doubt it-then you should publish it in a scientific journal so it can be scrutinized by experts in the field.
@Dennis Bolanos i’m not a doctor or a scientist, just someone who has A strong interest in drugs and pharmacology, particularly neuropharmacology. as I said at the start of my previous comment, these are just my opinions but if there is anything you disagree with, I’ll be more than happy to hear your opinions.
Interesting text, but please use more line breaks and paragraphs - long block of text is hard to read and your writing deserves to be in more readable form.
@hibakusha0 sorry about that. I am blind and I’m writing these comments on my phone using dictation, so there are many mistakes. these range from unintended words in the middle of sentences to commas and full stops in inappropriate parts of the sentence.
Thanks for letting me know anyway, I understand that one large block of text can be very difficult and off putting to read.
Unfortunately, I can’t edit my past comments, but in future I will try to write on a new line for each Paragraph, in addition to taking time to go through the comment and remove any inappropriate punctuation Inc by the voice activated software.
Thank you so much
In my opinion, there needs to be much more media attention on 5HT2A antagonists. The research is all there, showing they are extremely beneficial in the treatment of psychiatric disorders. Yes, they might have failed in the treatment of psychosis, but their effects on anxiety/panic and sleep quality are much more promising. unfortunately, no one has really pushed for their public acknowledgement because they lack addiction potential so pharmaceutical companies probably aren’t that interested. Likewise, I assume their lack of hallucinogenic effects means no one from the general public is really that interested in learning about them, let alone lobbying for them as people have done with psychedelics. finally, it’s interesting to note that the supposedly very subtle psychoactive effects of selective 5HT2A might remove an element of placebo effect, tricking patients into thinking these medicines are not working. for example, in a study of 5HT2A antagonists for insomnia patients, researchers noted clear improvements in sleep quality, including a significant increase of slow wave (deep sleep) using brain scans. unfortunately, patience themselves generally said they found these medications ineffective in improving the subjective quality of their sleep. Researchers put this down to The patient believing they have not slept. traditional insomnia drugs like benzodiazepines, The Z drugs and even powerful first generation antihistamines generate a so-called sleep queue, that is a signal for the patient to go to sleep. Furthermore, decreased consciousness and memory formation can create the illusion that the patient has slept, thus changing their perspective and making them more psychologically prepared to face the day. ironically, most benzodiazepines and Z drugs actually worsen sleep quality and continue to cause drowsiness and memory impairment the next day. this is why some researchers have suggested using drugs like S mirtazapine and its analogues, which combine serotonin2A antagonism with histamine H1 antagonism. whilst antagonism of both receptor types promotes efficient sleep and diminish frequency of awakenings, the antiserotonergic effect boosts deep sleep, whilst the antihistamine effect helps transition from the waking to the sleep state but also generates a heavy sense of drowsiness which acts as a signal for the patient to psychologically prepare for sleep. if I remember correctly, these drugs lack anticholinergic effects at reasonable doses so shouldn’t impede memory formation or promote dementia.
Brilliant!!
Coud DT in OH withdrawal be explained by this lack of inhibition of glutamate?
Does anyone has an idea, where can i get all these videos in full version for free??
Would benzodiazepine help with the lost GABA inhibition?
visual snow syndrome? do this explain?
Don’t 5-HT2A antagonists (administered chronically) upregulate the receptor? I’m confused 🤔
correct, but that is not what he is talking about
If i remember correctly 5ht2a and maybe even 5ht2c can downregulate either with agonist or antagonist, but some antagonists does upregulate it. Even the downregulation by psychedelics it is not completely understood trough witch pathway it happen
In general, both agonists and antagonists down regulate the 5HT2A receptor at least in the early stages of drug administration and this should have been a major therapeutic advantage. Unfortunately, this begins to reverse in the long term. researchers studying The decrease in effectiveness of the antipsychotic drug clozapine, have discovered that after prolonged administration, A gene regulating protein called HDAC2 is upregulated and this causes an up regulation of 5HT2A receptors and halts their down regulation. interestingly, both non-selective and selective HDAC inhibitors, already being researched for cancer and schizophrenia treatment, could reverse this effect and boost the therapeutic effectiveness of 5HT2A receptor antagonists.
Paradoxical down regulation
I dont understand any of these stuff. But I hope for KarXT because schizophrenia is hard to live with
why stimulation of serotonin receptor a2 lead to depression
The way I understand it is that the 5-ht2a receptors being overstimulated leads to a depletion of 5-ht (serotonin) in other parts of the brain.
I have mild OCD, and OCD can be caused by overstimulation of 5-ht2a receptors, and, as my psychiatrist explained, this leads to less serotonin elsewhere, thus reducing the brain's mood.
Of course, I'm sure this is grossly oversimplified
@@CoffeeAddictEvan thanks alot
Pity you don't know the pharmocology of tinnitus. That would be fascinating
Seriously!?? This can only be fully taken in by non STEM students
So you are telling me I can trip balls on pimavanserin, thanks Herb!!!
No, you definitely could not trip on Pimavanserin. actually, theoretically it would be the complete opposite, and it would probably end any classical psychedelic trip. it was actually developed as an antipsychotic for Parkinson’s disease, but I think it was not that effective, as it didn’t address the downstream, dopamine pathways.
@@saifmohsin2493 lol totally realized that after writing it. Off-market psychedelic cure, there you Dr. Meltzer
you sound exactly like jordan peterson and it's so close that it's scary
Jordan Peterson can benefit indeed by 5HT2A antagonists.
@ mushroom head I guess you’re the one who tried to comment on my comments to advertise your psychedelic garbage. i’m sure you’re the same one who did this on other videos, you post your advertising whenever you find a comment against psychedelics. I don’t mind if others like using these kind of substances, but why can’t you accept the fact that they have negative effects and some people shouldn’t use them.
Do you remember a video called “I tried DMT, it was hell“. I think you’re the one who commented on that video as well. in my opinion, psychedelics are not good at all, they can ruin lives, but they don’t get the same attention as cocaine or heroin. psychedelics can cause PTSD and bring on mental illnesses People didn’t have before.
It’s nothing to do with genetics or predisposition, it’s the result of intense psychological effects These drugs have on the user, sometimes causing them to question their entire reality to the point they become suicidal. Others develop severe anxiety, depression or otherwise become delusional, withdrawing from their friends and family and viewing Everyone else as worthless to them.
I believe psychedelics might have help some people, but they are seriously overhyped and their harm is severely underestimated. Many psychedelic enthusiasts can’t get there heads around the fact psychedelics can cause serious psychological harm and instead, they prefer to blame and ridicule any user Who has suffered from the symptoms I mentioned above. professor Carl heart, a famous proponent of drug legalisation used the term“Psychedelic exceptionalism“ to describe the hypocrisy of many psychedelic enthusiasts. these enthusiasts try to portray themselves and their dangerous drugs of choice as different from traditional drugs of abuse.
These people will look down on users of methamphetamine or cocaine/heroin and view themselves as morally superior. I truly believe a meth user can offer me far more practical insight and real-world advice than any psychedelic enthusiast ever could. when you listen to a psychedelic user describing the world, you’ll often find they speak in very strange terms about how they have a connection to the universe through random objects like walls or trees. they talk about ego death like it’s The most amazing experience and the ultimate goal of life. What you might not know is that the ego actually refers to your entire sense of self, your identity and how you view your place in the world. unless you had severe depression for your entire life and are on the verge of suicide, do you really think it’s wise to destroy your entire ego in a few hours? of course, our Eego’s can have negative aspects, but we can work on those through putting a little effort into self reflection and maybe meditation. you should also know that The ego has many positive benefits and has helped our survival throughout human history. It is the thing that motivates us to get up and work every day, drives us to contribute in society, shapes our social lives and most importantly, gives us a sense of purpose to exist.
As I’ve mentioned previously, I respect the decision of other people to use psychedelics or to recommend them to others. all I ask in return is that psychedelic enthusiasts respect the decision of people not to try psychedelics as well as any warnings against them as well as to acknowledge that psychedelics have harmed many people.
He appears a bit like Joe Biden.....