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Author: Subject: Ayahuasca psychedelic tested for depression
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[*] posted on 11-5-2015 at 18:18


AMT aka IT290, WAS being used to treat depression. Folks on this board, expressed concern when they were no longer able to obtain it. Too sexy. Too much fun. Large doses make you high as a kite. And thus, it is no more.

Not a "snap" to make either. DET might be a decent antidepressant candidate.

Reported to be orally active, and not requiring the Ayahuasca type additives that DMT requires to be orally active.

[Edited on 12-5-2015 by zed]

[Edited on 12-5-2015 by zed]
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[*] posted on 12-5-2015 at 05:41


Quote: Originally posted by zed  
AMT aka IT290, WAS being used to treat depression. Folks on this board, expressed concern when they were no longer able to obtain it. Too sexy. Too much fun. Large doses make you high as a kite. And thus, it is no more.

Not a "snap" to make either. DET might be a decent antidepressant candidate.

Reported to be orally active, and not requiring the Ayahuasca type additives that DMT requires to be orally active.

[Edited on 12-5-2015 by zed]

[Edited on 12-5-2015 by zed]

That's a little bit of an awkward comparison to make seeing as AMT is not only a serotonin receptor agonist, but an MAOI and reuptake inhibitors as well as releaser of serotonin, noradrenaline and dopamine, giving it additional stimulatory effects associated with antidepressant action (PMCID: PMC3582025). It's the MAOI efficacy which spurred antidepressant research, which is unlikely to account for the effects purported in some of these instances (PMID:14204959).

AET (PMID:13742239), similarly, was marketed as an antidepressant under the tradename Monase (AMT was Indopan in the USSR) in sub-psychedelic doses without reported hallucinogenic side effects noted at the time, and doesn't have any acute dose-related deaths associated with it, as opposed to the former. The problem with Monase was agranulocytosis (PMID:13875179), which might very well be an issue with AMT. Curiously, both isomers have purported MAOI activity, though less potent than harmaline, and thus are likely poor candidates to determine more precise target profiles for efficacy (PMID: 204959 and 13898151).

I have noted DET as being a possible test candidate in excluding receptors of clinical implication, particularly MAO-A, but the lack of an MAO-AI effect, present in the alpha substituted tryptamines, would be as mechanistically important in terms of efficacy and toxicity as ease of patient compliance from oral administration. In further discussion of the mechanistic aspects and why they are important to determine, I had mentioned the lack of specificity in 5-HT2R agonism of many of the tryptamine psychedelics, and 5-HT2C receptors in particular are being examined for various therapeutic uses, including potential treatment of depression (PMID: 17297636 and 11082448). These are relatively recent developments compared to fairly selective serotonin receptor antagonists (ex. SB-242084, SB-243213, CEPC, RS 102221, etc.), and antagonism has the pre-clinical benefit of allowing very easy reversibility of putative effect upon challenge.

Using rational drug design concepts with anti-targeting of MAO and other 5-HT2 isoforms, one may be able to avoid 5-HT2B associated cardiac toxicities and MAOI drug-drug/drug-food interactions. It's important to note that non-tryptamine, non-ergoline drug candidates without presumed 5-HT2A psychedelia are being investigated for these purposes (obesity, schizophrenia, depression,etc.), and should have no DEA recommended legal burdens in addition to normal FDA development guidelines. Examples are the WAY series of candidates (WAY-162545 and WAY-163909) and others. In keeping with my previous statements on 5-HT2A antagonism and therapeutic potential, and my hints of interest in 5-HT2C promiscuity, selective antagonism of 5-HT2C has also shown some potential in SSRI potentiation (PMID: 1513847). At face value, this may have initially derailed some investigations into agonist therapeutic efficacy and development.

[Edited on 12-5-2015 by Chemosynthesis]
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[*] posted on 14-5-2015 at 13:44


Quote: Originally posted by Zombie  
In all fairness I don't really see any difference. If you are physically addicted to something or mentally addicted you still have an issue.

But how can one be "mentally addicted" to LSD? It is like saying you are mentally addicted to elevators because you use them rather than using the stairways. Your interpretation of the term "addiction" makes the term obsolete.

Quote:
Did I read this correctly?
"The proportion of people who used a psychedelic drug at least once in their life (coded as "lifetime classic psychedelic drug users") is 13.6% of the population"

Use LSD once, and it is coded as Lifetime user? Then I must be a lifetime soccer player.
That makes no sense to me.


Yes, the survey analysis separates the subjects into psychedelic experienced and naive.
Obviously, if you experienced the psychedelic state at least once you cannot became naive again. This is not like playing football. You can imagine how it feels to play football even if you only see it on TV, but it is not possible to imagine the psychedelic state.
Given that the data analysis was looking for potential harm/benefit from using the psychedelics, which are known to bring changes on acute application (unlike alcohol, narcotics or stimulant drugs which cause personality changes only upon chronic use), it is only reasonable that the control group would be the naive subjects. I think the authors decided correctly on this issue.
Besides, only a small proportion of people uses a psychedelic drug more than just once or a few times in a life. Since psychedelic drugs do not give any pleasure, there is little interest to repeat the experience.

Quote:
Why keep this "shotgun" style research going if they do not apply it where it is KNOWN to work?


It is not "shotgun" style research at all. All the disorders where the psychedelic or psycholytic therapies are successful (these are the two most researched therapeutic methods employing psychedelic drugs) have one thing in common. The origin of all these disorders, like alcoholism, smoking, depression, PTSD, narcotics addictions, fear of dying, etc., appears to be in the malfunctioning ego that got stuck in a certain repetitive pattern. If you've read the fMRI study by Carhart-Harris, or at least listened his lecture, you can see how the same mechanism of action is able to unstuck the destructive thought patterns in all the mentioned disorders.

Quote: Originally posted by zed  
AMT aka IT290, WAS being used to treat depression. Folks on this board, expressed concern when they were no longer able to obtain it. Too sexy. Too much fun. Large doses make you high as a kite. And thus, it is no more.

AMT is not a clean psychedelic, if at all. It has hybrid activity, resembling somewhat to MDA in its subjective effects (it also has some entactogenic activity, besides minor psychedelic effects and stimulation). As such, AMT can be dangerous at the doses where it shows some psychedelic effects. The current understanding of the psychedelics as a cure to depression is that they require a few sessions of acute application as adjuncts to psychotherapy, so you would want the drug activity to be as "clean" as possible. Hence, psilocybin is currently considered as the most appropriate of the commonly used and available psychedelics. Duration is also very important as few therapist would be motivated to work more than 8 hours per session.
AMT-like drugs could have their own virtues in a therapeutic session. MDMA, which is a very "clean" entactogen, proved to be the most effective currently known treatment for PTSD when administered in three consecutive therapeutic sessions spaced a few months in between. So, perhaps there might also be some use for entactogen/psychedelic hybrids that we do not know of yet, but something safer than AMT should be used.

Quote:
DET might be a decent antidepressant candidate.

DET is qualitatively much inferior to psilocybin, at least by oral application. It would be very difficult to generate a mystical experience with DET and this appears required for the therapeutic effect to become long lasting.




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[*] posted on 14-5-2015 at 14:22


I think Chemo makes all that up. :o
No living person could know so much about anything... You impress the hell out of me, no doubt.

I had to look 90% of that post up to understand 40% of it. I get one major point... The mechanism of action.

This is what I think matters more than anything in all of this discussion. As soon as I hear/read, "It's not completely understood how this works" or We believe this is what happens", I'm out like a light.

Nicodem brings up the point that the "trip" may be the action that creates the changes in a person. Having been down that road a few times I can say it does bring change but I'm not sure you could cure a cold let alone depression with tripping. At least it was a failure for me.

I also can't see being high all day every day, and calling that a win.
It seems to me that there is something in the compounds that does not require the trip to effect a "cure".

DMT... Sure. The spirituality aspect is interesting in itself. The suspicion that the spirit cures the body is fine. I can easily agree with this. But is it trip needed or is the compound itself enough?

I know with psilocybin you do not need to take trip levels for it to do wonderful things for you. Just a few grams a day, just like a multi-vitamin but three times a day, and life is easier.
For ME, I can think more clearly, solve complex engineering problems faster, and more "cleanly", and I said it before... If the house burns down... so what? Get another one.

Problem is... The law!

Again I blame the stoners for this. I wish they would have all walked around w/ Sherlock Homes pipes, and smoked ounces of tobacco instead.




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[*] posted on 14-5-2015 at 16:54


Well, in some ways, use of these materials mimics a natural state of consciousness....Sahaj Samadi. Subjectively, the effects are quite similar. A sense of well being, and a mild to profound degree of disassociation with your physical form. Ecstasy.

Too much, and you can't drive your car. To little, and you can't bear living.

Don't know if your body produces a greater abundance of natural neurotransmitters to achieve this state, or yogic or other practices changes your physio

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[*] posted on 14-5-2015 at 17:10


I can relate to that post directly.

There have been moments in my life where if I were pressed to describe the feeling, psychedelics would be the closest I could come to a description.

In my 20's I was into bodybuilding. That is a non stop committed chore. I actually grew to hate the routine, and hit a wall in development, and the amount I could lift (around five years in).

I developed my own routine where I would force everything out of my senses. I couldn't see or hear what was around me, and I could actually "pop" every joint in my body using the attached muscle groups. From there the weight had no weight. It was simply a motion that HAD to be completed.

I found a way to incorporate the same feeling into snow skiing, motorcycle racing (dirt bikes), work, pretty much anything.

To explain it I guess I could say I took my body out of the equation, and my mind was in control. The times I have done LSD or Mushrooms, I had the exact same feeling. Fortunately for the population at large all I wanted to do then was chill, and enjoy my mind.

Point of all that is I KNOW the mind can do anything you want it to. There are doors that must be opened, and if you learn how you don't need the chemicals. Getting to that point takes a HUGE commitment.

I think I just solved my own issues... Time to get back to what worked in the past.

Enough personal shit. The point Zed just made is a good one. Is there really a line? What part is triggered, and what part is created chemically form an outside source?
I think I answered that in this post. I believe it is in us already.

Thanks Zed!




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[*] posted on 15-5-2015 at 13:59


Its interesting that you mentioned "disassociation with your physical form".

From http://en.wikipedia.org/wiki/Ketamine , a well known disassociative.

"Ketamine has been tested in treatment-resistant bipolar depression, major depressive disorder, and people in a suicidal crisis in emergency rooms.[26] Benefit is often of a short duration.[27] The quality of the evidence supporting benefit, however, is generally low.[27]

The drug is given by a single intravenous infusion at doses less than those used in anesthesia, and preliminary data have indicated it produces a rapid (within 2 hours) and relatively sustained (about 1–2 weeks long) significant reduction in symptoms in some patients.[28] Initial studies with ketamine have sparked scientific and clinical interest due to its rapid onset,[29] and because it appears to work by blocking NMDA receptors for glutamate, a different mechanism from most modern antidepressants that operate on other targets.[27][30]"

And now a new series of drugs based on this mechanism.

http://en.wikipedia.org/wiki/Esketamine
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[*] posted on 15-5-2015 at 14:33


I have known people that abuse ketamine, and I have heard that the effect was like psychedelics only without the reality shifts.

I couldn't imagine what they meant until your post Greg. Now that I have something to grasp the idea from the concept sounds interesting.

I wouldn't have chosen the word "disassociation" but I guess it does apply. I believe that we all have that state of mind or place in our mind where everything is both fine, and possible.
Now in reaching that state I know it is not easy. It's something like meditation only very different. You have to have a clear goal, and nothing else is in your mind except completing that goal. No doubts or distractions.

Now this has me thinking.. How can a person relate to the entire rest of the world when you have to get that out of you field of focus?
Its kind of a catch 22 IMHO.
If you want to improve your own life it appears to me the only way it really works is to disassociate from the causes of your anxieties. People...
That sounds counter productive at best, and anti social at worst.

If you take this to a middle ground where you are aware of all the negative crap but force it to the side that alone is a distraction from the centering or focus required to improve your life.

I assume ketamine/dmt/lsd/psilociiben, ect... allow you to achieve that state thru chemically activating the areas of the mind that we want activated. Sort of a shortcut to the training I referred to.

This is where my personal dilemma in life has always been. I have no need for something to force limits in my thought process. I have a hard enough time as it is. IF I were to describe perfection in MY life it would be solely based on EVERYONE ELSE being a better person. IF everyone fed their kids, supported their spouses, worked their fair share, and contributed to their communities... I would have NO PROBLEMS at all.

Try to figure out a cure for that!!!

I worry so f'n much about all the problems in the world that it emotionally effects me directly.

Maybe that's why I would volunteer to push that "button". It;s very tiring worrying about things that will never change.

Even the fact that everyone else doesn't worry about this drives me insane!

[Edited on 5-15-2015 by Zombie]




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[*] posted on 15-5-2015 at 14:38


Another point of interest is that we continually study the brain. The youngest part of our nervous system, and while that is interesting stuff, there are more players in the game. Subjectively one my own centers of well-being seems to be largely centered in the Anahata Chakra, an area in the middle of the chest. Seems to be a sort of bronchial plexus. It's the AHHHHHHHHH spot.

The clever newcomer (brain) is fairly proficient at integrating experiences and solving quadratic equations, but our sense of well being is an emotional state, and is largely associated with other areas of the nervous system.

Anti-depressants are a kind of first aid, for bad feelings brought about by the difficulties of modern life. The whole of your being is screaming out "This ain't right", but you still gotta kiss the ass of the boss you wanna kill, take care of the wife or husband that doesn't love you, and provide for a gaggle of kids that disrespect you. Ain't right.

Gotta activate the kundalini force, open the Anahata Chakra, gain a little transcendental consciousness, and learn to laugh at the whole thing. Of course, you will maybe get fired, get divorced, and hafta live in a log cabin, but what the heck? Might beat trying to pound a round peg into a square hole, with the aid of antidepressants.

Not that I am totally against first aid via antidepressants. Tell me more.



[Edited on 15-5-2015 by zed]
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[*] posted on 15-5-2015 at 14:46



This entactogen qualification Nicodem mentions is likely important as well, and very good to mention in the absence of a well understood mechanism despite the controversy surrounding exact characterizations of psychedelia vs. enactogenicity/empathogenicity. Anyone not familiar should probably check out "The Great Entactogen-Empathogen Debate" for starters, and then see terminology such as used in PMID: 7913128, whereby entactogens are called "peripheral psychedelics," which is not an uncommon type of characterization for these fascinating compounds. Dose dependent response curves and neuropharmacological state throughout drug state complicate.

Both psychedelia and entactogenicity are thought to be mediated predominantly through serotonin, which is particularly distinguishable from most dopaminergic stimulants (AMT and AET being unusually stimulating in canon for the drug class given PMCID: PMC1557788), which are more strongly associated with manias. It is easier to differentiate between locomotor stimulation than self report, especially in animal models, so sometimes there are discrepancies in classification that are overlooked in light of easier groupings. Increased serotonin effects from MDMA are typically understood as what differentiates it from methamphetamine, and has led to it sometimes being called a "weak" or "selective" psychedelic. One point of confusion may be the differing effects of isomers in the prototypical entactogen MDMA (PMCID: PMC2775256). However, there is evidence of dopamine and serotonin interplay in distinguishing among classes and extinguishing deleterious mental states and behaviors PMCID: PMC2683464, PMID: 17661017 and various papers on aminoindanes such as PMCID: PMC48544 being relevant. I think further research into the effects of serotonin release or reuptake inhibition versus agonism may elucidate some distinctions, though the spectrum of actions and affinities of action on receptors pertinent to even just the two neurotransmitters dopamine and serotonin are unlikely to allow very dichotomous categorization.

If the initial post's source article is to be taken as clinically and statistically valid, it does appear as though psychedelia is not necessary for long lasting antidepressant effect at least in some patients with some ayahuasca compositions, though statement either way is tenuous due to the vast variation in depression presentation and durations. It is possible that psilocybin requires psychedelia for optimum therapeutic effect (tentatively indicated in PMID: 21674151 and similar to smoking cessation in PMID: 25563443) whereas DMT or DET can be used for therapy without the psychedelia itself being the integral component in therapy due to ligand specific signal pathway bifurcation, receptor plasticity, etc. It is also possible that psychedelia itself is just part and parcel of the optimum dose of psilocybin under normal administration, but locking a g-protein subunit in an inactive conformation with one of the tools I mentioned earlier to alter psychedelia and/or hallucination in some manner would not necessarily impact treatment as the two may be separable. Another possibility in future treatment is that some of the compounds' psychoactivity other than antidepressant action could be obviated entirely by very specific regional targeting and distribution in subregions of the brain, or mimicked by transcribing magnetic stimulation, implants, etc.
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[*] posted on 15-5-2015 at 14:54


Quote: Originally posted by gregxy  
Its interesting that you mentioned "disassociation with your physical form".

From http://en.wikipedia.org/wiki/Ketamine , a well known disassociative.

"Ketamine has been tested in treatment-resistant bipolar depression, major depressive disorder, and people in a suicidal crisis in emergency rooms.[26] Benefit is often of a short duration.[27] The quality of the evidence supporting benefit, however, is generally low.[27]

The drug is given by a single intravenous infusion at doses less than those used in anesthesia, and preliminary data have indicated it produces a rapid (within 2 hours) and relatively sustained (about 1–2 weeks long) significant reduction in symptoms in some patients.[28] Initial studies with ketamine have sparked scientific and clinical interest due to its rapid onset,[29] and because it appears to work by blocking NMDA receptors for glutamate, a different mechanism from most modern antidepressants that operate on other targets.[27][30]"

And now a new series of drugs based on this mechanism.

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

You may find this interesting:
"premise of the present review is that many of the shared psychedelic effects of serotonergic hallucinogens and NMDA antagonists can be understood as an effect downstream of a common neurotransmitter system or final pathway. First, both serotonergic hallucinogens and NMDA antagonists produce sufficient overlapping psychologial alterations despite different primary modes of action. Second, there is converging evidence from brain imaging, behavioral, and electrophysiological studies that both serotonergic hallucinogens and NMDA antagonists disrupt information processing within corticostriato-thalamic pathways implicated in the pathogenesis of psychotic disorders. Since entactogens such as MD.M.A are expected to produce only mild psychedelic symptoms, it will be of interest to know to what extent MDMA-induced neurobiological alterations differ from those seen in the states induced by hallucinogens and NMDA antagonists."
MLA Vollenweider, Franz X. “Brain Mechanisms of Hallucinogens and Entactogens.” Dialogues in Clinical Neuroscience 3.4 (2001): 265–279.
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[*] posted on 15-5-2015 at 15:03


Quote: Originally posted by Chemosynthesis  


If the initial post's source article is to be taken as clinically and statistically valid, it does appear as though psychedelia is not necessary for long lasting antidepressant effect at least in some patients with some ayahuasca compositions, though statement either way is tenuous due to the vast variation in depression presentation and durations. It is possible that psilocybin requires psychedelia for optimum therapeutic effect (tentatively indicated in PMID: 21674151 and similar to smoking cessation in PMID: 25563443) whereas DMT or DET can be used for therapy without the psychedelia itself being the integral component in therapy due to ligand specific signal pathway bifurcation, receptor plasticity, etc. It is also possible that psychedelia itself is just part and parcel of the optimum dose of psilocybin under normal administration, but locking a g-protein subunit in an inactive conformation with one of the tools I mentioned earlier to alter psychedelia and/or hallucination in some manner would not necessarily impact treatment as the two may be separable. Another possibility in future treatment is that some of the compounds' psychoactivity other than antidepressant action could be obviated entirely by very specific regional targeting and distribution in subregions of the brain, or mimicked by transcribing magnetic stimulation, implants, etc.



That's what I said. mostly :)

From the personal observations I posted above (scientifically irrelevant but valid none the less) I don't believe that "tripping" is the deciding factor in the effects of these compounds.

It's more of a quick re mapping of the circuitry of the mind/body. Someone in this thread mentioned learned behaviors, and a sort of sticking of the receptors in the mind making for a constant pattern. I believe this 100%. Water or electricity will follow the path of least resistance always BUT it can be rerouted.
I think that is all we are discussing here. Methods of rerouting the brains pathways.




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[*] posted on 17-5-2015 at 03:06


Quote: Originally posted by Zombie  
Nicodem brings up the point that the "trip" may be the action that creates the changes in a person. Having been down that road a few times I can say it does bring change but I'm not sure you could cure a cold let alone depression with tripping. At least it was a failure for me.


Cold is a viral disease and as far as I know no psychedelic drug has any antiviral activity. Depression on the other hand is something different and well within the realm of the currently understood mechanism of action of these drugs. As to actual how and why they work, you cannot expect from a scientist to give definitive and detailed answers. It would be unscientific, especially after this topic has been politically completely banned from research for 30 years, partially resumed only in the 90's and still being quite inhibited. But non-definitive answers are already available from what was done up to now.

Like I said several times, at this level of knowledge, there is no actual evidence that it is the "trip" that does the change (I assume that by "trip" you mean the psychedelic experience). There are two basic methods for treatment with psychedelic drugs and they appear to have a different mechanism of action. Both are acute treatments (generally one or a few sessions) and require an experienced therapist, so these have no exclusively physiological mechanism. Both methods have some more or less effective variations.

The first is the psycholytic therapy and can use several types of drugs (psychedelics, entactogens, even dissociatives have been used). It is based on psychoanalytical methods assisted by moderate doses of a drug that allows the patient safely bring out material for analysis. MDMA is currently in phase II clinical trials for just this kind of use as an adjunct for PTSD psychotherapeutic treatment. The current results are astonishing, way better than any of the currently used chronic pharmacological treatments. The major drawback is in that it requires expert therapists to actually work as intended (manufacturing GMP quality MDMA is way easier that producing a number of experienced therapists). With psychedelic drugs, it is Stanislav Grof that did most of the pioneering work on this method (as well as some other researchers).

The psychedelic therapy was developed in Canada by Osmond and Hoffer (see their excellent book Hallucinogens) and is based on high enough doses of a psychedelic drug that is given in a controlled and assuring setting. It appears that it only works if the patient achieves a mystical experience, for this reason it works more reliably only at very high dosage and after a single application. The mere psychedelic state was not found to be enough. It used to be the most effective treatment for alcoholism in the times when the method was still in use. Most recently it was studied against fear of dying in the Johns Hopkins study on cancer patients and provided astonishing results.

Of course, it is possible that some talented people are able of self-analysis and can actually benefit from psychedelic or entactogenic drugs in the absence of a therapist or experienced sitter. Population studies cited up-thread certainly indicate this might be the case, yet this certainly cannot be the case for just anyone, for just any disorder, and might even be counterproductive. For example, even in the presence of a therapist, it was discovered that at certain dosages (30-40 mg), MDMA actually has an anti-therapeutic effect in PTSD treatment (performing worse than the control group using non-drug therapy). Take a too low a dose of MDMA and you do more damage instead of curing the patient. There is a similar problem with psychedelics. People tend to use too low dosages which are not enough for the psychedelic method, so they achieve nothing. Such low dosages might be fine for the psycholytic method, but this generally only works well in the presence of a therapist. I might tend to guess that in the absence of a therapist, a too low a dose might even worsen things.

Quote:
I also can't see being high all day every day, and calling that a win.
It seems to me that there is something in the compounds that does not require the trip to effect a "cure".

That is what I'm saying all along. The "trip" or the psychedelic state of mind does nothing particularly permanent to a person (except for the astonishing recognition of what the human mind is actually capable of). As in any life situation, it is the insight that such a state can catalyze that is needed for any permanent change.

Quote:
I know with psilocybin you do not need to take trip levels for it to do wonderful things for you. Just a few grams a day, just like a multi-vitamin but three times a day, and life is easier.

I assume you meant milligrams rather than grams!
Anyway, what benefit would psychedelics have over any other drug, if you would have to use them chronically as you propose? It's not healthy, it's unpractical and it is pointless given the alternatives. There are already drugs that are used in such a way and they do not cure the illness, just relieve you of symptoms. I believe the only way psychedelics can have any advantage over other drugs is in that they can be used acutely and still give better results than any chronically applied drug. Obviously, the exception being the treatment of allergies and rheumatoid arthritis as discussed earlier in this thread, where certain psychedelics like DOI or DOB show anti-inflammatory activity at sub-threshold doses (but this would be in the same context as the current use of ergometrine and ergonovine at sub-threshold doses).

Quote: Originally posted by Chemosynthesis  

This entactogen qualification Nicodem mentions is likely important as well, and very good to mention in the absence of a well understood mechanism despite the controversy surrounding exact characterizations of psychedelia vs. enactogenicity/empathogenicity. Anyone not familiar should probably check out "The Great Entactogen-Empathogen Debate" for starters, and then see terminology such as used in PMID: 7913128, whereby entactogens are called "peripheral psychedelics," which is not an uncommon type of characterization for these fascinating compounds. Dose dependent response curves and neuropharmacological state throughout drug state complicate.


I don't think there is anymore debate on this topic, though there used to be some at the beginning, mainly for political reasons (for example, initially DEA and even NIDA classified MDMA as a psychedelic hallucinogen, apparently to apply the success from the anti-psychedelic propaganda on one newly appearing drug). Psychedelics and entactogens(=empathogens) are clearly differentiated (while the entactogen vs. empathogen term usage is a purely semantic issue). There are animal models that distinguish entactogens from psychedelics, there is the obvious pharmacodynamic difference, there is the chemical/pharmacological difference with the SAR of the drugs being unrelated, and so on. Of course, the major difference is in the subjective effects on humans. Entactogens generally are not able to cause a psychedelic state of mind (with the exception of hybrid drugs like racemic MDA). There are some resemblances, but it is like comparing psychedelics with other hallucinogens, where the resemblances are generally in the minor aspects of the experience.
I agree that you can still occasionally see the term psychedelic being used liberally for entactogens, cannabinoids, dissociatives, and other type of drugs. But this become extremely rare in the scientific literature where concise classifications are expected. On the other hand, you will see some political applications, like the Multidisciplinary Association for Psychedelic Studies using the term psychedelics for entactogens like MDMA. It appears to me this is done on purpose, because MDMA has a much better acceptance in public than psychedelic drugs, so they want to achieve acceptance of psychedelics by calling MDMA a psychedelic drug.




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[*] posted on 17-5-2015 at 23:50


Quote:
Ok Mr. Nicodem. To say I a totally confused now is an understatement. I'm trying very purposefully to NOT cherry pick quotes to take things out of context.

I believe that the compounds we are discussing simply open pathways or close pathways in the brain that allow "improvements" in the thought process.everyone seems to have evidence that this is the case or at least as much as it can be understood, and called evidence.

In some of your posts you attest this is correct, and other sections you dispute this, stating that the "trip" is required for a therapeutic effect.

Quote: Originally posted by Nicodem  

Like I said several times, at this level of knowledge, there is no actual evidence that it is the "trip" that does the change (I assume that by "trip" you mean the psychedelic experience). There are two basic methods for treatment with psychedelic drugs and they appear to have a different mechanism of action. Both are acute treatments (generally one or a few sessions) and require an experienced therapist, so these have no exclusively physiological mechanism. Both methods have some more or less effective variations.

The first is the psycholytic therapy and can use several types of drugs (psychedelics, entactogens, even dissociatives have been used). It is based on psychoanalytical methods assisted by moderate doses of a drug that allows the patient safely bring out material for analysis. MDMA is currently in phase II clinical trials for just this kind of use as an adjunct for PTSD psychotherapeutic treatment. The current results are astonishing, way better than any of the currently used chronic pharmacological treatments. The major drawback is in that it requires expert therapists to actually work as intended (manufacturing GMP quality MDMA is way easier that producing a number of experienced therapists). With psychedelic drugs, it is Stanislav Grof that did most of the pioneering work on this method (as well as some other researchers).

The psychedelic therapy was developed in Canada by Osmond and Hoffer (see their excellent book Hallucinogens) and is based on high enough doses of a psychedelic drug that is given in a controlled and assuring setting. It appears that it only works if the patient achieves a mystical experience, for this reason it works more reliably only at very high dosage and after a single application. The mere psychedelic state was not found to be enough. It used to be the most effective treatment for alcoholism in the times when the method was still in use. Most recently it was studied against fear of dying in the Johns Hopkins study on cancer patients and provided astonishing results.


It seems to me that there is something in the compounds that does not require the trip to effect a "cure".

That is what I'm saying all along. The "trip" or the psychedelic state of mind does nothing particularly permanent to a person (except for the astonishing recognition of what the human mind is actually capable of). As in any life situation, it is the insight that such a state can catalyze that is needed for any permanent change.

.



Quote: Originally posted by Nicodem  


For example, even in the presence of a therapist, it was discovered that at certain dosages (30-40 mg), MDMA actually has an anti-therapeutic effect in PTSD treatment (performing worse than the control group using non-drug therapy). Take a too low a dose of MDMA and you do more damage instead of curing the patient. There is a similar problem with psychedelics. People tend to use too low dosages which are not enough for the psychedelic method, so they achieve nothing. Such low dosages might be fine for the psycholytic method, but this generally only works well in the presence of a therapist. I might tend to guess that in the absence of a therapist, a too low a dose might even worsen things.

.



I am in NO WAY debating what you say. I am only trying to understand it.
Is my confusion due to the fact you are discussing different applications for different treatments? (careful on the question "is my confusion due to". I'm already laughing...);)


Quote: Originally posted by Nicodem  

Quote:
I know with psilocybin you do not need to take trip levels for it to do wonderful things for you. Just a few grams a day, just like a multi-vitamin but three times a day, and life is easier.

I assume you meant milligrams rather than grams!
Anyway, what benefit would psychedelics have over any other drug, if you would have to use them chronically as you propose? It's not healthy, it's unpractical and it is pointless given the alternatives. There are already drugs that are used in such a way and they do not cure the illness, just relieve you of symptoms. I believe the only way psychedelics can have any advantage over other drugs is in that they can be used acutely and still give better results than any chronically applied drug. Obviously, the exception being the treatment of allergies and rheumatoid arthritis as discussed earlier in this thread, where certain psychedelics like DOI or DOB show anti-inflammatory activity at sub-threshold doses (but this would be in the same context as the current use of ergometrine and ergonovine at sub-threshold doses).

.



This part I understand you point somewhat more.
Low dosing Psilocybin can, and should be considered as a "band aid". I will tell you tho... for ME it is one hell of a band aid.
I have done mushrooms by the pound in days gone by, and tripped for days at a time. I've had the deepest of discussions with very close friends, and not once did I feel that anything was different in my life afterwards.

When my friends came along and told me about their low dose regime I was instantly curious (of course), and tried it for thirty days. Day ONE, and it worked. The only sensation I had out of the "norm" was a sort of flowing completeness with my surroundings where I could select what I wanted to feel, and exclude what I did not. Everything from the microwave sensation of the Florida sun burning you to toast to the thought in the back of your head that has bothered you for weeks.

This to me was showing that with psilocybin there was no need for a psychedelic experience for a positive effect to occur.
I would HOPE it could be the same with all the other compounds that we have discussed.

Maybe compare this to opioids for a moment... Take a Percoset, and your fine. The propose of the drug is realized, pain gone. Take 3, and it's a different ball game.

In typing this I see your point in some of the above posts... Take a 1/4 of a Percoset, and perhaps nothing... I guess they are different topics but I see the point.


Quote: Originally posted by Chemosynthesis  


If the initial post's source article is to be taken as clinically and statistically valid, it does appear as though psychedelia is not necessary for long lasting antidepressant effect at least in some patients with some ayahuasca compositions, though statement either way is tenuous due to the vast variation in depression presentation and durations. It is possible that psilocybin requires psychedelia for optimum therapeutic effect (tentatively indicated in PMID: 21674151 and similar to smoking cessation in PMID: 25563443) whereas DMT or DET can be used for therapy without the psychedelia itself being the integral component in therapy due to ligand specific signal pathway bifurcation, receptor plasticity, etc. It is also possible that psychedelia itself is just part and parcel of the optimum dose of psilocybin under normal administration, but locking a g-protein subunit in an inactive conformation with one of the tools I mentioned earlier to alter psychedelia and/or hallucination in some manner would not necessarily impact treatment as the two may be separable. Another possibility in future treatment is that some of the compounds' psychoactivity other than antidepressant action could be obviated entirely by very specific regional targeting and distribution in subregions of the brain, or mimicked by transcribing magnetic stimulation, implants, etc.


Hell. I'm retired enough. Maybe I'll just move next door to Johns Hopkins research center, and volunteer to be their lab rat for the next few years.
I wonder if they'll let me ride my Triumph around the halls?




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[*] posted on 18-5-2015 at 01:05


I definitely agree on "entactogen" and "empathogen" terminology being synonymous, though the "debate" is useful in seeing some of the interesting linquistic questions that get involved during the course of discussion for people not actively aware of the debate. I disagree on the clarity of distinction between many psychedelics and entactogens, particularly since varying effects can be had at different doses. Unless one takes a Taber's style definition of "entactogen" which ties the term inherently to "any psychoactive drug similar in chemical structure to MDMA[.]" Even with SAR, MDMA itself has somewhat controversial pharmacology still, in at least some aspects ( ex. Citation claiming this PMID: 24403876). I believe there is still an element of ambiguity in the terms and scientific usage, in much the same way general analgesics and anesthetics can vary in SAR to produce a clinical effect. The Taber's definition goes on to state "Members of this drug class are derived from 1-(1,3-benzodioxol-5-yl)-2-butanamine." I think this would clearly and erroneously rule 5-APB (arguable) or mephedrone (more clearcut) as a pure stimulants, rather than having a position in a continuous spectrum of clinical effects. I would also say this is arguably very wrong, as mephedrone very interestingly substitutes in animal models for entactogens at a certain dose range (PMID: 23881878). NIDA still does characterize MDMA as a stimulant hallucinogen, from their description in http://www/drugabuse.gov/publications/drugfacts/mdma-ecstasy-or-molly
I believe argument to support this is probably drawn from animal generalization studies such as PMID: 9259001
Of course, given that methylone substitutes for MDMA, but not DOM in trained rats complicates this paradigm (PMID: 22169943). Training and cross-generalization at varying doses may cause artifacts in testing, as well as other phenomena. Some animal studies found AMT to generalize to DOM. (Biochemical Pharmacology, 32, 1267-73) And potentially the training drug used may also bias a study depending on whether or not DOM, (+)LSD, mescaline, DMT, or 5-OMe DMT is used. Compare PMID 2296621 with PMID 8584618. Very importantly, discrimination is not necessarily considered an all-or-none binary response or generalization or discrimination. In PMID: 21474568, one can see varying degrees of discrimination/generalization even among classical psychedelic hallucinogens. Exactly where to draw a line in activity can be murky. In fact, this kind of quirk is used as rationale for the authors in PMID: 6805022, with different psychedelics:

"The psilocybin cue generalized to psilocin (the dephosphorylated congener of psilocybin) and to the prototypical indoleamine hallucinogen LSD, but not to the phenylethylamine hallucinogen mescaline. These results indicate that the hallucinogenic effects of these drugs in humans may not be identical with their discriminative stimulus functions in animals, and that these four compounds may not be members of a single drug class. The term 'hallucinogen' may thus be a misnomer in the context of drug discrimination studies in nonhumans."

SAR, unless you want to take somewhat arbitrary cutoff values in terms of affinity, efficacy, or Tanimoto coefficients is difficult to use for discriminatory purposes on promiscuous agents such as combined releaser-agonists. It also can be manipulable depending on what you are using as a definition of activity, and what descriptors you decide to emphasize. Where to draw the cutoff values becomes a matter of personal choice and interpretation in many cases. It also is of limited value in determining integration and downstream effects, particularly when multiple receptors are involved, or neuronal signaling pathways. Some drugs or isomers with greater selectivity are clearly dichotomously categorizable to a greater extent as one or the other type of psychotropic, but there is a great deal of pharmacodynamic overlap otherwise. I can even see this continued to be referred to in descriptions of clinical effects in texts such as An Introduction to Drugs and the Neuroscience of Behavior by Prus, 2013, p329, whereby the term "mixed-stimulant psychedelic drugs" is used as a bolded study term. 2C-B is what comes to my mind first under this term.

Similarly, psychedelia itself is often considered a very open-ended definition, particularly in clinical dictionaries such as Taber's or Black's medical, including the weak/mixed/peripheral or 'atypical' psychedelics, such as salvia divinorum or some cannabinoids. Piperazines, methylone, and some 4-and 5-substituted tryptamine psychedelics generally display some stimulant activity. The clinical manifestations of their effects may be similar at a given dose, much like how dissimilar dissociatives and deleriants are also hallucinogenic, and antipsychotics can be classed in first generation 'typical antipsychotics,' though the context of discussion in terms of pharmacology and dose, clinical application, chemical similarity, etc. can shift designations somewhat fluidly as needed.

But that's my take. I also think any perceived divides in the general classes of these drugs are likely to further overlap with the proliferation of novel psychoactives as research chemicals of differing pharmacological profiles.

[Edited on 18-5-2015 by Chemosynthesis]
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[*] posted on 19-5-2015 at 10:21


The thing that I found most interesting about using ketamine for depression was that a single dose was effective for 2 weeks. The ketamine should have been eliminated in < 12 hours. How does it exert such an effect after it has been eliminated?

Electric shock therapy is also still used for severe depression. Likewise there
is an effect after the current stops.

In electrical circuits (something that I actually know about as opposed to drugs) instability is often caused by unintended positive feedback. In a system with positive feedback, a small trigger can cause the system to latch into an undesired state. To unlatch it, you have to reset the system. The body is full of negative feed back loops which regulate everything from blood sugar to testosterone. Two negative loops can form a positive feedback loop and due to the high degree of coupling between all the biochemical systems there are probably positive loops as well.

Latchup in integrated circuits:
http://wikipedia.org/wiki/Latchup

[Edited on 19-5-2015 by gregxy]
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[*] posted on 19-5-2015 at 11:13


As a general conceptual rule, some drug effects could be either from metabolites, which add a functional half life to the chemical half life of the parent drug (this can be important in benzodiazepines), or (as is often considered relevant in the latency period to clinical onset in SSRI drugs) receptor regulation and other downstream processes end up being important, which can have varying conditions and latencies to onset, as well as durations. Sometimes these signaling pathways can exert effects after a drug is fully eliminated to varying degrees, but the specifics of why are unknown and hard to account for as neuronal networking changes may also occur from drug administration. Some of these are being explored in drug dependence, and specific drug, dosage and dosage regimen as well as individual susceptibility play a role.
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[*] posted on 19-5-2015 at 15:05


Quote: Originally posted by Zombie  
I believe that the compounds we are discussing simply open pathways or close pathways in the brain that allow "improvements" in the thought process.everyone seems to have evidence that this is the case or at least as much as it can be understood, and called evidence.

In some of your posts you attest this is correct, and other sections you dispute this, stating that the "trip" is required for a therapeutic effect.

I don't think I ever said that the trip is required for the therapeutic effect. I may have been misunderstood though. What I said in details above is that the currently most supported hypothesis on how the psychedelic psychotherapeutic method does its magic is by allowing the patient to achieve a mystical experience. This phenomenon of a mystical experience is relatively well researched in psychology and it is understood that by the rule it changes people, sometimes quite dramatically (it allows for the rewiring of your neural networks, if you prefer a more technological analogy). Obviously, you don't need the trip to achieve a mystical experience. People have achieved this in times of intense personal crisis, religious zeal, prayer, meditation, physical exhaustion, as well as intoxications, not necessarily with psychedelics. However, it was experimentally observed that the psychedelics are the least intrusive method to more or less reliably achieve this state under certain conditions (see Roland Griffiths' works). The psychedelic state (the trip) apparently is a platform from which this jump is easier, though it does not necessarily happen, particularly if there is no personal crisis to bring up the necessity. Now, how the mystical experience changes your "wiring", that is the relevant question which is currently unanswered. It is not even known, if it is the cause or the rewiring, or just a mind manifestation of a deeper change (cause or consequence?).

Quote:
I am in NO WAY debating what you say. I am only trying to understand it.Is my confusion due to the fact you are discussing different applications for different treatments? (careful on the question "is my confusion due to". I'm already laughing...);)


Of course I'm discussing different treatment approaches. I explicitly explained that. The two may not even share the same therapeutic mechanism. The psycholitic method is certainly simpler to comprehend as it is more or less an enhanced psychotherapy (think of it as years of psychotherapy condensed in a single session). This is more or less a modern version of the shamanic therapeutic session (with or without drugs involved), except that shamans generally use drama to achieve the healing, while modern psychotherapy relies more on the patient-therapist transfers.

Like I mentioned, the psychedelic therapeutic approach is more of a mystery because it is not exactly clear how the mystic experience, which is apparently a mind phenomenon with a certain content, affects the brain "rewiring". I think once we'll understand how this works on a neuronal level, we will be able to understand the obviously related mechanisms of external events or environments that trigger depressions, PTSD, addictive behaviors, phobias, and all the other neurosis based disorders. Ultimately, this could lead to some understanding on how the mind and the body are interconnected. The theory of neuronal plasticity was the first step in this direction. We now have plenty of other evidence, but don't yet have enough to see the whole picture. Psychedelics could make a change.

I believe this is a promising research topic, as we are not talking about ibogaine, reserpine, or electroconvulsive therapy that affect the neurochemistry of the brain on a single acute exposure. There was never found any evidence that psychedelics do anything of that kind. I also think ayahuasca is not suitable candidate for such studies, because I'm quite convinced the harmala alkaloids can cause long lasting physiological changes to the brain, though apparently beneficial. I hypothesize that in ayahuasca the psychedelic effects from DMT and the hallucinogenic/physiological effects of harmala alkaloids act synergistically in respect to the therapeutic effect. For this reason ayahuasca would be a poor choice for researching the neurotic disorders triggering mechanisms. DMT alone yes, but ayahuasca might actually induce physiological changes independent of the mind manifestations, kind of like ibogaine.

Quote:
I have done mushrooms by the pound in days gone by, and tripped for days at a time. I've had the deepest of discussions with very close friends, and not once did I feel that anything was different in my life afterwards.


You sound so convinced, but do you have actual evidence, like a control Zombie that remained naive from prior that point in life afterwards? Can you imagine how your life would have been, if you would now at your age be oblivious of the psychedelic experience? Perhaps you have not been "healed" from anything, that I can agree, assuming there even was something to heal in the first place (I don't know what kind of neuroses zombies have, but I guess fear of dying may not be relevant to them). Yet, are you definitively sure that afterwards you did things exactly as you would have, took the same decisions, adhered to the same ideological systems, had the same appreciation of life and others? Would you even know?

The same questions can be asked on a societal level. We tend to underestimate how much art and science has been inspired during the psychedelic trips. How much movies, music, literature and other art that affects the society was actually conceived with the help of psychedelics? How many new concepts and philosophy? I'm also quite sure a lot of scientific and technological breakthroughs have been impacted by psychedelics. Unfortunately not many are as courageous to speak out, like the Nobel laureate Kary Mullis did, who invented the polymerase chain reaction that revolutionized the biochemistry and had a huge impact on civilization. Speaking about getting the inspiration by using psychedelic drugs is risky and can cost you more than just the employment, so we know nearly nothing about it.

Quote:
This to me was showing that with psilocybin there was no need for a psychedelic experience for a positive effect to occur.
I would HOPE it could be the same with all the other compounds that we have discussed.


I think, the effects you talk about are common to practically all the psychedelic drugs. Except of course DMT, 5-MeO-DMT and similar metabolically unstable ones. You can use LSD or DOx compounds to get the same, and unlike the mushrooms it lasts from the morning to the evening. However, I'm quite sure this is not a healthy practice. Chronic use of any drug brings way more hazards than acute use. I would seriously recommend against it. Acute effects of psychedelic drugs are well known and these drugs do not pose any major physiological risk to healthy humans in normal dosages, but nobody ever seriously studied chronic exposures. (I feel like I keep repeating myself in ever longer explanations of the same issues - just don't say you still feel confused!)




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[*] posted on 19-5-2015 at 15:18


Quote: Originally posted by Nicodem  
as well as intoxications, not necessarily with psychedelics

OK. Experiment underway.




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[*] posted on 20-5-2015 at 16:44


Gotta love ya Mr. Aga!

Mr. Nick... I do understand your concepts a bit better. I have an analytic mind where ideas have to be complete to make sense.

I'm not simplistically endowed, and gaps in a thought leave me free to roam around in space, where anything is possible. I have to envision anything as a process with a beginning, and an end. Every step of the process has to make sense for me to accept it.

That's why I have a difficult time digesting some of this.

Now I would HAVE to think that much of the "brain wave" scans that we all see, could be put to perfect use in following these chemical trails. Is it unrealistic to think that blood chemistry or whatever it is called could be sampled to detect real time changes in the brain?

Couldn't you just follow a brain "map" in real time, and monitor changes in blood chemistry to see what is happening?

Or taken a step further... Since we know what receptors are being triggered, and which ones are blocked, couldn't we simply adjust the blood chemistry to make these changes "full time?
Have animals been tested in this way? Have humans?

I know that's an off couple of questions. I have to find a better way to phrase it...

Take a known "emotionally healthy" person, their blood chemistry, and their brain "map". How do these factors relate to a "troubled person? How do they relate to a person using psychedelics? Does the healthy persons "base line" compare to a troubled persons base line while the troubled person is under the influence of psychedelics?

It would all seem to be less of a "shotgun" approach if there were more constants in the studies. As in every study had to use the same methods for comparison.


Lololol... as for my control zombie, I just don't know what happened to him. Last I heard he was in Hoboken, New Jersey.
Something about a band, and a blue haired woman. That was decades ago so she's most likely grey now.

I think I nailed the reason I didn't see any changes tho in a previous post. I expected people to change after I tripped. Go figure. Maybe I didn't do enough? :D




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[*] posted on 20-5-2015 at 20:51


mentioI menmentioned a technique that has been used for realtime brain chemistry detection called in vivo micodialyasis. The problem is it is an invasive surgerh. requiring a shunt to be fed into specific observed regions of the brain.

Also, get ready to see me in Whimsy once my request is processed.
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[*] posted on 20-5-2015 at 21:45


Quote: Originally posted by Chemosynthesis  
mentioI menmentioned a technique that has been used for realtime brain chemistry detection called in vivo micodialyasis. The problem is it is an invasive surgerh. requiring a shunt to be fed into specific observed regions of the brain.

Also, get ready to see me in Whimsy once my request is processed.



I'm going to look up "vivo microdialyasis". While the idea sounds a little less than ideal... What about radioactive tracing?
I don't know much about it but I can see this as a non invasive alternative. Say you do whatever it takes to irradiate a molecule (DMT, Psilocin, whatever), and track that. I assume this will show the pathway but could you correlate changes in blood/body chemistry in real time from that?


Whimsy eh? Request? Sound awful cryptic!!! :o
Should I sign on thru a Proxy before viewing? ;)




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[*] posted on 20-5-2015 at 21:51


Radioligand binding assays, among other things, can tell a lot about drug localization and some metabolites, but you run into resolution issues and not seeing what goes on from the receptor through a signaling cascade. They can also require more paperwork for anything radioactive, which some labs really want to avoid.
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[*] posted on 20-5-2015 at 22:41


Quote: Originally posted by Chemosynthesis  
Radioligand binding assays, among other things, can tell a lot about drug localization and some metabolites, but you run into resolution issues and not seeing what goes on from the receptor through a signaling cascade. They can also require more paperwork for anything radioactive, which some labs really want to avoid.



The "signaling cascade" would be perhaps the most important aspect, correct?
Knowing what is triggered, and what is "shunted" would go a long way toward a real therapy. Why is that so difficult to study? I mean aside from volunteers not wanting micro probes in their brain, and radioactive juice being the bottom of the happy hour list...

Isn't there research into finding better ways to map the brain? What about the thing I read (somewhere) about living organs outside the human body? Can this be done with a brain?

I know these are rudimentary questions at BEST but I find it so hard to grasp that so little is known in the most important aspect of humanity.


Edit:
There are a bunch of articles like this one... http://www.fastcoexist.com/3015553/futurist-forum/not-scienc...

Fiction or fact?

[Edited on 5-21-2015 by Zombie]




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[*] posted on 21-5-2015 at 08:22


Quote: Originally posted by Zombie  
Now I would HAVE to think that much of the "brain wave" scans that we all see, could be put to perfect use in following these chemical trails. Is it unrealistic to think that blood chemistry or whatever it is called could be sampled to detect real time changes in the brain?

I already cited the Carhart-Harris and Nutt, et al. studies for the fMRI measurments that were crucial to determine the mechanism of action of psychedelic drugs (in short, the inhibition of certain brain hubs that direct or filter out information from being processed; see also their new study on DMT and ayahuasca DOI: 10.1523/JNEUROSCI.2063-13.2013). The same group also uses magnetoencephalography (MEG) and EEG.
See also Vollenweider's studies that managed to connect brain scanning results with psychometric results, particularly nicely with the psychological indicator for mystic experiences (so called "oceanic boundlessness").
Quote:
Couldn't you just follow a brain "map" in real time, and monitor changes in blood chemistry to see what is happening?

There are several techniques to monitor the activity of brain regions. See the already cited studies.
I don't think I understood your question about "blood chemistry". The activity is in the brain, not in the blood. There are very few applicable markers of mental states detectable in the blood (mostly partially physiological states, like some stress markers and similar). Most neurotransmiters and neuromodulators in the brain are used also as hormones in the periphery, serotonin included, so it is not possibly to use their metabolites as markers of increased release in the CNS. Evolution found an economic way to use the same ligands and receptors in unrelated systems.
Quote:
Or taken a step further... Since we know what receptors are being triggered, and which ones are blocked, couldn't we simply adjust the blood chemistry to make these changes "full time?
Have animals been tested in this way? Have humans?

You mean by using 5-HT2A agonists? Yes, millions of people do that, except that it cannot be full time as luckily enough the receptors rapidly internalize.
Or you can chronically use various more or less selective releasers or enzyme inhibitors, like the SSRI or MAOI. Of course, they are only selective on the ligand side, which means that they affect all the receptor subtypes, and they will still cause downregulation. That's why chronic use of these drugs is such a drag.
Besides, for chronic application, only the 5-HT2A antagonists and inverse agonists were found to have antidepressant activity. Agonists actually increase depression symptoms, at least in the forced swim test animal model of depression (measuring the strength of the will to survive in rats) and also some other models like the tail suspension test (for a review, see DOI: 10.3389/fphar.2015.00046). There are actually a few atypical antidepressants on the market whose main activity is 5-HT2A antagonism (see nefazodone and similar). Yet, things are not as simple, as it turns out that 5-HT2A receptor genetically knocked out mice are actually more depressed that wild type mice.

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Take a known "emotionally healthy" person, their blood chemistry, and their brain "map". How do these factors relate to a "troubled person? How do they relate to a person using psychedelics? Does the healthy persons "base line" compare to a troubled persons base line while the troubled person is under the influence of psychedelics?


Are you asking if neuroses cause detectable changes in the receptor density, neuronal firing frequency, and so on, all the way to neuronal plasticity? Of course they do. That is how the brain works. Every event, every piece of information, every neural signal that enters your brain, can and generally does physically alter the brains. There is no such thing as the concepts of hardware and software to be applied for the brains. Regardless of how complex the animal and its brain is, neuronal plasticity is at the very base of its functionality. In fact, that external information causes physical and observable changes in the brain was first discovered in some simple slugs, if I remember correctly.

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It would all seem to be less of a "shotgun" approach if there were more constants in the studies. As in every study had to use the same methods for comparison.


Would you mind to cite these studies with "shotgun" approaches so that we at least know what you are talking about.

[Edited on 21/5/2015 by Nicodem]




…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)

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