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Offlineummikko
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Re: How Hallucinogenic Drugs Work [Re: redgreenvines]
    #3750315 - 02/08/05 09:13 AM (19 years, 5 months ago)

Quote:

redgreenvines said:
all fine, so...
then what happens?





There is no short answer to this, and I don't know where to begin. DadeMurphy's link provides a good and detailed explanation. A was merely trying to explain the synaptic mechanism to symanta in a nutshell. :smile:

A short attempt of an answer:

serotonin(5-HT) has several types of receptors, each with slightly different properties and different roles in behaviour. (Note that there is only one type of serotonin, but many receptors for serotonin in different areas of the nervous system) LSD(most hallucinogenic research has been done on LSD, so I'm using it as an example) has a strong affinity for some of these types (5-HT 1A, 5-HT 1D, 5-HT 2, 5-HT 1C, 5-HT 5A, 5-HT 5B and 5-HT 7, according to S.J.Peroutka). By binding to these receptors, LSD stimulates them at abnormal times and blocks serotonin from stimulating it the normal way. Presumably, these receptors contribute to perception and conscious experiences in some way, and an abnormal pattern of stimulation of these receptors leads to abnormal perceptions/experiences.

We know where in the brain LSD exerts its effects, but we don't know why those effects induce hallucinations and alter consciousness. The neural basis of consciousness, consious experiences and the mind is not known (the mind-body problem). The chemistry is easier to explain than the psychology.


--------------------
"All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy." -Paracelsius

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Offlinecurenado
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Re: How Hallucinogenic Drugs Work [Re: ummikko]
    #3750556 - 02/08/05 10:34 AM (19 years, 5 months ago)

<<the interesting stuff (layering etc.) lies in what happens when the neurons are encouraged to keep firing after the excitatory stimulus has faded.

that applies to both serotoninergic and KOR chemical events which become interesting as the whole brain tissue begins to handle stimuli in a more resonant way. >>

Absolutely!  :cool:
It shouldn't be any surprise that too many become obsessed of some minuatae at the expnse of the entire concept - that happens across the disciplines.
But will science have struggled, at great cost and labor, up this mountain of knowledge - slashing courageously through theory after theory - only to find at the top a group of old shaman drinking cocoa and saying "We told you. Everybody told you. Want some?" :wink:


--------------------
Yours in the Natural State Land of Enchantment!

"Tell you what. It seems to me if somethin's ready for you to do somethin, it don't much matter if you're ready or not." - Charlie Utter

No makin funna my pomes!

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Invisibleshymanta
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Re: How Hallucinogenic Drugs Work [Re: mjshroomer]
    #3750674 - 02/08/05 11:12 AM (19 years, 5 months ago)

Wow, thanks for the reply. That was very informative.

Just to clarify. You're saying that substances that effect the post synaptic neuron will not effect the production/re-uptake/etc. of serotonin because its associated with the pre synaptic neuron?

Also, what happens to the serotonin when a serotonin agonist activates a receptor cell? Does it (the serotonin) build up or absorb back into the pre synaptic neuron?

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Offlineummikko
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Re: How Hallucinogenic Drugs Work [Re: shymanta] * 1
    #3750989 - 02/08/05 12:51 PM (19 years, 5 months ago)

Quote:

shymanta said:
Wow, thanks for the reply.  That was very informative. 

Just to clarify.  You're saying that substances that effect the post synaptic neuron will not effect the production/re-uptake/etc. of serotonin because its associated with the pre synaptic neuron?




Yes!  :grin:(at least not directly, there may be feedback mechanisms, but that's off the topic)

Quote:


Also, what happens to the serotonin when a serotonin agonist activates a receptor cell?  Does it (the serotonin) build up or absorb back into the pre synaptic neuron?




That depends on several factors...

First, the sequence of (normal)chemical events at a synapse is:

1. The neuron synthesises chemicals that serve as neurotransmitters

2. The neuron transports these chemicals to the axon terminals

3. An axon potential causes the release of the neurotransmitters from the terminals

4. The released molecules attach to receptors on the postsynaptic neuron, and alter the activity of that neuron

5. The molecules separate from the receptors and (in some cases) are converted into inactive chemicals. In the case of serotonin, which is a monoamine, this is done by the enzyme MAO (monoamine oxidase). MAOI drugs work by blocking MAO, so monoamine neurotransmitters remain in the synaptic cleft(the space between the pre- and postsynaptic neurons) longer and can thus stimulate the postsynaptic neuron longer without being inactivated.

6. In some cells, some of the neurotransmitters are taken back into  the presynaptic cell for reuse or recycling (SSRI:s work by preventing this reuptake so more serotonin is left in to the synaptic cleft where it can rebind with a receptor)

7. In some cells, empty vesicles return to the cell body.

A chemical that can fit to a receptor and activate that receptor is an agonist. A chemical that can fit to a receptor but doesn't
activate the receptor(just blocks it) is an antagonist.

The affinity of a chemical (neurotransmitter,drug,whatever) means how well it fits into a given receptor (or "how badly it wants to bind" with the receptor). If the drug has a higher affinity than the neurotransmitter, it will "override" the receptor and can block the actual neurotransmitter from binding with it (I'm simplifying things). The amounts of the neurotransmitter and the drug in the synapse also matter (For example, 50% of the receptors on a postsynaptic neuron can have serotonin attached to them while 50% have LSD...)

Another factor is HOW the drug binds with the receptor. In most cases the binding is temporary, and the attached molecule will release on its own after a time, or it can be overridden with another chemical that has a higher affinity for the receptor. In some cases, however, the binding is permanent. If the permanent binder is an agonist, it causes permanent activation (for example, choleratoxin does this). A permanent antagonist causes permanent inactivation of the receptor. A permanently attached chemical cannot, of course, be overridden.

Now, if the drug has an effect only on the postsynaptic neuron, it won't affect the serotonin in any way. The serotonin will be partially reuptaken and partially recycled as usual. Because of MAO it cannot build up in the synaptic cleft. If the drug in question is not a permanent binder, the serotonin in the cleft competes with the drug for binding (This is why nonpermanent binders are called competitive agonists/antagonists), and the amounts+affinities determine how many receptors are bound with serotonin and how many with the drug.


--------------------
"All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy." -Paracelsius

Edited by ummikko (02/09/05 04:26 AM)

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Invisibleshymanta
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Re: How Hallucinogenic Drugs Work [Re: mjshroomer]
    #3755157 - 02/09/05 08:06 AM (19 years, 5 months ago)

Awesome, I think I understood all that.

So, it sounds like substances that bind permanently are to be avoided.

Is that the case and is there a "scientific name" for a permanent binder whether agonists or antagonists?

Thanks,
ummikko

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OfflinePsiloman
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Re: How Hallucinogenic Drugs Work [Re: shymanta]
    #3757819 - 02/09/05 06:06 PM (19 years, 5 months ago)

I guess it can be called "irreversible" ("irreversible agonist" or "irreversible antagonist").There are some MAO inhibitors (yes i know,its kind outa of context here) ,usually pharmaceuticals, that bind on the MAO enzyme irreversibly thus killing it.Your body then has to make more of this enzyme which means going through the whole proccess of DNA->RNA->Protein.Certainly an irreversible agonist or antagonist could be bad news if we are talking receptors in the brain..

I do not think irreversible 5HT-2a agonists exists...Or at least i dont know any of them....

Edited by Psiloman (02/09/05 06:10 PM)

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Invisibleshymanta
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Re: How Hallucinogenic Drugs Work [Re: mjshroomer]
    #3757874 - 02/09/05 06:19 PM (19 years, 5 months ago)

That sound like good news. Wow, you've given me so much information. Thank you for this enlightening discussion. I've learned a lot from it.

May your thoughts be positive & productive and joy fill your life.

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OfflinePsiloman
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Re: How Hallucinogenic Drugs Work [Re: shymanta]
    #3757919 - 02/09/05 06:26 PM (19 years, 5 months ago)

Well,rest assured that "classic hallucinogens" such as mescaline,psilocybin and dmt are reversible,they dettach themselves from the receptor.

By the way,here is also a paper on aeruginascin (a component of some Inocybe mushrooms) that is a relative of psilocybin ,i think its trimethylated instead of psilocybin which its dimethylated ( i think we are talking of a 4-phosphoryloxy-TMT). Here is the paper: http://webdoc.sub.gwdg.de/diss/2004/jensen/jensen.pdf

Now,the paper is huuuuuuuuuuuuuuuuuuuuuuuuuuge and so technical ,but please have a look to its contents...You will find a method of action of hallucinogens in it (a chapter) which is data more recent than the ones on the original paper of this thread.A good read all and allo,dont be to intimidated by its size and technical mumbojumbo....Stick to the topics that interest you!

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Offlineummikko
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Re: How Hallucinogenic Drugs Work [Re: shymanta]
    #3760527 - 02/10/05 04:58 AM (19 years, 5 months ago)

Quote:

shymanta said:
So, it sounds like substances that bind permanently are to be avoided.

Is that the case and is there a "scientific name" for a permanent binder whether agonists or antagonists?





I only know the finnish name :wink:

The difference between temporary and permanent binding, on the chemical level, is that temporary binding is usually based on relatively weak physiochamical forces (typically ion bonds, hydrogen bonds, van der Waals bonds, and hydrofobic interactions) and permanent binding is based on covalent bonding, which is much stronger.

Well-known examples of permanent binders are organophosfates, which are used in insecticides and in chemical warfare.


--------------------
"All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy." -Paracelsius

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InvisibleHermes_br
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Re: How Hallucinogenic Drugs Work [Re: ummikko]
    #3763210 - 02/10/05 05:25 PM (19 years, 5 months ago)

hi, the following is a page a had from the hive.ws

-------------------------------------------------
Rhodium
(Chief Bee)
04-24-02 21:24
No 300866
LSD and DOB: interaction with 5-HT2A receptors
(Rated as: excellent) Reply

LSD and DOB: interaction with 5-HT2A receptors to inhibit NMDA receptor-mediated transmission in the rat prefrontal cortex
by
Arvanov VL, Liang X, Russo A, Wang RY
Department of Psychiatry and Behavioral Science,
SUNY at Stony Brook,
NY 11794-8790, USA
Eur J Neurosci 1999 Sep; 11(9):3064-72

ABSTRACT
Both the phenethylamine hallucinogen (-)-1-2, 5-dimethoxy-4-bromophenyl-2-aminopropane (DOB), a selective serotonin 5-HT2A,2C receptor agonist, and the indoleamine hallucinogen D-lysergic acid diethylamide (LSD, which binds to 5-HT1A, 1B, 1D, 1E, 1F, 2A, 2C, 5, 6, 7, dopamine D1 and D2, and alpha1 and alpha2 adrenergic receptors), but not their non-hallucinogenic congeners, inhibited N-methyl-D-aspartate (NMDA)-induced inward current and NMDA receptor-mediated synaptic responses evoked by electrical stimulation of the forceps minor in pyramidal cells of the prefrontal cortical slices. The inhibitory effect of hallucinogens was mimicked by 5-HT in the presence of selective 5-HT1A and 5-HT3 receptor antagonists. The inhibitory action of DOB, LSD and 5-HT on the NMDA transmission was blocked by the 5-HT2A receptor antagonists R-(+)-alpha-(2, 3-dimethoxyphenil)-1-[4-fluorophenylethyl]-4-piperidineme thanol (M100907) and ketanserin. However, at low concentrations, when both LSD and DOB by themselves only partially depressed the NMDA response, they blocked the inhibitory effect of 5-HT, suggesting a partial agonist action. Whereas N-(4-aminobutyl)-5-chloro-2-naphthalenesulphonamide (W-7, a calmodulin antagonist) and N-[2-[[[3-(4'-chlorophenyl)- 2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4'-methoxy-b enzenesulphonamide phosphate (KN-93, a Ca2+/CaM-KII inhibitor), but not the negative control 2-[N-4'methoxybenzenesulphonyl]amino-N-(4'-chlorophenyl)-2-propeny l-N -methylbenzylamine phosphate (KN-92), blocked the inhibitory action of LSD and DOB, the selective protein kinase C inhibitor chelerythrine was without any effect. We conclude that phenethylamine and indoleamine hallucinogens may exert their hallucinogenic effect by interacting with 5-HT2A receptors via a Ca2+/CaM-KII-dependent signal transduction pathway as partial agonists and modulating the NMDA receptors-mediated sensory, perceptual, affective and cognitive processes.

-----------------------------------------------------------------------

Antoncho
(Official Hive Translator)
04-25-02 09:30
No 301160
Interesting... Reply

Makes one wonder if by chance there is any connection between the action of psychedelics and dissociatives (which, as we know, are noncompetitive NMDA antagonists).

Of course, NMDA receptor is so common in the brain that it's hard to associate any particular reaction with its blockade, but maybee thereis some specific network of such neurons that are responsible for "holding the reality intact" or "filtering out the unneeded stimuli" or, in Castanedian terms, "keeping the assemblage point in place" - that, when being gently inhibited (as we see in case of 5HT-2A-mediated action), 'soften' the reality's boundaries and, being rudely turned off by plugging up their NMDA channels (like in case of PCP), result in wild and chaotic experiences.

This is, of course, a very inscientific/far-fetched theory, but still rather cute, IMHO.


Antoncho

------------------------------------------------------

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Offlineeve69
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Re: How Hallucinogenic Drugs Work [Re: Hermes_br]
    #3886720 - 03/08/05 10:06 AM (19 years, 4 months ago)

Obviously DMT doesn't work merely by affecting serotonin. My guess is also that no group of objective scientists will ever understand the brain as it is its own testing apparatus. I have never believed any scientific conclusion yet, nor will I ever. We hear things today like, the Earth is actually 14 billion years old instead of 6, and that the speed of light may have slowed down since the BB. So there is nothing that doesn't change including theories. It may be that tomorrow the sun goes nova and all of a sudden gravity ceases. Then apples may float up instead of down thus negating Newton's observation of gravity. All science is searching in the dark. I am always leary of pat theorems about things as any theory negates the ever changing and wholistic nature of our universe. Somewhere in another universe non humans are smoking antiweed, and negating the antiserotonin in their clavicals while they float in antigravity in a dark matter antiexistentialistic pond where the goal is to cease instead of to be. There the goal is to snuff awareness and so on. We are anthropods and we see what we are only. To trust science is to step in front of a speeding car. Science has no thought, no morals, and no guidance, and is no guidance to others. It is a bandaid, and not a cure. Life is the source, course and goal, science is merely some dust on someones brain that got shaken free. We think that since the Renaissance humans have gotten more analytical, but that's not true when compared to the population explosion of the Earth. My guess is that there are a lesser percentage of great minds compared to the general population today compared to the Renaissance. So my point is that I argue any specific theory for how hallucinogens work. Because none of those theories take into acount the nature of non hallucinogenic visions, perceived in waking state, ie., paranormal or visionary experiences. My guess from experience is that the serotonin is merely an aspect of brain stem fight or flight sublimation, which preceeds a fierce synaptic cross coordination and new brain pathway perusal. The new synaptic connection falling into disuse after a quick hallucinogen bout but becoming more poignant in daily life as those pathways are repeatedly used, like learning anything the psychedelic also can become incorporated into the material world. Similar to training the mind through yoga and meditation or other religious triggers. I can tell you that I can easily know what tripping would be like in any situation, even when straight due to repeated experience over the course of my life. this training.Gotta go score. Ciaoders.


--------------------
...or something






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Invisiblebadchad
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Re: How Hallucinogenic Drugs Work [Re: eve69]
    #3893028 - 03/09/05 02:26 PM (19 years, 4 months ago)

Quote:

eve69 said:
Obviously DMT doesn't work merely by affecting serotonin.



This certainly seems to be true, although the it is thought to work primarily via the serotonin system. It's my opinion that the current research is focuing on these "other" neurotransmitters, and the downstream effects of disrupting the serotonin system.
Quote:

eve69 said: My guess is also that no group of objective scientists will ever understand the brain as it is its own testing apparatus.



I tend to agree, but we are continuing to learn at a very fast rate. How much we understand about the brain depends on how you look at it. Is the glass half full or half empty? even if we never "understand" the brain, does this mean we should give up?



Quote:

eve69 said:I have never believed any scientific conclusion yet, nor will I ever.



What about that guy who said the earth was round? What about scientific conclusions regarding DNA? There are many scientific achievements that have stood the test of time.
Quote:

eve69 said:We hear things today like, the Earth is actually 14 billion years old instead of 6, and that the speed of light may have slowed down since the BB. So there is nothing that doesn't change including theories.It may be that tomorrow the sun goes nova and all of a sudden gravity ceases. Then apples may float up instead of down thus negating Newton's observation of gravity..



Which is exactly why science should continue and we should challenge oursleves to learn.
Quote:

eve69 said:All science is searching in the dark.



Nothing could be further from the truth. While some discoveries are Serendipitous the nature of science is to build upon what others have discovered. For instance, while LSD was discovered "by accident", it's structure led scientists to believe it acted via a serotonergic mechanism. This was by no means a "shot in the dark" it was a good hypothesis. Obtaining grants and federal funding to perform science is by no means an easy task. It would be impossible to get funded without a strong hypothesis and previous work to back up your claims.
Quote:

eve69 said: I am always leary of pat theorems about things as any theory negates the ever changing and wholistic nature of our universe. Somewhere in another universe non humans are smoking antiweed, and negating the antiserotonin in their clavicals while they float in antigravity in a dark matter antiexistentialistic pond where the goal is to cease instead of to be. There the goal is to snuff awareness and so on.



Do you realize that your logic follows scientific theory (antimatter, dark matter etc) which are scientific theories, which you initially stated you would never believe?
Quote:

eve69 said: To trust science is to step in front of a speeding car. Science has no thought, no morals, and no guidance, and is no guidance to others. It is a bandaid, and not a cure.



Smallpox has been eradicated from this world, polio is soon to follow. Excellent examples of science "curing" ailments. If we cannot trust science, What should we trust? (perhaps your local religious diety who would tell us as long as we believe in god everything will be allright?) And there are obvious morals within science. Try writing an experimental protocol using animals, strict guidelines must be followed.

Quote:

eve69 said:Life is the source, course and goal, science is merely some dust on someones brain that got shaken free. We think that since the Renaissance humans have gotten more analytical, but that's not true when compared to the population explosion of the Earth. My guess is that there are a lesser percentage of great minds compared to the general population today compared to the Renaissance.



I'm not sure whether I agree or not. Think back to the Renaissance. I don't have figures for the literacy rate, I would assume there was no formal, standardized system of education. On the contrary compared to the renaissance, I think there sre still plenty of great minds because the process of learning has been facilitated and accelerated.
Quote:

eve69 said:So my point is that I argue any specific theory for how hallucinogens work. Because none of those theories take into acount the nature of non hallucinogenic visions, perceived in waking state, ie., paranormal or visionary experiences. My guess from experience is that the serotonin is merely an aspect of brain stem fight or flight sublimation, which preceeds a fierce synaptic cross coordination and new brain pathway perusal. The new synaptic connection falling into disuse after a quick hallucinogen bout but becoming more poignant in daily life as those pathways are repeatedly used, like learning anything the psychedelic also can become incorporated into the material world. Similar to training the mind through yoga and meditation or other religious triggers. I can tell you that I can easily know what tripping would be like in any situation, even when straight due to repeated experience over the course of my life. this training.Gotta go score. Ciaoders.




One aspect of hallucinogen study is relating their effects to what is going on normally within the brain. Indeed there have been several papers comparing the effects of hallucinogens to those experienced by religious leaders.

Anywho in an effort to keep the thread slightly on track I tend to think that newer studies of hallucinogenesis are focusing on interactions amongst neurotransmitters rather than a single type in isolation. As stated in the Arvanov and Wang article someone posted previously (Eur J Neurosci 1999 Sep; 11(9):3064-72) glutamate has come into the spotlight recently. This specific paper refutes some of the theories by Aghajanian and colleagues that 5-HT2A stimulation causes a focal release of glutamate. The laboratory I work in has recently decreased the effects of LSD (in rats) by administering ligands which indirectly decrease glutamate.

Somewhat related along these lines is a article by Nichols (whom was mentioned earlier in this thread and has published an excellent review as of late) Where he attributes the temporal phases of LSD to different neurotransmitters.

All in all we're making progress but theres plenty more to be done!

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Invisibleambros
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Re: How Hallucinogenic Drugs Work [Re: badchad]
    #3915763 - 03/14/05 10:21 AM (19 years, 4 months ago)

i dont if they are interesting, they are taken from nature.com where you cant see if a file is downloadable or not.

Serotonin and Hallucinogens
http://www.myfilestash.com/userfiles/sympetrum/Serotonin%20and%20Hallucinogens.pdf

a single dose of lsd influences gene expression patterns within the mammalian brain (can someone comment this one)
http://www.myfilestash.com/userfiles/sym...ian%20Brain.pdf

Agonist-Directed Signaling of Serotonin 5-HT2C Receptors, Differences Between Serotonin and LSD
http://www.myfilestash.com/userfiles/sym...20and%20LSD.pdf

Neurometabolic Effects of Psilocybin, 3,4-Methylenedioxyethylamphetamine
(MDE) and d-Methamphetamine
http://www.myfilestash.com/userfiles/sympetrum/Neurometabolic%20Effects%20of%20Psilocybin.pdf

Serotonin Neurons, Neuroplasticity, and
Homeostasis of Neural Tissue
http://www.myfilestash.com/userfiles/sym...al%20Tissue.pdf

Modulating the Rate and Rhythmicity of Perceptual Rivalry
Alternations with the Mixed 5-HT2A and 5-HT1A Agonist
Psilocybin
http://www.myfilestash.com/userfiles/sym...0Psilocybin.pdf

http://www.myfilestash.com/userfiles/sym...20variasjon.pdf

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Invisiblebadchad
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Re: How Hallucinogenic Drugs Work [Re: ambros]
    #3930236 - 03/17/05 11:49 AM (19 years, 4 months ago)

What a nice blast from the past!, I read the first three articles when they were first published, however it?s been a few years since I dug them out of my files.

The first three are by reputable authors whom are respected in the field. I wasn?t familiar with the last 4 articles or their authors (not to say they were ?bad?, I?m just not familiar with the investigators and the quality of their work).

As far as comments are concerned, there are multiple aspects of each paper that can be criticized/commented on. Since you asked about the second paper I?ll offer my opinion and others are free to expand/comment/agree/disagree on what I?ve said.

?A Single dose of Lysergic Acid Diethylamide Influences Gene Expression Patterns Within the mammalian Brain? Nichols, C.D. and Sanders-Bush, E. Neuropschopharmacology 26(5):634-642

A nicely written paper looking at the transient effects of LSD on gene expression patterns within the brain of rats. Essentially, the paper used a very unique approach to study the effects of LSD, although the reality is that this paper produced very little useful knowledge.

The authors made use of gene chip technology which allowed them to screen approximately 8800 genes simultaneously and determine relative upregulations/downregulations of protein products in response to LSD. Considering the amount of genes screened the results seemed rather disappointing. Changes were seen in about 7 gene products.

While gene chip technology allows for analysis of a large amount of gene products, the technology has significant drawbacks, all of which undermined the usefulness of this paper:

1. First off it is very difficult to quantitate absolute changes in expression levels using this method.
2. In a similar manner how does one define what magnitude of change is needed for a significant change to occur?

Even with these factors accounted for (which the authors did to a small extent) the actual results weren?t impressive. Of the gene products affected most were immediate early genes and known to be affected by multiple stimuli, making questionable their relevance to LSD. For instance, one gene that was upregulated in response to LSD was c-fos. If you look at the literature, c-fos is upregulated in response to almost anything and is often used as a marker for neuronal firing. If I squeeze a rat, scare him or otherwise expose him to stress, you?ll find c-fos is upregulated. If I administer an antidepressant, such as an SSRI, c-fos may be upregulated. In a similar manner cocaine can upregulate the NOR1 gene (which was also upregulated by LSD).

Since all these ?other things? can result in upregulation of the same genes as LSD they do not seem unique to LSD. For instance, if LSD and cocaine both upregulate NOR1, how can we say NOR1 is involved in the effects of LSD, as cocaine and LSD are clearly different from one another. This same story holds true for the other genes, none seem specific to LSD.

Finally, (and most importantly) look at the dose of LSD used in the study. 1.0mg/kg. That is an enormous does in terms of human consumption, imagine what it does to a small rat?

All in all the paper demonstrated promise by using a new technique but the results were less than interesting. If someone were to find a gene that is upregulated ONLY in response to a behaviorally relevant dose of LSD, one may begin to speculate on its role in hallucinogenesis, unfortunately, that didn?t happen.


--------------------
...the whole experience is (and is as) a profound piece of knowledge.  It is an indellible experience; it is forever known.  I have known myself in a way I doubt I would have ever occurred except as it did.

Smith, P.  Bull. Menninger Clinic (1959) 23:20-27; p. 27.

...most subjects find the experience valuable, some find it frightening, and many say that is it uniquely lovely.

Osmond, H.  Annals, NY Acad Science (1957) 66:418-434; p.436

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OfflinePsiloman
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Re: How Hallucinogenic Drugs Work [Re: badchad]
    #3967909 - 03/25/05 08:39 AM (19 years, 3 months ago)

I hope im not off topic but i would liek to comment on some practical implications for they layman of the discovery of the glutame role in the mediation of 5HT-2a agonist halucinogens effects..

Badchad has said :" Anywho in an effort to keep the thread slightly on track I tend to think that newer studies of hallucinogenesis are focusing on interactions amongst neurotransmitters rather than a single type in isolation. As stated in the Arvanov and Wang article someone posted previously (Eur J Neurosci 1999 Sep; 11(9):3064-72) glutamate has come into the spotlight recently. This specific paper refutes some of the theories by Aghajanian and colleagues that 5-HT2A stimulation causes a focal release of glutamate. The laboratory I work in has recently decreased the effects of LSD (in rats) by administering ligands which indirectly decrease glutamate.
"

So it makes me wonder...So far for modifying the experience from serotoninergic hallucinogens we have utuilized different administration routes (IV,IM,per os) ,played with the pharmackinetics (full stomach,liquid infusion,empty stomach),and also with metabolism (MAOinhibitors...).These laymans experiments have brought forth some conclusion on how these factors modify experience...

Now...How about glutame? Could glutamate release be facilitated by another agent co-administered with a hallucinogen? Im not talking merely about "potentiation",but talking about alteration of different stages of the experience...

Any thoughts on that?

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Invisiblebadchad
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Registered: 03/02/05
Posts: 13,379
Re: How Hallucinogenic Drugs Work [Re: Psiloman]
    #3968067 - 03/25/05 09:51 AM (19 years, 3 months ago)

Quote:

Psiloman said:
Now...How about glutame? Could glutamate release be facilitated by another agent co-administered with a hallucinogen? Im not talking merely about "potentiation",but talking about alteration of different stages of the experience...

Any thoughts on that?




Well, in my opinion, the simple answer is "yes". As you may know, NMDA antagonists (PCP, ketamine, etc.) are thought to work by increasing glutamate release. Thus, it seems to me that if you combined a hallucinogen and an NMDA antagonist, you would get some sort of effect. I would think this would result in the "potentiation" you spoke of (or perhaps an attenuation), however you may get some interesting effects (which might be described simply as "different").

In a similar manner, there has been an increased interest glutamate ligands recently. Two new "mglu" ligands have been introduced (mglu2 and 3), which are purpoted to selectively bind to metabotropic glutamate receptors. Supposedly these ligands modify glutamate release (with the mglu2 agonist decreasing glutamate release). These compounds contributed to the hypothesis of glutamate being involved in the effects of PCP, when they were found to decrease some of the effects of PCP in rats (reference:Moghaddam, B and Adams, A: Reversal of Phencyclidine Effects by a Group II Metabotropic Glutamate Receptor Agonist in Rats. SCIENCE: V. 281, issue 5381, 1349-1352, 2000).

Recently, another paper was published exploring the effects of these mglu ligands on LSD, an obviously "more serotonergic" compound, and they were found to decrease the effects of LSD in rats. So it seems that there is at least a modest contribution of glutamate to the effects of hallucinogens. How large of a "contribution" glutamate makes however, is still being explored.

Now, to make it even more confusing, note that Nichols (as I said a couple posts up) just published a hypothesis of the involvement of dopamine during the latter stages of LSD. So, in the context of modifying glutamate this would have to be taken into account as well (e.g. modifying glutamate may have different effects on hallucinogenesis, depending on WHEN it is modified). In short (as I've said before) now that serotonin is predominantly been implicated in the mechanism of action of hallucinogens, its interactions with additional (or "secondary) neurotransmitters seems to tbe the focus of current research.


--------------------
...the whole experience is (and is as) a profound piece of knowledge.  It is an indellible experience; it is forever known.  I have known myself in a way I doubt I would have ever occurred except as it did.

Smith, P.  Bull. Menninger Clinic (1959) 23:20-27; p. 27.

...most subjects find the experience valuable, some find it frightening, and many say that is it uniquely lovely.

Osmond, H.  Annals, NY Acad Science (1957) 66:418-434; p.436

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OfflinePsiloman
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Re: How Hallucinogenic Drugs Work [Re: badchad]
    #3968222 - 03/25/05 10:27 AM (19 years, 3 months ago)

Ah Doctor Nichols...If im correct the study you mention shows an increase of dopamine release in the "comedown" period of LSD administration,right? (Ny the way i think this man has a lot of aces up his sleeve but he is smart and knows how to keep quiet...Think of bromodragonfly!)

Of course timing is crucial and this is such an interesting field of research,because many variables come into play...

I may want to research the glutamate hypothesis (and yes,i mean research as in reading not as in "gulping down" :laugh:) and find out many substances that can enhance glutamate release  or increase glutamate content in the brain,if possible others than PCP and Ketamine (have you heard of Memantine by the way? Thats an interesting compound...) .Monosodium Glutamate keeps coming into mind (yes,the "unami" taste) but i havent found any data on what exactly it does on the brain and if indeed it reaches the brain...Maybe Pubmed can help here

From what i gather glutamate release in big quantities can cause  exitatory apoptosis in some brain cells...Am i correct? I think some "antialzheimer" medications aim at its modulation...Death of neural tissue by overstimulation is not something desired...

By the way do you know if ibotenic acid and muscimol of the species Amanita Muscaria modulate in any way glutamate "stock" of the brain or glutamate release? Maybe you are going to laugh here but the taste of this mushroom is close to the one of monosodium glutamate...I dont know if it contains any or if those compounds give it the nice taste,but i "smell" exitatory compounds of the glutamate kind to be responsible for the flavor..It oculd be completely unrelated it could also be of importance...

EDIT: On the MSG issue look at this paper http://www.ncbi.nlm.nih.gov/entrez/query...t_uids=15047981

Edited by Psiloman (03/25/05 10:32 AM)

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Invisibleredgreenvines
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Re: How Hallucinogenic Drugs Work [Re: ambros]
    #3968311 - 03/25/05 11:00 AM (19 years, 3 months ago)

Quote:

ambros said:
i dont if they are interesting, they are taken from nature.com where you cant see if a file is downloadable or not.

Serotonin and Hallucinogens
http://www.myfilestash.com/userfiles/sympetrum/Serotonin%20and%20Hallucinogens.pdf





in the first document, figure 2 shows a nice chart of what I call the primary effect of halucinogen. - postsynaptic potentiation.

We experience much more vibrance from each sensory input and memory.
we even may experience a stacking of full gestalts of experience as things fade more slowly.

they call it the "nonsynchronous component of the EPSCs "
specifically they show some extended electrical activity after synaptic excitation for more than 0.25 second (I think the full extension of that chart would be interesting.)

I will reply to each one in sequence WRT what I find interesting.
(my computer is crashing a lot today)


--------------------
:confused: _ :brainfart:🧠  _ :finger:

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Invisibleredgreenvines
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Re: How Hallucinogenic Drugs Work [Re: ambros]
    #3968328 - 03/25/05 11:05 AM (19 years, 3 months ago)

Quote:

ambros said:
a single dose of lsd influences gene expression patterns within the mammalian brain (can someone comment this one)
http://www.myfilestash.com/userfiles/sym...ian%20Brain.pdf





this study relates to growth and adaptation to the environmental influence of LSD over the short term of exposure.

it is inconclusive but seems to highlight the thalamus and the cortex in the fixation of new memory, and may only indicate that the LSD is stimulating activity/learning/adaptation over a resting state.


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Invisibleredgreenvines
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Re: How Hallucinogenic Drugs Work [Re: ambros]
    #3968341 - 03/25/05 11:10 AM (19 years, 3 months ago)

Quote:

ambros said:

Agonist-Directed Signaling of Serotonin 5-HT2C Receptors, Differences Between Serotonin and LSD
http://www.myfilestash.com/userfiles/sym...20and%20LSD.pdf





again RNA level molecular biological analyses are being used to evaluate a snapshot of chemical behaviour during an environmental exposure that may not be entirely relevent to what we experience, but they are learning more and more about serotonin and lsd WRT to phoshphorous movement and electrical potential of the neurons.


--------------------
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