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Invisiblehelix
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how shrooms work vs how lsd works vs how other psychedelics work
    #14424820 - 05/09/11 02:02 PM (12 years, 8 months ago)

I've been able to find plenty of "shrooms vs. LSD" threads in terms of experience of the chemicals, but not really in terms of how they function on the brain. It seems to me that analyzing the sort of information each psychedelic gives us and the process through which they relay the information to us would require really seeing how they act on our neurons compared to each other. Is there a page somewhere on this site that I overlooked that discusses this? Or is this still not really known too well? How do they compare chemically and do they pretty much click into the same synapses or do they operate on different serotonin receptors? Do they operate somewhat on different receptors than eachother and also on some of the same receptors?


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Re: how shrooms work vs how lsd works vs how other psychedelics work [Re: helix]
    #14424882 - 05/09/11 02:21 PM (12 years, 8 months ago)

Quote:

Psilocybin is rapidly dephosphorylated in the body to psilocin which then acts as a partial agonist to several receptors involved with the neurotransmission of serotonin. Psilocin has a high affinity for the 5-HT2A serotonin receptor in the brain, where it mimics the effects of serotonin (5-HT). Psilocin binds less tightly to other serotonergic receptors 5-HT1A, 5-HT1D, and 5-HT2C.[50] Serotonergic receptors interact with pyramidal neurons in the cerebral cortex, which are thought to be involved in the perception of pain and anxiety.[51] The psychotomimetic effects of psilocin can be blocked in a dose-dependent fashion by the 5-HT2A antagonist drugs ketanserin and risperidone.[52] Psilocybin and psilocybin analogues have been used to help model the structure and function of the 5-HT2C G-protein coupled receptor.[53][54] In contrast to LSD, psilocybin and psilocin have no affinity for the dopamine D2 receptor.[50]

Psilocybin is absorbed through the lining of the mouth and stomach. Effects begin 10–40 minutes after ingestion of psilocybin-containing mushrooms, and last from 2–6 hours depending on dose, species, and individual metabolism. A typical recreational dosage is from 10–50 mg psilocybin. However, a very small number of people are unusually sensitive to psilocybin's effects, where a normal threshold dose of around 2 mg of psilocybin can result in effects usually associated with medium and high doses. Likewise, there are some people who require relatively high doses of psilocybin to gain low-dose effects. Individual brain chemistry and metabolism play a large role in determining a person's response to psilocybin.[67]

Psilocybin is metabolized mostly in the liver where it becomes psilocin, which is broken down by the enzyme monoamine oxidase to produce several metabolites in blood plasma, including 4-hydroxyindole-3-acetaldehyde, 4-hydroxytryptophol, and 4-hydroxyindole-3-acetic acid.[50] Some psilocybin is not broken down enzymatically, and instead forms a glucuronide—a biochemical method animals use to eliminate toxic substances by linking it with glucuronic acid, which may then be excreted in the urine.[46] Psilocin concentrations in the plasma of adult volunteers averaged about 8 µg/L within 2 hours after ingestion of a single 15 mg oral psilocybin dose;[68] psychological effects occur with a blood plasma concentration of 4–6 µg/L.[50]

Mental and physical tolerance to psilocybin builds and dissipates quickly. Taking psilocybin more than three or four times in a week (especially on consecutive days) can result in diminished effects. Tolerance dissipates after a few days, so frequent users often keep doses spaced five to seven days apart to avoid the effect. Studies have demonstrated that a cross-tolerance can develop between psilocybin and the pharmacologically similar LSD.[69][70] MAO inhibitors (MAOI) have been known to sustain the effects of psilocybin for longer periods of time; people who are taking an MAOI for a medical condition may experience highly potentiated effects.[71]

The repeated use of psilocybin does not lead to physical dependence on the drug.[50] A 2008 study concluded that, based on US data from the period 2000–2, adolescent-onset (defined here as ages 11–17) usage of hallucinogenic drugs (including psilocybin) did not increase the risk of drug dependence in adulthood; this was in contrast to adolescent usage of cannabis, cocaine, inhalants, anxiolytic medicines, and stimulants, all of which were associated with "an excess risk of developing clinical features associated with drug dependence".[72]

http://en.wikipedia.org/wiki/Psilocybin






Quote:

LSD affects a large number of the G protein coupled receptors, including all dopamine receptor subtypes, and all adrenoreceptor subtypes, as well as many others. LSD binds to most serotonin receptor subtypes except for 5-HT3 and 5-HT4. However, most of these receptors are affected at too low affinity to be sufficiently activated by the brain concentration of approximately 10–20 nM.[84] In humans, recreational doses of LSD can affect 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, and 5-HT6 receptors.[1][85] 5-HT5B receptors, which are not present in humans, also have a high affinity for LSD.[86] The psychedelic effects of LSD are attributed to its strong partial agonist effects at 5-HT2A receptors as specific 5-HT2A agonists are psychedelics and largely 5-HT2A specific antagonists block the psychedelic activity of LSD.[84] Exactly how this produces the drug's effects is unknown, but it is thought that it works by increasing glutamate release in the cerebral cortex and therefore excitation in this area, specifically in layers IV and V.[87] LSD, like many other drugs, has been shown to activate DARPP-32-related pathways.[88]

http://en.wikipedia.org/wiki/Lsd




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Invisiblehelix
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Re: how shrooms work vs how lsd works vs how other psychedelics work [Re: Nunbuh_Chrubble]
    #14424905 - 05/09/11 02:25 PM (12 years, 8 months ago)

ah, thank you!


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Re: how shrooms work vs how lsd works vs how other psychedelics work [Re: helix]
    #14426118 - 05/09/11 06:24 PM (12 years, 8 months ago)

google is your friend young mycologist.


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Invisiblehelix
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Re: how shrooms work vs how lsd works vs how other psychedelics work [Re: k00laid]
    #15540540 - 12/19/11 03:50 PM (12 years, 1 month ago)

So i've been thinking more about this recently and realizing i'm still not quite clear on the effects of the psychedelics on serotonin, because of the relative scientific and non-user friendly information published on this topic (also i've been studying all day and my brain feels pretty fried. I've been searching far and wide and haven't quite found a "psychedelics and serotonin for dummies" style explanation

I know psychedelics are super similar looking to serotonin and so locks into the receptors where serotonin would normally lock into. I know psilocybin locks into significantly fewer receptors than lsd or mescaline. But I'm not clear - When it locks in does it block serotonin from being released, or does more serotonin just flood the brain like how mdma does? Or does it do different things depending on what receptor? Or is it completely random, what it does, and are we not quite sure yet?


Edited by helix (12/19/11 03:51 PM)


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Re: how shrooms work vs how lsd works vs how other psychedelics work [Re: helix]
    #15540605 - 12/19/11 04:01 PM (12 years, 1 month ago)

I found this a few weeks ago. It's a little long but it's probably the most complete and up to date work. It's pretty easy to understand too but if theres a term you don't understand it doesn't hurt to look it up. Trust me it's worth reading. Take care

http://www.maps.org/research/psilo/psilo_ib.pdf


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Invisiblehelix
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Re: how shrooms work vs how lsd works vs how other psychedelics work [Re: MachineElf1.618]
    #15540704 - 12/19/11 04:19 PM (12 years, 1 month ago)

Quote:

mtlmike90 said:
I found this a few weeks ago. It's a little long but it's probably the most complete and up to date work. It's pretty easy to understand too but if theres a term you don't understand it doesn't hurt to look it up. Trust me it's worth reading. Take care

http://www.maps.org/research/psilo/psilo_ib.pdf




Thank you! I sorta scanned it, you're right it's a lot to read.
But in my scan this is the only thing I found that addressed what i'm not sure about:

"Direct application of psilocybin to dorsal raphe nucleus (DRN) cells is associated with a decline in firing, a property it shares with LSD that is likely the result of action at 5HT1A autoreceptors."

Which means it prevents firing of neurotransmitters right? Like serotonin? But do they know whether action at the other receptors causes an increase or decrease of firing?


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Re: how shrooms work vs how lsd works vs how other psychedelics work [Re: MachineElf1.618]
    #15540782 - 12/19/11 04:30 PM (12 years, 1 month ago)

Oh hey, I finally found something to help me understand:

If the drug increases the effect of the neurotransmitter it is called an agonist. If it decreases  the effect of the neurotransmitter it is called an antagonist. So, if a neurotransmitter is inhibitory, an agonist will increase the inhibitory effect of the neurotransmitter, whereas an antagonist will decrease the inhibitory effect. If the neurotransmitter is excitatory, an agonist will increase the excitatory effect, and an antagonist will decrease the excitatory effect.

So now I see why understanding these drugs is complicated.

So serotonin is an inhibitory neurotransmitter...which means a psychedelic (since it's an agonist) decreases the effects of serotonin...or is the effect more like reducing the amount of serotonin that is sent?


Edited by helix (12/19/11 04:31 PM)


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OfflineMachineElf1.618
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Re: how shrooms work vs how lsd works vs how other psychedelics work [Re: helix]
    #15540820 - 12/19/11 04:37 PM (12 years, 1 month ago)

Quote:

aronf13 said:
Quote:

mtlmike90 said:
I found this a few weeks ago. It's a little long but it's probably the most complete and up to date work. It's pretty easy to understand too but if theres a term you don't understand it doesn't hurt to look it up. Trust me it's worth reading. Take care

http://www.maps.org/research/psilo/psilo_ib.pdf




Thank you! I sorta scanned it, you're right it's a lot to read.
But in my scan this is the only thing I found that addressed what i'm not sure about:

"Direct application of psilocybin to dorsal raphe nucleus (DRN) cells is associated with a decline in firing, a property it shares with LSD that is likely the result of action at 5HT1A autoreceptors."

Which means it prevents firing of neurotransmitters right? Like serotonin? But do they know whether action at the other receptors causes an increase or decrease of firing?




Quote:

aronf13 said:
Quote:

mtlmike90 said:
I found this a few weeks ago. It's a little long but it's probably the most complete and up to date work. It's pretty easy to understand too but if theres a term you don't understand it doesn't hurt to look it up. Trust me it's worth reading. Take care

http://www.maps.org/research/psilo/psilo_ib.pdf




Thank you! I sorta scanned it, you're right it's a lot to read.
But in my scan this is the only thing I found that addressed what i'm not sure about:

"Direct application of psilocybin to dorsal raphe nucleus (DRN) cells is associated with a decline in firing, a property it shares with LSD that is likely the result of action at 5HT1A autoreceptors."

Which means it prevents firing of neurotransmitters right? Like serotonin? But do they know whether action at the other receptors causes an increase or decrease of firing?




Yes the DRN is a part of the brain that contains a high concentration of serotonin receptors. In a documentary I saw some researchers show that blood delivery in that area declines which also means that neuron activity decreases as well.

As for other receptors lsd is shown to agonize several other recptors, dopamine being one of the main ones next to serotonin. It's still unsure what other receptors psilocybin effects other then serotonin. You should really read the whole thing you'll leran a whole lot more.


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Re: how shrooms work vs how lsd works vs how other psychedelics work [Re: helix]
    #15540852 - 12/19/11 04:42 PM (12 years, 1 month ago)

yes you understood it! I had trouble getting that at first also. Think about it this way. If serotonin is inhibitory and psilocybin is an agonist then that means more serotonin will be sent across the synapses. Psilocybin mimics the structure of serotonin so its not that you also produce more serotonin but the psilocybin acts as the neurotransmitter. It's also been shown that psilocybin shows some reuptake inhibitor action.


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Invisiblehelix
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Re: how shrooms work vs how lsd works vs how other psychedelics work [Re: MachineElf1.618]
    #15540873 - 12/19/11 04:46 PM (12 years, 1 month ago)

mtlmike90 said:
Quote:

aronf13 said:
Quote:

mtlmike90 said:
I found this a few weeks ago. It's a little long but it's probably the most complete and up to date work. It's pretty easy to understand too but if theres a term you don't understand it doesn't hurt to look it up. Trust me it's worth reading. Take care

http://www.maps.org/research/psilo/psilo_ib.pdf




Thank you! I sorta scanned it, you're right it's a lot to read.
But in my scan this is the only thing I found that addressed what i'm not sure about:

"Direct application of psilocybin to dorsal raphe nucleus (DRN) cells is associated with a decline in firing, a property it shares with LSD that is likely the result of action at 5HT1A autoreceptors."

Which means it prevents firing of neurotransmitters right? Like serotonin? But do they know whether action at the other receptors causes an increase or decrease of firing?




Quote:

aronf13 said:
Quote:

mtlmike90 said:
I found this a few weeks ago. It's a little long but it's probably the most complete and up to date work. It's pretty easy to understand too but if theres a term you don't understand it doesn't hurt to look it up. Trust me it's worth reading. Take care

http://www.maps.org/research/psilo/psilo_ib.pdf




Thank you! I sorta scanned it, you're right it's a lot to read.
But in my scan this is the only thing I found that addressed what i'm not sure about:

"Direct application of psilocybin to dorsal raphe nucleus (DRN) cells is associated with a decline in firing, a property it shares with LSD that is likely the result of action at 5HT1A autoreceptors."

Which means it prevents firing of neurotransmitters right? Like serotonin? But do they know whether action at the other receptors causes an increase or decrease of firing?




Yes the DRN is a part of the brain that contains a high concentration of serotonin receptors. In a documentary I saw some researchers show that blood delivery in that area declines which also means that neuron activity decreases as well.

As for other receptors lsd is shown to agonize several other recptors, dopamine being one of the main ones next to serotonin. It's still unsure what other receptors psilocybin effects other then serotonin. You should really read the whole thing you'll leran a whole lot more.





yeah i will now, but it was difficult for me to understand because I wasn't totally clear on what an agonist or antagonist really means.

Actually i think I'm still not totally sure. :frown:

Let me explain my confusion in the next post


Edited by helix (12/19/11 05:05 PM)


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Invisiblehelix
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Re: how shrooms work vs how lsd works vs how other psychedelics work [Re: helix]
    #15540894 - 12/19/11 04:50 PM (12 years, 1 month ago)

sorry this is really hard for me to grasp lol :willynilly:


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Re: how shrooms work vs how lsd works vs how other psychedelics work [Re: MachineElf1.618]
    #15540988 - 12/19/11 05:04 PM (12 years, 1 month ago)

that post was kinda convoluted, let me sum up what confuses me:

Quote:

mtlmike90 said:
If serotonin is inhibitory and psilocybin is an agonist then that means more serotonin will be sent across the synapses. Psilocybin mimics the structure of serotonin so its not that you also produce more serotonin but the psilocybin acts as the neurotransmitter.




doesn't that^ contradict this:
Quote:

mtlmike90 said:
Quote:

aronf13 said:
"Direct application of psilocybin to dorsal raphe nucleus (DRN) cells is associated with a decline in firing, a property it shares with LSD that is likely the result of action at 5HT1A autoreceptors."

Which means it prevents firing of neurotransmitters right? Like serotonin?





Yes the DRN is a part of the brain that contains a high concentration of serotonin receptors.






?


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Re: how shrooms work vs how lsd works vs how other psychedelics work [Re: helix]
    #15541056 - 12/19/11 05:14 PM (12 years, 1 month ago)

First you have to make sure you understand the difference between a serotonin neurotransmitter and a serotonin receptor. If I'm not mistaken and anyone can correct me if I'm wrong, the serotonin receptor can be both inhibitory or excitatory. There are many different types of 5HT receptors and they can read many different types of neurotransmitters. There is only one 5HT neurotransmitter, this is the chemical that carries the signal.

As mentioned there are many 5HT receptors. Each specific receptor has a different job to do. The 5HT transmitter is the one that carries the inhibitory effect. So if more 5HT travels across the synapse and into a receptor. Then the job that receptor carries out is inhibited. Psilocybin along with other simillar psychedlics kinda look like the 5HT neurotransmitter and therefor mimic its function. But just because it may look like the neurotransmitter and mimic it, it doesn't mean that all the receptors can read it. Think of it as puzzle pieces. This is why psilocybin for example fits the 5HT2a receptor, but not other 5HT subtypes.

Did this help?


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Re: how shrooms work vs how lsd works vs how other psychedelics work [Re: MachineElf1.618]
    #15541137 - 12/19/11 05:33 PM (12 years, 1 month ago)

let me try to build more on that. Because I just read your previous post lol and it seem like you know most of that already.


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Re: how shrooms work vs how lsd works vs how other psychedelics work [Re: MachineElf1.618]
    #15541264 - 12/19/11 06:00 PM (12 years, 1 month ago)

Since the chemical mimics serotonin it's delivered to the pre-synaptic cleft where it is released into the synapse. All the receptors are located in the post-synaptic cleft. The neuron contains all the differnt types of receptors, but only a select few have the puzzle piece that fits the psychelic chemical. Once this chemical binds to the receptor site it tells it to give a message that its time to cut down. Psilocybins inhibitory effect is so great that it nearly stops all activity in that part of the brain. This is why it is said to be an agonist because it tells that specific receptor to carry out the job that serotonin tells it to do, which in this case is an inhibitory effect.

Also some of psilocybins long term effects can be explained by its possible reuptake mechanism. Kind of what SSRI's do. They prevent serotonin from being reabsored into the pre-synaptic cleft therefore increasing serotonin concentrations in the synapse. Psilocybin directly effects 5HT2a receptors while it can potentially also indirectly effect other receptors just by allowing more serotonin in the synapses.


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