Sciencemadness Discussion Board

Ayahuasca psychedelic tested for depression

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Mesa - 20-4-2015 at 10:44

The author of that drugs forum thread is the same guy who claimed ingesting certain combination of essential oils such as safrole, myristicin, elemicin, etc. a few years back. Hes posted rediculous claims with longwinded and hilariously flawed explanations on psychadelic drug forums for over 7 years. Someone with the old Mycoptopia forums archived would find a couple of them.

Edit:
link to his previous "work."
https://drugs-forum.com/forum/showthread.php?t=156755


[Edited on 20-4-2015 by Mesa]

Chemosynthesis - 20-4-2015 at 14:16

Quote: Originally posted by CrimpJiggler  


Well according to the studies mentioned here: https://books.google.ie/books?id=FUM-AwAAQBAJ&pg=PA129&a...

Harmine with an IC50 of of 0.013 microM is a slightly more potent MAOI than harmaline (0.016) and both of them being more potent than THH, but a few anecdotal reports here:

1. Potency at MAO-A inhibition has nothing to do with psychedelia... nothing in and of itself, that is, nor necessarily modulatory other than in a pharmacokinetic sense of altering brain compartment psychedelic amine concentrations, and is discussed at length in the very post I linked to. Please go back and read it. Also, this is rat data, and may have model/assay artifacts.
2. If you find a source claiming psychedelia, please compare with the date of the McKenna paper I cited in my post, claiming to debunk prior research methodologies.


Quote:
https://drugs-forum.com/forum/showthread.php?t=68849
seem to suggest that harmaline has more potent effects when taken alone than harmine. Maybe this is due to different mechanisms of action though, i.e. maybe harmaline has stronger SSRI effects than harmine.

Something I find interesting is how ingesting these beta carbolines by themselves induces psychedelic effects. If it was just a matter of an SSRI in combination with an MAO-A inhibitor then you'd think that say moclebimide + sertraline (in sufficiently low dose to avoid serotonin syndrome) would induce psychedelic effects but thats not the case AFAIK.

1. There is no current scientific evidence of beta carbolines being psychedelic, unless you have new peer-reviewed citations saying otherwise. Potency is irrelevant unless you put it into context, which depends on the receptor, receptor source (clonal human, animal, etc.) and the assay for comparative purposes.
2. Binding promiscuity is far more nuanced than that, and I have seen no evidence that brofaromine, moclobemide, or some novel substitutes can't provide a clinically indistinguishable effect, though that is what pharmacological studies should be for determining. I very specifically mentioned the former in my posts as a test case due to its SERT inhhibition.
3. Not all of the receptor effects are necessarily of clinical significance. Sometimes you get washout indistinguishable in subjects.
4. Please, don't speculate on SSRI activity if you don't put it with data. What you're speculating on is in now way differentiable from stronger MAO-AI potency, which has already been discussed. I have passingly mentioned the general canonical MAOI/tyramine/catecholamine secretion pathway.
5. Pseudonymous online forums with no scientific studies as a source? We are talking about substances that affect your mental and psychological state here, so self-report in anecdotal quantities is even more questionable than otherwise, which is usually hugely so. Don't believe everything you read on drugs-forum. Some of their much-vaunted members suggest chemically impossible reactions for home narcotic manufacture, and at least the majority of their pharmacology is of dubious quality, at best. I don't browse there often, but I have only seen a couple posters appear to really know what they were talking about from a pharmacological perspective, and supposedly have an academic background in it.

CrimpJiggler - 22-4-2015 at 03:43

Chemosynthesis: I get your points, I'll be more careful about how I post about pharmacology related things. You have some pretty extensive knowledge, I'll give that thread you linked a read when I have the time.

Chemosynthesis - 22-4-2015 at 05:54

Thanks. I do want to say that I believe the data you linked to is very important as a rough gauge of just how potent these reversible MAOI alkaloids can be, despite the difficulty in cross-comparison. 0.002 and 0.003 micromolar hMAO-A inhibition or 0.013 and 0.016uM rMAO-A come to within an order of magnitude of the Hoffer and Osmond claims (at worst, to be conservative) vs. previously cited 1.55±0.12 iproniazid pig data in Neuro Endocrinol Lett. (2010); 31(5): p645-56 despite using different receptor sources and likely different apparati (didn't bother checking). As wary as I am of cross-comparing affinities between species, it's not uncommon and I do it for preliminary data. Using the same pMAO-A data (1105uM) for moclobemide makes quite the comparative statement, whether this bears out in clinical reality or not.

Nicodem - 22-4-2015 at 05:59

I have little time so I can't reply to all the issues I would like to.
Chemosynthesis, thanks for the post where you review the toxicology of beta-carbolines. It is nice to have such information condensed in one place.
Quote: Originally posted by Chemosynthesis  
I would like to note that your claim "In fact, the harmala alkaloids alone are hallucinogenic, though they are not psychedelic" is disputed in The Heffter Review of Psychedelic Research (1998)1: 65–77. McKenna is first author, if it makes a difference.
"The notion that the ß-carbolines, by themselves, are hallucinogenic and thus contribute to the overall hallucinogenic activity of the ayahuasca beverage, was based on flawed earlier research (Naranjo, 1967) and has been discredited (Callaway, et al., 1997).

I'm quite sure that Dennis McKenna (not to be confused with his brother Terence) never checked Callaway's claims before he wrote that. Rather trust me, I know the harmala alkaloids are hallucinogenic and I know this experimentally. The ethnobotanists who researched the traditional use of Banisteriopsis caapi and Peganum harmala have no doubts about them being hallucinogenic. Richard Evans Schultes studied the use of B. caapi and found it is often used alone, as a training visionary aid by the apprentice shamans. I already mentioned why is this so. The harmala alkaloids produce visions with a story-telling quality, which is unlike the psychedelics, but unlike psychedelics they require skills for them to work properly. It is kind of like a meditation. It only works once you master the technique - hence the use in training. It is a skill that has transformative properties and comes handy for the shamanic "therapeutic techniques".

Of the harmala alkaloids, harmaline is the most potent hallucinogen. Harmine and tetrahydroharmine are nearly inactive. See Shulgin's review of the bioassays:
harmaline, harmine, and tetrahydroharmaline. You can also easily find some articles about the clinical observations of patients poisoned with Peganum harmala seeds where hallucinations are described as a typical symptom.

CrimpJiggler is however wrong in one thing. None of the harmala alkaloids was ever found to be a psychedelic. Their hallucinogenic effects have very little in common with the typical psychedelic effects. They fail already in the basic criteria: they don't induce the psychedelic state of mind. In addition, the closed eyes visuals are of a very different nature, the open eye visuals are mainly limited to tracers, the nausea and the body load is way more than psychedelics cause, etc..
In fact, I would be extremely surprised, if anyone ever discovered a psychedelic based on the beta-carboline structure. Their restricted conformation in not in accordance with the well known structure-activity relationship for psychedelics.

Mesa - 22-4-2015 at 08:33

I think it's important to point out that the vast majority of Harmaline/harmine/THH specific bioassays mentioned here are little more than crude alkaloid extracts without them giving any results of testing/analysis(Shulgin was reputable enough to be excepted.)
Claims of hallucinagenic or psychedelic activity should really refer to "harmala alkaloid extract" rather than anything more specific unless there is some evidence of analysis.

Likewise with drawing conclusions from ayahuasca experiences. Use them in discussions of ayahuasca, fine. But they aren't even close to reliable evidence of activity etc. of specific compounds that are assumed to be present in the brew.

[Edited on 22-4-2015 by Mesa]

Chemosynthesis - 22-4-2015 at 09:12

Nicodem, thank you both for the compliment and for both your experiences and the interesting (and unknown to me) ethnopharmacognostic uses of harmala alkaloids as training aids for shamans.

This is interesting, and I am not sure of my thoughts on the matter at the moment, but (as with poisoning, ex. aforementioned IJPT(2002) vol.1, no. 1 p1-4), the large doses required for reported effect, onset and the reported symptoms according to Shulgin with pure substances seem to indicate that a mild/moderate case of serotonin syndrome could account for this. This had been my previous supposition to such reports, but this may very well be too simplistic on my part.

Interestingly, at least in treated rats, the article Exp Neurol. 1987 Jun;96(3):703-19 concludes "[their] data describe a complex convulsive myoclonic syndrome that is behaviorally related to but pharmacologically distinct from the serotonin syndrome, which may be useful in studying serotonergic-benzodiazepine interactions in the pathophysiology of myoclonus". I'm not sure if I entirely buy their conclusion based solely on poor efficacy of 5HT antagonists given 1. the difficulties in characterizing a heterologous clinical syndrome with one specific pharmacological cause, 2. recent understanding of animal model problems (Behavioural Brain Research (2015) Vol. 277, p204–210), and 3. other papers' noting implications of possible adrenergic storm, which could certainly confound the standard head-twitch test, but I am not familiar enough with animal models firsthand to definitively dispute this, nor does it appear such an in-depth investigation has been done on such possible variations. It would be interesting to me if elucidation upon the syndromatic differences and their applicability to various species were eventually determined. Dexmedetomidine might be a good agent for this.

Nicodem - 24-4-2015 at 09:51

I just had an interesting conversation with a friend, also a chemist, that touched on the topic of chronic use of sub-threshold doses of psychedelic drugs (the idea Zombie keeps promoting and I don't like). Since I know this friend suffers from hay fever every year when spring starts, a few months ago I emailed him the two references that I also posted here in my first reply, believing he would find them interesting (DOI: 10.1124/jpet.108.143461 and 10.1371/journal.pone.0075426).

Today we meet after a long time and he told me that lately he did an experiment in connection to those two articles. One morning on the way to his job he had a fairly strong allergic attack to pollen (burning eyes, sore throat, nose, etc.). Instead of taking antihistamines, which he anyway dislikes due to their negative psychoactive side effects, he took about 0.25 mg of DOB sublingually. Now, this is a threshold dose for psychoactivity, but since it is a threshold of a psychedelic, it does not affect the daily performance in a negative way. What's interesting and what surprised me, was that he claims that all the hay fever symptoms disappeared in about 15 minutes and did not reappear for the rest of the day. He was very enthusiastic and told me that he is interested in finding the threshold for this type of activity. He did retry this on a later occasion with a minuscule dose of about 20 micrograms, but he found this test "inconclusive" (as far as I understood him, he found the symptoms alleviated, but they were not very strong in the first place).

When it comes to allergies, I'm always skeptical for psychosomatic responses. And one or two experiments on one subject with self reported results is not something to take conclusively. But in this case, there is a known mechanism of action to support there could be some truth in this. In any case, he will continue with his experiments and will even suggest this to a friend that is allergic to cat hairs. The claimed relief of symptoms in about 15 min suggest a completely peripheral mechanism of action. DOB usually takes at least 1 h for centrally mediated effects and he indeed experienced central effects only a couple of hours later. He also said that the experienced threshold effects made him more effective and creative at the job, something that did not surprise me at all.

The two articles by B. Yu, C. D. Nichols and others report that DOI had truly remarkable potency for anti-inflammatory effects (in the pM concentrations!). Two other similarly potent psychedelics were tested, but were found much less potent against TNF-alfa induced inflammatory response. The current hypothesis is that this is due to second messenger discrimination among these 5-HT2A agonists. The authors did a few experiments that indicate "that PKC plays a critical role in the mechanism of action of 5-HT2A receptor-mediated inhibition of proinflammatory markers." There is probably no dramatic difference between DOI and DOB when it comes to the activation of the PKC mediated second messenger system, though I don't think this has been measured yet.

The downside of all this is that the originator pharmaceutical companies would likely not be motivated enough to invest in the trials. Enhancing peripheral selectivity and increasing the selectivity for PKC could all be done, but the problem is that the compounds would unlikely be strongly patentable, because the SAR of psychedelic drugs is too well researched and all the most attractive structures and structural families are already disclosed (so no Markush structures). It might be possible to design a novel compound just for the sake of a narrow patent protection that would efficiently protect against the generic drug companies. But there is no way to protect against any me-too drugs, therefore giving not much of a head start from the IP perspective (a few years of advantage can mean billions of $). I guess it might be possible for some company to see enough commercial profit to motivate for paying the clinical trials, but that the compound would be only the third psychedelic drug in the pharmacopoeias, is certainly a drawback.

Chemosynthesis - 24-4-2015 at 13:24

That is curious. Interesting to me is DOB and DOI, though originally thought to be 5HT2A specific, are now thought to be be 2A/2C non-specific, and that both of these receptors canonically function through a Gq (IP3/PLC/PKC) signaling pathway. Prophylaxis and challenge attempts with one of the -serins (such as volinanserin) may help distinguish some effects.

I think it would be very cool to use new intracellular probes (DOI: 10.1016/j.bmc.2014.04.035) to elucidate some of the second-messenger mediated, downstream effector characteristics of these with regard to such ligands, which may have previously been considered a more daunting task due to their PTX-resistance. Labs like Lefkowitz' and Luttrell's, among others, should be good sources of beta arrestin and functional selectivity techniques to apply towards GPCRs such as this. At risk of making a terrible pun, I should probably disclose heavy bias towards their works. Another aspect of this I find interesting which may free things up on the intellectual property front is that potential glaucoma drug GLC756's agonism of beta-2 adrenoceptors and antagonism of alpha-2 adrenoceptors are implicated in decreased TNF-alpha in rat models (PMID:16938291).

Comparisons with AL-34662, another peripherally-acting glaucoma candidate drug, may be fruitful due to the latter's structural similarity to psychedelics. If these drug candidates could be used for irritable bowel diseases, rheumatoid arthritis, and other conditions with a simple abbreviated new drug application, things could get very interesting on the market even if efficacy isn't entirely optimized for what would otherwise be off-label use.;)

Nicodem - 25-4-2015 at 01:07

I feel a bit silly for not checking what new studies that group published lately. There is at least this newer article that gives quite optimistic results:

Serotonin 5-HT2 receptor activation prevents allergic asthma in a mouse model
Felix Nau Jr., Justin Miller , Jordy Saravia , Terry Ahlert , Bangning Yu , Kyle I. Happel , Stephania A. Cormier , Charles D. Nichols
American Journal of Physiology - Lung Cellular and Molecular Physiology, 2015, 308, L191-L198
DOI: 10.1152/ajplung.00138.2013

The report received an lots of positive media attention in the medical news:
http://www.medicalnewstoday.com/articles/289211.php
http://www.news-medical.net/news/20150210/Psychedelic-drug-p...
http://www.eurekalert.org/pub_releases/2015-02/lsuh-lhn02091...
http://hometestingblog.testcountry.com/?p=28149
(...and plenty other such news)

Also, by searching the net for anti-allergic properties of psychedelic drugs I found dozens of anecdotal accounts of allergies disappearing during the trips (too many to list links, search for allergy+psychedelic and the like). Some even claim that their allergy disappeared forever after a psychedelic experience.

Quote: Originally posted by Chemosynthesis  
That is curious. Interesting to me is DOB and DOI, though originally thought to be 5HT2A specific, are now thought to be be 2A/2C non-specific, and that both of these receptors canonically function through a Gq (IP3/PLC/PKC) signaling pathway. Prophylaxis and challenge attempts with one of the -serins (such as volinanserin) may help distinguish some effects.

In reality, there are very few psychedelics that have a good selectivity for 5-HT2A over 5-HT2C receptors. Highly selective agonists have only been discovered relatively recently (a very selective ligand N-BOH-2C-CN is now available, DOI: 10.1021/cn400216u). Only recently have I read reports of (non-official) human trials with relatively highly selective 5-HT2A agonists. In fact, it was only a dozen years ago that the mechanism of action could be pinpointed to 5-HT2A agonism (based on animal models, using antagonists with some selectivity for 2C). Before that, there was always this lingering possibility that the 2C receptors could be involved beyond just modifying the experience. It is still speculated that some receptors add, or even act synergically with the 5-HT2A to induce the psychedelic state of mind. The role of 5-HT1A is often speculative (DMT and several other tryptamine psychedelics have a high affinity to it). One of the dopamine receptors might also contribute (LSD is among the least selective 2A ligands with affinities to 5-HT1A and some D receptors as well, but is also nearly the most potent psychedelic, perhaps because it activates just the right combination of receptors for a synergistic effect).

Chemosynthesis - 25-4-2015 at 05:11

That is, rather unfortunately, a really prevalent trend in these highly homologous receptors, which is precisely why I made light of antagonist treatment; I definitely believe that antagonist blockade will be more immediately insightful than sole agonist due to the higher current selectivity in antagonism. 8-OH-DPAT's agonist promiscuity seems less useful than the antagonist derivative UH-301's specificity, certainly giving credence to 1A modulation in the routine head-twitch test (PMID: 8870031), though other behavioral studies appear to question the validity of this in actual drug discrimination (PMCID: PMC3763814). Counterpart 1A agonists such as befiradol and robalzotan lagged behind in development by several years, as seems to be the general trend (compare YM-348 with RS-102221 or SB-243213 in terms of selectivity and discovery). Correspondingly, many of the 5THR antagonists have clinical data behind them, and may be more amenable to ANDA trial filings than some of the newer peripheral agonists that drug companies have been developing.

Localization of receptors on the neuron might be the next big extraneuronal challenge, and research for pre/post-synaptic specificities in ongoing. Volinanserin in particular seems like one of the most selective 5-HT2A -serin series developed from (DOI: 10.1002/ddr.430130104), and has been used in cocaine addiction studies (PMID:19331461). Having different pre/challenge groups with something such as primavanserin and/or ritanserin, which has safety and some efficacy profiling done in humans and shows known 2A/2C specificities intermediate to volinanserin should allow good discrimination and a better understanding of additive or synergistic effects between many of these presumptively involved receptors (PMID: 24016069). As for determining any downstream differences in DOI and DOB, it might be possible to correlate FLIPR assays with TNF-alpha inhibition and avoid utilizing some of the G-protein subunit/RGS inhibitors.

[Edited on 25-4-2015 by Chemosynthesis]

Classical hallucinogens as antidepressants?

solo - 25-4-2015 at 06:22



Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles
David Baumeister, Georgina Barnes
Ther Adv Psychopharmacol
2014,1–14,
DOI: 10.1177/2045125314527985


Abstract
Hallucinogens have been part of spiritual practice for millennia, but controversy surrounding their mind-manifesting effects led to their proscription by the mid-20th century, largely without evidence of harm or toxicity and despite nascent data suggesting therapeutic utility in treating depressive illnesses. This review explores their pharmacodynamic actions and the current limited data on their clinic effectiveness. These drugs appear to exert their psychedelic effects through their agonist or partial agonist activity at the serotonergic 5-HT2A receptor, though they also have affinity for other metabotropic serotonin receptors. Hallucinogen binding affects a wide range of intracellular signalling pathways, the precise nature of which remains incompletely understood. They alter the serotonergic tone of brainstem raphe nuclei that project through the brain; they interact with receptors in the prefrontal cortex altering connectivity patterns and intracellular functioning; and they disrupt inhibitory control of sensory input via the thalamus to the cortex. The serotonergic system has long been implicated in anxiety and depressive disorders, and is a major target of most existing antidepressants. Classical hallucinogens alter the functioning of this system, but not in the same way current medications do: whilst there are identified receptors and neurotransmitter pathways through which hallucinogens could therein produce therapeutic effects, the neurobiology of this remains speculative at this time. There is currently an extremely limited but growing literature on hallucinogen safety and clinical application. The drugs appear well tolerated by healthy controls and clinical populations, and the rapid tolerance to repeated administration might reduce the possibility of dependency. Clinical trials reported over the past decade have generally shown positive therapeutic potential, but they are notably few in number. Legislative policy has had a freezing effect on evaluation of these compounds, a better understanding of which might improve our knowledge of the processes involved in consciousness, the neuropathology of depression, and potentially open up new pharmacological therapies.

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Chemosynthesis - 25-4-2015 at 07:55

Funny, Nicodem and I were just earlier discussing both the evidence of inflammatory roles and selective antagonism, respectively, in the ayahuasca/depression thread you posted.
Links to posts: https://www.sciencemadness.org/whisper/viewthread.php?tid=62...

What interests me is how various antidepressants have 5-HT2A antagonism (ex. PMID: 14642974, PMCID: PMC3900701, PMCID: PMC446220), and antagonist pretreatments in conjunctions with an SSRI have begun to be investigated, presumably due to more rapid receptor downregulation in combinatorial therapy (ex. 1) DOI: 10.1176/appi.ajp.158.12.2080 ; 2) DOI: 10.1007/BF00167182 ; 3) DOI: 10.1111/j.1471-4159.1993.tb03217.x), and the entire concept of receptor agonists having therapeutic potential as well, while sensible from a molecular neuropharmacological perspective, appear contradictory upon only shallow examination.


What is annoying from a pharmacological elucidation perspective is the relatively non-specific binding of the classical indolealkylamines vs the psychedelic amphetamines DOI and DOB mentioned there, though these are also 5-HT2C agonists in addition to 2A. With the proper antagonist preatments, as mentioned in the linked post of the ayahuasca thread and methodologies such as mentioned in this post's paper, and the continued development of selective agonists such as Ro cmpds (PMID: 9694950) and more recent developments with the structurally different lorcaserin (ISSN: 1082-801X, PMCID: PMC3047218), as well as further probing into the intracellular signaling cascade components of GPCR activation (PMCID: PMC3047218, PMID: 24818958), the likelihood of tailoring treatments to the presumably heterologous psychological disorders while minimizing toxicities increases despite regulatory controls on many psychotropic compounds.

S.C. Wack - 25-4-2015 at 10:08

IIRC several years ago I posted somewhere else that I found the mostly purified harmine/harmaline mixture from harmala extract to have surprising subtle residual antidepressant effect, and might be useful for same...in no way was there any other effect at the doses I tried. There were only a handful of doses before I ran out. It's a shame the best harmala vendor is in Iran, which I'd rather not do business with at present...

BTW piperine has been suspected of having antidepressant activity in mice, this was mentioned in a piperine thread here.

Also from Nature...and potentially more interesting, for mice at least...maybe we have a lot of depressed members here or something...

Quote: Originally posted by mayko  
In other recent ayahuasca-related news:


Quote:

A chemical called harmine, which occurs naturally in a number of plants around the world, has been shown to regenerate pancreatic cells lost in diabetes.


Harmine drug that restores beta cells seen as key diabetes treatment


http://www.nature.com/nm/journal/v21/n4/full/nm.3820.html

They speak only of harmine analogs as being of future interest, not harmine itself of course, since one can just buy harmala seeds...no doubt in 20 years or so their INDY or some other not-harmine will be available for treatment, for $100 a mg....

Chemosynthesis - 25-4-2015 at 10:15

Quote: Originally posted by S.C. Wack  
IIRC several years ago I posted somewhere else that I found the mostly purified harmine/harmaline mixture from harmala extract to have surprising subtle residual antidepressant effect, and might be useful for same...in no way was there any other effect at the doses I tried.

I am not sure what is surprising about it. They have known MAOI activity, which is quite an old antidepressant mechanism.

Quote:
They speak only of harmine analogs as being of future interest, not harmine itself of course, since one can just buy harmala seeds...no doubt in 20 years or so their INDY or some other not-harmine will be available for treatment, for $100 a mg....
Given my posts indicating potential toxicities of said harmala alkaloids, and the ability to engineer pharmacologically superior localization and half-lives, it might well be an opportune trafeoff for some patient groups.

Treatments for Arthritis and dermatitis with MDA (3,4methylenedioxyamphetamine)

solo - 25-4-2015 at 10:28




TREATMENTS FOR ARTHRITIS AND CAST
DERMATITIS

Thomas A. Hosick,
US Patent
#4120976



Abstract
This invention relates to treatments for arthritis and cast dermatitis by the administration to patients of 3,4methylenedioxyamphetamine and its non-toxic addition salts.

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[Edited on 25-4-2015 by solo]

Metacelsus - 25-4-2015 at 11:02

So, MDA is being proposed as a anti-inflammatory medicine? What's the proposed mechanism of action? I read the patent, but it wasn't clear on this.

Chemosynthesis - 25-4-2015 at 11:20

Patent's from 1978? Are there any literature citations in it?

Edit- make that, there are no peer-reviewed citations I can find in the patent. What is there to discuss on this? Respectfully, I don't see the merit. It's an old patent with no evidence of efficacy behind it that I see proposed, and has the additional bureaucratic burden of being on a scheduled narcotic that is not exactly viewed in a positive light in the United Nations Commission on Narcotic Drugs.

[Edited on 25-4-2015 by Chemosynthesis]

Zombie - 25-4-2015 at 14:14

This thread has come a long way, and the words continue to grow. I understood "Threads Merged". sort of.

Actually I can follow the ideas but all the citations keep distracting me. I bounce between trains of thought like a tennis ball in a clothes dryer.

Now for a layman kinda question.

Going back to Nicodems post re: anti allergy... The mechanism of action is what?
Is the DOB working receptors in such a way to trigger an antihistamine response from the brain? or is it actually the DOB that is acting as the antihistamine?

Same question qualifies all the way down to Solo's post citing Dermatitis, and Arthritis.

Are these compounds actively exciting responses in the brain that causes the brain to release or inhibit natural compounds in the body to do the end "work. OR are the compounds themselves the active "worker"?

Chemosynthesis - 25-4-2015 at 14:51

Quote: Originally posted by Zombie  

Now for a layman kinda question.

Going back to Nicodems post re: anti allergy... The mechanism of action is what?
Is the DOB working receptors in such a way to trigger an antihistamine response from the brain? or is it actually the DOB that is acting as the antihistamine?

It's complicated (as inflammation itself is) and not fully elucidated in public domain to the best of my knowledge, but see PMID: 18708586 cited by Nicodem twice now).

The working theory thusfar is that the 5HT-2AR has some kind of signaling effect to prevent inflammatory signal propagation, at least in enough peripheral tissues as to be considered systemic. I don't have the paper in front of me, so I am not sure if Nichols has speculated on this, but it is known that PKC variants can activate NFkappa-B through phosphorylation, and so this may somehow be involved here. Once you get inside the cell, all bets as to what is happening get really dicey, which is why I was very specific about mentioning a canonical pathway earlier. You learn the canonical pathways in school, and then question them in work.
Quote:
Same question qualifies all the way down to Solo's post citing Dermatitis, and Arthritis.

Are these compounds actively exciting responses in the brain that causes the brain to release or inhibit natural compounds in the body to do the end "work. OR are the compounds themselves the active "worker"?

The patent has zero associated data, so I don't see any reason to discuss it or believe it has any factual basis without further sources.

Other than possible uses for Alzheimer's, no, this is not localized to the brain. These are peripheral effects being cited thusfar, which would be in keeping with Nicodem's friend's anecdotal experiences.

Zombie - 25-4-2015 at 15:15

Now I can nod in agreement.

Apparently I can form the questions that have no absolute answers. That's been both my strong suit, and bane of my existence.

Concepts are easy. questioning a concept is easier. Finding answers that satisfy me??? Impossible!

So to break down the first answer... our physiology can be compared to an organic laboratory, and the brain can be compared to the lab tech making it all happen?

Some of these compounds we are discussing (DMT, DOB, DOI) are more of a set of instructions than they are actual parts of the machine?

Chemosynthesis - 25-4-2015 at 16:05

I don't like analogies. They are overly simplistic. The brain may have no bearing in peripheral or enteric systems, even if there are neuronal connections. We are discussing intracellular signaling cascades which may be competing to different extents, or partially/entirely absent depending on the specific cell type you discuss, even between different neurons. Not all neurons are central nervous system neurons, nor do all signal transduction pathways at the neuron-to-neuron level go through the brain (reflex arcs).

To expound on the canonical PKC pathways I mentioned, let's take the gonadotropin-releasing hormone (GnRH) receptor for an example, as it canonically is associated with a Gq signaling pathway as well. The receptor itself is different, but that has no bearing here. The pathway is similar. You might have a GPCR activated MAPK/ERK cascade or four, phosphorylating PLA2, which subsequently influences inflammatory signaling through the release of arachidonic acid and its signaling of neutrophils, cytokines, etc. Now you have an immunological response. Histamines can also cause this through a variety of signaling pathways (there being 4/5 receptors), so without getting into too much unnecessary conjecture without accompanying histamine data... it is sensible they may interact somehow, at least at the cytokine level if not elsewhere. This is kickstarted through the Gq/PLC/PKC pathway I mentioned earlier. These are known, fairly popular pathways, but the further you get from the surface of the cell, the harder it is to determine what is going on partially because of signal recursion, partially due to difficulty 'seeing' what is happening, and partially because too much begins happening at once to differentiate effects from various possible causes. Methodologically, it makes sense to determine which specific receptors you want to look at most. This could be done with the ligand probing (drugs) I mentioned.

Subtle changes in probe can bias the functionality or effects, changing the G-protein signaling slightly through sterics and dwell time affinity at the associated receptor, and subsequent downstream effector bindings, which are extremely complicated. By using novel probes that work one step or so removed, inside the cell, such as G-protein conformational blockers which can selectively deactivate some specific subunits to stop signal bifurcation, or RGS ligands to further modulate signaling and kinetics, we can try to tease apart the first intracellular layer of communication, or alter receptor pooling, or use fluorimetric assays to look at associated ion and channel kinetics.

Zombie - 25-4-2015 at 18:01

So Yes to the first question, no not really to the second, and sort of but they do play actual roles beyond that of an instruction set.

Overly simplistic, yes. once I have something to work off of the rest becomes much easier. Sort of a word association thing.

I always appreciate your patience with me, and the forum in general for that matter.

solo - 25-4-2015 at 18:13

Reference Information

Note: Reference information not necessary for discussion but as a source of some documented uses and benefits.



The Nature of the MDMA Experience and Its Role in Healing, Psychotherapy, and Spiritual Practice
Sophia Adamson and Ralph Metzner

Attachment: The Nature of the MDMA Experience and Its Role in Healing, Psychotherapy, and Spiritual Practice .PDF (1.5MB)
This file has been downloaded 394 times


Chemosynthesis - 25-4-2015 at 18:38

Quote: Originally posted by Zombie  
So Yes to the first question, no not really to the second, and sort of but they do play actual roles beyond that of an instruction set.

Overly simplistic, yes. once I have something to work off of the rest becomes much easier. Sort of a word association thing.

I always appreciate your patience with me, and the forum in general for that matter.
I dunno about the answers. I am dramatically simplifying things too, even from what is known, because AA interacts with NFkappaB, PLC can cleave some AA off through DAG, etc. These may compete, change kinetic prevalence, etc. with different ligands, or they instead vary more based on what is synthesized in the cell type. It's possible receptor localization, or extent of inundation affects these as well. I am hoping to see advances in these areas during my lifetime since some of these tools are new and do not seem well known.

You're welcome even though I don't know if I deserve any thanks.

Zombie - 25-4-2015 at 19:03

It's all good.

The more I begin to understand the more shocked I am at how little is actually completely understood.
Truthfully it is almost appalling that a Dr. will assign a diagnoses, prescribe a medication, and not fully understand what is happening. Worse yet is the fact he may not understand the diagnosis.

Trained rats pull the correct lever.

I'm not starting a Dr. slam rant. Not at all. Im just surprised at how much some of you know in these discussions, and you are the first to say that much of it is still unknown.

How much more can there be? Thousands of multi-syllable words, and they don't begin to cover everything... Surprising!

[Edited on 4-26-2015 by Zombie]

cyanureeves - 25-4-2015 at 19:30

i hope they do one day find a good anti depressant that works for all the world and completely different than todays popular medicines.i mean one time i took a blotter that was just so wonderful and felt so peaceful and happy that i was the happiest day of my life.granted everything around me looked magenta colored but it was an acid so different.this 2015 by golly and marihuana is legal in some states because alot people just had enough of what they believe were lies.if not for the whole world then at least to the severe manic because they will be better than the walking dead crap they get today.i would like to see the elderly in a happy mood even if it's in a magenta world.i so hate to see old folk fed crap that keeps them sedated all the time and the elderly make up a huge part of anti depressant market.i am getting up in years and i just want to feel good but i really dont like to be high, well i do but i dont also.we just need a good med.

Chemosynthesis - 25-4-2015 at 20:04

I wouldn't be too quick to levy judgment against most physicians, even though the vast majority are not drug specialists. Physicians simply don't have enough time to devote to being both a scientist and a clinician, nor do most of them have the training, in the vast majority of cases. An honest physician (or nurse, or whoever) will admit this, even if they dislike it. To keep up with just the clinical journals is basically impossible, even if that were the sole duty of a physician: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC521514/
Really deep analysis would take longer. If a physician lacks graduate scientific training, or desires to perform clinical work in addition to any research, they have a greater problem than someone with a non-truncated PhD, bachelors', and no patients to see.

However, their physician differential diagnosis skills and generalized medical knowledge are unparalleled. They may not know a diagnosis with certainty, or understand the etiology of a correct diagnosis, but they will likely understand it far better than anyone else, barring another physician. What alternative is there? A PhD pharmacologist or a pharmacist may have a much better understanding of medications, specific formulations, interchangeability, etc. but their ability to correctly differentially diagnose without very special training (partnered practices in a few states, some VA hospitals, certain applied pharmacology fellowships, etc.) are limited because their background in pathophysiology is different. They may be good for 9/10 ddx, but just as a typical physician without a specialization in pharmacology is unlikely to really know their non-prototypical drugs offhand, it is rare for all but the most experienced PAs to really compare to the differential diagnosing training of a physician, and parse when a mistake has been made as well as how best to try to resolve an issue.

The same could be said for surgical intervention... as some dental and pharmacy schools share gross anatomy cadaver labs with MD/DO students, yet are clearly not as qualified as any medical student to deliver a baby or perform an appendectomy. I might consider a microbiologist as having far more knowledge of P. aeruginosa than my general practitioner, and I am sure both could diagnose it adequately from culture (or their technicians could, with a kit and some form of Bergey's Manual), but I would prefer the physician treat such an infection every time, just in case there were a complication. Healthcare really is an interdisciplinary field, even just among physician specialties. If I need a heart surgery but have liver or kidney complications, I may need a gastroenterologist or nephrologist to talk to my cardiologist. During the surgery, I need an anesthetist on hand. I really don't see any viable alternatives given our knowledgebase keeps expanding, and so greater amounts of specialization are necessary. The problem is even more difficult with psychological problems, with the implausibility of having labwork give you a definitive diagnosis, as definitive as a diagnosis can be. Once psychiatry gets involved, you then have to discuss the psychiatry/psychology divide, which I am not qualified to speak on.

Zombie - 25-4-2015 at 20:29

No judgement meant at all. Merely an observation of where medicine is. Everything you just posted was in my head I just use less words.

I'm sorry for distracting the thread. It needed some breathing room for us lessor educated to be able to follow the bouncing ball. ;)



Quote: Originally posted by cyanureeves  
i hope they do one day find a good anti depressant that works for all the world and completely different than todays popular medicines.i mean one time i took a blotter that was just so wonderful and felt so peaceful and happy that i was the happiest day of my life.granted everything around me looked magenta colored but it was an acid so different.this 2015 by golly and marihuana is legal in some states because alot people just had enough of what they believe were lies.if not for the whole world then at least to the severe manic because they will be better than the walking dead crap they get today.i would like to see the elderly in a happy mood even if it's in a magenta world.i so hate to see old folk fed crap that keeps them sedated all the time and the elderly make up a huge part of anti depressant market.i am getting up in years and i just want to feel good but i really dont like to be high, well i do but i dont also.we just need a good med.



I'm with you 100%.

[Edited on 4-26-2015 by Zombie]

Nicodem - 26-4-2015 at 02:30

Back to depression... For those who like big data multivariate analysis, here is a very recent article using the data from the National Survey on Drug Use and Health (2008-2012) (USA population):

Classic psychedelic use is associated with reduced psychological distress and suicidality in the United States adult population
J. Psychopharmacol., 2015, 29, 280-288.
DOI: 10.1177/0269881114565653

quote:
Quote:

...
We also cannot rule out the possibility that classic psychedelic
use may have caused harm at the individual level. Indeed, classic
psychedelic use may exacerbate schizophrenia or other psychotic
disorders, can be dangerous in hazardous physical environments,
and can sometimes elicit feelings of anxiety, fear, panic, and par-
anoia (Johnson et al., 2008). Nevertheless, the associations
reported here suggest that if individual-level harms occurred,
they failed to obscure the apparent protective effect of classic
psychedelic use on psychological distress and suicidality at the
population level. Considering that carefully controlled conditions
are ideal in the administration of classic psychedelics (Johnson
et al., 2008), it is noteworthy that naturalistic classic psychedelic
use demonstrated evidence of benefit.
Not only could classic psy-
chedelic users have used in suboptimal settings, they could have
ingested substances of unknown purity and/or at sub- or suprath-
erapeutic doses. If the results do reflect salubrious effects of clas-
sic psychedelic use, these may very well be potentiated in
specialized treatment settings designed to maximize safety and
efficacy (Johnson et al., 2008).
...

Conclusion

Classic psychedelics carry a contentious recent history and
barriers to their clinical evaluation remain. Growing evidence
including the present research suggests that classic psyche-
delics may have the potential to alleviate human suffering
associated with mental illness. Further rigorous research is
warranted to better understand these substances, with the ulti-
mate goal of taking full advantage of their latent therapeutic
capacity.

(The emphasis is mine.)
Efficiency under uncontrolled conditions surprises me as well.

distress.jpg - 31kB
suicidal.jpg - 55kB

[Edited on 26/4/2015 by Nicodem]

Chemosynthesis - 26-4-2015 at 04:33

I actually meant to say anesthesiologist above, not anesthetist as the latter are nurses (not making a value statement).

Nicodem good find. Brand new!

That is a pretty big overall n, which I like, particularly to help support the study type. If the Araujo ayahuasca RCT placebo study finishes this year as expected, I think it would be really interesting to see if any kind of comparisons can be drawn between reports from lifetime users versus non-lifetime users just to see if any tentative generalizations could be drawn as to optimal presumptive treatment durations for investigation. Based on the high comorbidity of anxiety disorders and depression as well as the common use of antidepressants in treatment, and the legend phrasing in the first figure you graciously attached, it appears to me as though some of these studies, if properly designed, may also be used in support of/conjunction with ongoing research into psychedelic anxiety disorder treatment. With an optimal target treatment duration derived from future data, a comparison could be made with protocols such as recommended benzodiazepine treatment durations, the use of which may be contraindicated in depressed patients (PMID: 17711589).

Zombie - 26-4-2015 at 19:35

The results on those studies are not surprising at all.

I've stated that my entire family has had "issues", and just from first hand experience the charts are relate-able for me.
There is something that may not be worked into the data tho. Base line personality.

Coke heads are one type of person, and opiate users are another. So on and so forth.

What the study was comparing were apples, and oranges. Psychedelic users are generally more emotionally balanced (from my opinion but there may be studies to relate). I don't know IF Psychedelic users are less depressed as a result of the drug(s) or if they were better of in the first place.

The base line depression, and personality issues may have muddied up the results.

I avoid coke heads, can tolerate heroin addicts, take pill freaks for face value (opiates), drunks (no offense Mr Aga) they are fun if I'm drinking but I'd prefer to be well away from them, trippers on the other hand... I admire many of them. Not so much for the fact that they like Tie Dye, and cookies but for the fact that simple things make them happy.

As per usual... sweeping generalizations. Yes.
it's not the compounds they choose but instead the underlying personality that leads them to the compounds they choose.

For those of you that understand my "bare bones approach to things, there may be some valuable insights to apply bigger words to in my post.

I would much prefer to see non addictive persons with depression/anxiety whatever studied for comparative results vs. conventional treatment(s). Including relapse rates, and side effects.

Then the value of addictive "patients" would have more merit. How about DMT to break an LSD addiction? I'd like to see studies on this.

That could fortify many of my personal opinions on the DMT topic. Just because they are both psychedelics does not imply they are the same or even similar in their course of action.
(you all have already shown this to be correct.


Chemosynthesis - 27-4-2015 at 07:04

Quote: Originally posted by Zombie  

There is something that may not be worked into the data tho. Base line personality.


That is absolutely worth noting as possible.
There definitely is a proposal out there among some in the medical community that differences in neurology, genetics, or personality can predispose people to certain drugs (direct or indirectly reinforcing, dopaminergic ones due to predisposition to dopamine depression, for example), but this is part of why paired samplings in other studies are important and comparison with RCT like I am hoping to see.

Zombie - 27-4-2015 at 11:17

Exactly! ;) It only took me 15 words.:D:D:D:D:D

I get it. People (whether they realize it or no)t will gravitate toward something their body is lacking. Not always but basically.

There are so many complexities in this topic that I never realized. When I simplify the process in my minds eye, I can now understand how frustrating I can be to those who are aware of the underlying reality in this field of research.

I would have thought,,, Go get a bunch of hobos from the Salvation Army, hook up some wires, feed them sugar cubes, kick back w/ a bottle of Scotch, and see what happens.

I guess the smart guys rule here. :cool:

[Edited on 4-27-2015 by Zombie]

gregxy - 27-4-2015 at 15:48

Quote: Originally posted by Chemosynthesis  

That is absolutely worth noting as possible.
There definitely is a proposal out there among some in the medical community that differences in neurology, genetics, or personality can predispose people to certain drugs (direct or indirectly reinforcing, dopaminergic ones due to ....


Here is the well know example of Asians and Alcohol which illustrates how genetics can influence response to a drug:
http://en.wikipedia.org/wiki/Alcohol_flush_reaction

I suspect that due to genetics there are subtle differences in the receptors, & enzymes that cause differences in mood and how someone will respond to a given drug. Someday they will be able to analyze your DNA and figure out exactly what combination of drugs to give you to make you feel normal (whatever that is).

The other problem is that neurotransmitters and hormones are "time and position dependent signals". The levels change from second to second and they can have different, even opposing effects in different parts of the brain and body. All that medical science can do now is change the average
levels throughout the body.




[Edited on 27-4-2015 by gregxy]

Chemosynthesis - 27-4-2015 at 20:38

Quote: Originally posted by gregxy  
I suspect that due to genetics there are subtle differences in the receptors, & enzymes that cause differences in mood and how someone will respond to a given drug. Someday they will be able to analyze your DNA and figure out exactly what combination of drugs to give you to make you feel normal (whatever that is).
While this is true and useful, and is essentially what pharmacogenetics and pharmacogenomics study to avoid toxicities, this hypothesis I mentioned is more of a basal level dysfunction, where neurotransmitter synthesis or transport is affected. I think new target identification, dosing and predictions of idiosyncratic immunological responses will be the highlights of these genomic study techniques. The dopaminergic hypothesis actually is predicated on relatively normal dopaminergic response, rather than idiosyncratic. A good example is irritable bowel syndrome genome wide association studies. Peripheral serotonin transporter SNPs, which are expressed in some tissues, seems implicated in serotonergic visceral sensitivity and GI motility... but treatments are generally non-idiosyncratic (though alosetron has some better results in women). Example treatments are lubipristone or linaclotide for IBS-C subtypes, pregabalin or k-opioids or NSAIDs for visceral pain. None of these are unique treatments to IBS. SNPs have been correlate with behavior, and the example you give is aversive to alcohol due to aldehyde buildup, and thus associated with a diminished risk fo alcoholism, for example, but the aldehyde dehydrogenase functions the same way as a wildtype individual, just with diminished effectiveness. With a SNP in the promoter region, you will influence gene expression (higher/lower) and with a SNP in the coding region, you will potentially alter the affinity or kinetics of enzymatic reaction, but are unlikely to dramatically affect signaling. Some other apparent behavioral examples:DOI: 10.1371/journal.pone.0099152 and PMID: 25403479.
Quote:
The other problem is that neurotransmitters and hormones are "time and position dependent signals". The levels change from second to second and they can have different, even opposing effects in different parts of the brain and body. All that medical science can do now is change the average levels throughout the body.
I disagree with this. For one thing, it ignores allosteric drugs, such as is very common with the GABAa receptor and its multiple drug sites. Also, drug dosing schedules are much more complex than just taking a time resolved average unless you are maintaining a steady state concentration, as peak concentrations can be very important. Differential compartmentalization also occurs for various reasons (transport, partitioning, ionization, metabolism), and so average levels throughout the body don't necessarily mean much if targeting is specific or only paracrine signaling is initiated.

[Edited on 28-4-2015 by Chemosynthesis]

Nicodem - 2-5-2015 at 01:56

Quote: Originally posted by Zombie  
The results on those studies are not surprising at all.

They are surprising for the scientist, as they represent empirical results.
Quote:
There is something that may not be worked into the data tho. Base line personality.

The survey they used as the source of data did not include personality tests, but the authors nevertheless used a multivariate analysis. They looked for confounding of psychedelic use with the following factors:
Quote:
Multivariate logistic regression was used to test the associations between life-
time classic psychedelic use and the primary outcomes while
controlling for the following covariates: age in years (18–25,
26–34, 35–49, 50–64, or 65 or older); gender (male or female);
ethnoracial identity (non-Hispanic White, non-Hispanic African
American, non-Hispanic Native American/Alaska Native, non-
Hispanic Native Hawaiian/Pacific Islander, non-Hispanic Asian,
non-Hispanic more than one race, or Hispanic); educational
attainment (5 th grade or less, 6 th grade, 7 th grade, 8 th grade, 9 th
grade, 10 th grade, 11 th grade, 12 th grade, freshman college year,
sophomore or junior college year, or senior college year or more);
annual household income (less than $20,000, $20,000–$49,999,
$50,000–$74,999, or $75,000 or more); marital status (married,
divorced/separated, widowed, or never married); self-reported
engagement in risky behavior (“How often do you like to test
yourself by doing something a little risky?”; never, seldom,
sometimes, or always) and lifetime illicit use of cocaine, other
stimulants, sedatives, tranquilizers, heroin, pain relievers, mari-
juana, 3,4-methylenedioxymethamphetamine (MDMA)/ecstasy,
phencyclidine (PCP), and inhalants (each aforementioned drug
category coded as separate covariates). All analyses were con-
ducted in SAS version 9.3 using PROC SURVEYLOGISTIC and
accounted for the complex study design variables and sampling
weights as recommended by the NSDUH.

Some of these factors reflect the demographic and social background of the subjects, which may or may not be connected with personality issues. The authors do emphasize that the non-availability of some factors may lead to biased results:
Quote:
Population survey studies cannot control for
all possible sources of confounding and therefore we cannot rule
out that a shared underlying factor may have contributed to both
classic psychedelic use and decreased psychological distress and
suicidality. Psychedelic drug users commonly report autognostic
(Móró et al., 2011), “mind expansion,” spiritual, and curiosity
motives for such use (Lyvers and Meester, 2012). Although these
interests may be lasting effects of classic psychedelic drug use,
they may also represent predrug characteristics among classic
psychedelic users that might protect against suicide as well (e.g.
openness, curiosity, and spiritual tendencies; Carhart-Harris et al.,
2014; Kashdan et al., 2004; Rasic et al., 2009, 2011; Weber and
Pargament, 2014). Lerner and Lyvers (2006) found that classic
psychedelic users reported less materialistic values and greater
mysticism, spirituality, and concern for others than non-classic
psychedelic drug users, and speculated that both predrug factors
and classic psychedelic drug effects contributed to group differ-
ences. This too may be the case with regard to the present find-
ings. However, as classic psychedelic use was associated with
self-reported engagement in risky behavior and illicit substance
use, some who use classic psychedelics may also have a premor-
bid liability for suicidality. The picture is undoubtedly complex.
Nevertheless, future research should attempt to delineate longitu-
dinal predictors of classic psychedelic use that also relate to men-
tal health and suicidal behavior.

Quote: Originally posted by Zombie  
Coke heads are one type of person, and opiate users are another. So on and so forth.

The data from the survey does not support your stereotypes:
Quote:
Table 1 displays the characteristics of lifetime classic psyche-
delic users versus non-lifetime classic psychedelic users. Lifetime
classic psychedelic use was concentrated among 26–64 year olds
and rare among those aged 65 years and older. Furthermore, life-
time classic psychedelic use was more common among men,
non-Hispanic Whites and Native Americans/Alaska Natives,
those with greater educational attainment and income, individuals
who were divorced/separated or who had never been married,
those with greater self-reported engagement in risky behavior, and
those who reported lifetime illicit use of each of the other sub-
stances. Among lifetime classic psychedelic users, only 240 (0.9%
weighted) reported never having used any other illicit substance
whereas among non-lifetime classic psychedelic users, 85,601
(58.2% weighted) reported never having used any other illicit
drug.

In fact, the self-reported cocaine use among the "lifetime classic psychedelic drug users" was 71.4%, compared to 7.5% for the "non-lifetime classic psychedelic drug users" (also, heroin use: 10.6% vs. 0.4%; pain reliever use: 46.5% vs. 9.5%; marijuana: 97.7% vs. 36.2%; and so on). It appears that the use of psychedelics is way more common among the users of stimulants, opioids, marijuana and other drugs (interestingly, data for alcohol users is not given!). At least partially, this might have to do with the prohibition laws, skewing the demographics as a factor limiting the use of psychedelics mostly only to those that are willing to ignore the prohibition as such, rather than reflecting personality connected drug use preferences. The lower difference in co-use of legal opioids and psychedelics could be an indication of such a prohibition based data distortion (those willing to use legal opioids, the use of which is still socially barely acceptable, might be more prone to use drugs in general, including psychedelics - those willing to only use alcohol, tobacco, caffeine and other socially acceptable drugs might be unwilling to use the socially unacceptable psychedelic drugs).
The prohibition is likely to distort the data in other ways as well, even such that give more credit to your stereotypes. For example, the multi-drug users are probably much more relaxed in self-reporting psychedelic drug use when compared to prohibition abiding citizens, so perhaps the group of people whose only drug of choice is a psychedelic may be under represented. If one is willing to report cocaine use, then there is no obstacle in reporting LSD or mushrooms use as well. On the other hand, if you only use LSD or mushrooms, but no other illegal drug, you might be less willing to share the information due to the social and legal oppression in a prohibition based society.
Quote: Originally posted by Zombie  
What the study was comparing were apples, and oranges. Psychedelic users are generally more emotionally balanced (from my opinion but there may be studies to relate). I don't know IF Psychedelic users are less depressed as a result of the drug(s) or if they were better of in the first place.

Like the authors suggested, it is unlikely they were better of in the first place, given that they tend to use a lot of other drugs as well. If they were better in the first place, it would be unlikely they would be using psychedelic drugs in a country well known for its unusually repressive attitude toward drug offenders.
Quote: Originally posted by Zombie  
I avoid coke heads, can tolerate heroin addicts, take pill freaks for face value (opiates), drunks (no offense Mr Aga) they are fun if I'm drinking but I'd prefer to be well away from them, trippers on the other hand... I admire many of them. Not so much for the fact that they like Tie Dye, and cookies but for the fact that simple things make them happy.

From the scientific perspective, your preferences toward disliking/admiring specific drug-type users could be just as much a consequence of your own personality traits, as is the personality involved in selecting one's drug of choice. You may have confounding factors here.
Quote: Originally posted by Zombie  
I would much prefer to see non addictive persons with depression/anxiety whatever studied for comparative results vs. conventional treatment(s). Including relapse rates, and side effects.

Like it was mentioned several times in this thread, all this has already been done. For example this last article does a good review of the psychoterapeutic and physiological aspects of psychedelics use:
Quote:
The past three decades have witnessed a gradual return to
research on classic psychedelics. Though limited in number,
these studies indicate that classic psychedelics may warrant the
attention they received five decades ago, not least in part because
they appear to target a number of factors that modulate suicide
risk. For instance, affective disturbance is one of the most promi-
nent contributors to suicidality (Hawton and van Heeringen,
2009). Under carefully controlled conditions, a single adminis-
tration of psilocybin can occasion profoundly meaningful experi-
ences that bring about persisting elevations in mood among
healthy, hallucinogen-naïve volunteers (Griffiths et al., 2006,
2008, 2011). In a pilot trial among individuals with advanced-
stage cancer a single dose of psilocybin was associated with
long-term reductions in anxiety and depression (Grob et al.,
2011), and in a pilot trial among individuals with life-threatening
diseases two administrations of LSD produced lasting reductions
in anxiety (Gasser et al., 2014; in press). Substance misuse also is
robustly related to suicide risk (Borges et al., 2000; Britton and
Conner, 2010; Center for Substance Abuse Treatment, 2008;
Hawton and van Heeringen, 2009; Wilcox et al., 2004), and sev-
eral lines of research suggest that classic psychedelics have anti-
addictive effects (Bogenschutz and Pommy, 2012). For example,
a recent meta-analysis of six randomized clinical trials of treat-
ment for alcoholism conducted between 1966–1970 found that a
single dose of LSD reduced the probability of alcohol misuse
almost two-fold relative to comparison conditions (Krebs and
Johansen, 2012). Furthermore, a single-arm trial of smoking ces-
sation involving up to three administrations of psilocybin yielded
abstinence rates of 80% at long-term follow-up, more than dou-
bling abstinence rates typical of approved contemporary tobacco
dependence interventions (Johnson et al., 2014). Moreover, natu-
ralistic hallucinogen use predicted a reduced likelihood of recidi-
vism among more than 25,000 individuals under community
corrections supervision with a history of substance involvement
(Hendricks et al., 2014). Additional prominent suicide risk fac-
tors include impulsive-aggressive personality characteristics and
early traumatic life events (Hawton and van Heeringen, 2009).
Psilocybin may occasion enduring improvements in inner peace,
patience, good-natured humor/playfulness, interpersonal regard,
anger, and compassion (Griffiths et al., 2006, 2011), and may
facilitate processing of prior trauma by enhancing recall of auto-
biographical memories (Carhart-Harris et al., 2012a). Finally,
classic psychedelics may boost spirituality (Bogenschutz and
Pommy, 2012; Griffiths et al., 2011), which has been shown to
protect against suicidality (Rasic et al., 2009, 2011; Weber and
Pargament, 2014). Although sample sizes in recent medical
administration studies have been limited, no serious adverse
events were reported, consistent with historical data indicating
that these substances can be administered safely in medical con-
texts by using appropriate safeguards (Johnson et al., 2008).

Neurobiological experiments echo clinical findings, adding
further evidence to suggest that classic psychedelics may modify
processes implicated in suicidality. Increased 5-HT 2A receptor
density in the prefrontal cortex is associated with suicide risk fac-
tors (e.g. major depression) and suicidal behavior, and may
reflect compensatory up-regulation of 5-HT 2A receptors stem-
ming from dysfunctional serotonergic transmission (Bhagwagar
et al., 2006; Carballo et al., 2008; Meyer et al., 2003; Shelton
et al., 2008). Classic psychedelic use down-regulates 5-HT 2A
receptors in the prefrontal cortex which may, in turn, normalize
limbic hyperactivity associated with affective disturbance
(Baumeister et al., 2014, Kraehenmann et al., in press;
Vollenweider and Kometer, 2010). Reduced neuroplasticity (i.e.
expression of brain-derived neurotrophic factor) is also associ-
ated with affective disturbance and suicide, and classic psyche-
delic use may elicit neuroplastic adaptation via glutamatergic
transmission (Baumeister et al., 2014; Bogenschutz and Pommy,
2012; Dwivedi, 2010; Dwivedi et al., 2003; Vollenweider and
Kometer, 2010). Furthermore, the default mode network (DMN)
is hyperactive and hyperconnected among those with affective
disorders, a state that may underpin negative rumination and
rigid pessimism characteristic of these conditions (Carhart-Harris
et al., 2014; Whitfield-Gabrieli and Ford, 2012). Classic psyche-
delics may normalize the DMN, thereby reducing this cognitive
fixedness (Carhart-Harris et al., 2012b; Carhart-Harris et al.,
2014; Muthukumaraswamy et al., 2013; Roseman et al., 2014;
Tagliazucchi et al., 2014). In support of this view, a single dose of
psilocybin increased personality openness 14 months post-
administration (MacLean et al., 2011). Some studies show that
openness may protect against suicide in older adults, though find-
ings are mixed (Segal et al., 2012). Finally, emerging evidence
suggests that classic psychedelics might reduce markers of cen-
tral nervous system inflammation that are implicated in a host of
mental health conditions and suicidal behavior (Black and Miller,
in press; Szabo et al., 2014).

(I suggest you read the whole article.)

Quote: Originally posted by Zombie  
Then the value of addictive "patients" would have more merit. How about DMT to break an LSD addiction? I'd like to see studies on this.

You can't just make up ideas for trials. Trials are hypothesis based, so you need some understanding of what the treated condition is supposed to be. For example, there is no such thing as "LSD addiction", so how are you going to find/create your clinical subjects? Psychedelics do not induce craving and they cause up to one week long tolerance, so that any physiologically based addiction is made impossible. Psychological addiction (if any such thing even exists) requires regular use and some kind of self-abusive behavior (else it is just a normal compulsion). This is made quite difficult by the extremely rapid tolerance building and general repulsion from closely repeated use of psychedelics in nearly all people.
But let's assume there was something like an "LSD addiction". DMT could not be used as a replacement drug therapy because it is a full agonist while LSD is a partial agonist. DMT effects last a few minutes, while LSD lasts for 12 hours. DMT is the only known psychedelic that does not induce tolerance (probably because its action is too short to cause receptor internalization). So, utmost, LSD could be used as a to treat a hypothetical "DMT addiction", but not the other way around.

Zombie - 2-5-2015 at 17:17

My mouse is screwing up, and I can't quote properly. Sorry...


I see problems all over this report, and contradictions galore.
They do agree that demographics are not any sort of bias free basis, and personality testing is not included. In a sense it is because they ASSUME basic traits, yet they contradict their assumptions.
Example:

" Psychedelic drug users commonly report autognostic
(Móró et al., 2011), “mind expansion,” spiritual, and curiosity
motives for such use (Lyvers and Meester, 2012). Although these
interests may be lasting effects of classic psychedelic drug use,
they may also represent predrug characteristics among classic
psychedelic users that might protect against suicide as well (e.g.
openness, curiosity, and spiritual tendencies; Carhart-Harris et al.,
2014; Kashdan et al., 2004"

next paragraph...


However, as classic psychedelic use was associated with
self-reported engagement in risky behavior and illicit substance
use, some who use classic psychedelics may also have a premor-
bid liability for suicidality. The picture is undoubtedly complex.

Then to finish...

The picture is undoubtedly complex.
Nevertheless, future research should attempt to delineate longitu-
dinal predictors of classic psychedelic use that also relate to men-
tal health and suicidal behavior.

I agree with this.
Not that I could ever claim fame here but a more defined set of parameters has to be established. How much money you pull down is useless data unless you are comparing rich to poor. Same for most of the "questionnaire" or the ,
Quote:
Multivariate logistic regression system they employed.

Compare addicts blindly. Heroin addicts to cocaine addicts, and both to non addicts.
See who responds to the treatments, and then determine why.
Comparing a heroin addict to a LSD addict is like comparing a drunk to a tree frog.
They are not in the same category.
They are both addictive personalities but for immensely different reasons that WILL skew the results or assumed results.

Quote Zombie:
Coke heads are one type of person, and opiate users are another. So on and so forth.

Quote Nicodem:
The data from the survey does not support your stereotypes:

As I stated above, I believe their data is skewed, and incorrect. They admit so in the first two quotes.
I have a lifetime of experience with many types of addicts, and they are all completely different animals. The only commonality is the predisposition to addiction, and the inability to solve it themselves.
Ps... I do NOT believe addiction is a disease any more than homosexuality is. Look at how the definitions have changed over the past few decades alone.


Quote:
Table 1 displays the characteristics of lifetime classic psyche-
delic users versus non-lifetime classic psychedelic users. Lifetime
classic psychedelic use was concentrated among 26–64 year olds
and rare among those aged 65 years and older. Furthermore, life-
time classic psychedelic use was more common among men,
non-Hispanic Whites and Native Americans/Alaska Natives,
those with greater educational attainment and income, individuals
who were divorced/separated or who had never been married,
those with greater self-reported engagement in risky behavior, and
those who reported lifetime illicit use of each of the other sub-
stances

Meaningless to what the mechanism of action is.


Quote:
Among lifetime classic psychedelic users, only 240 (0.9%
weighted) reported never having used any other illicit substance
whereas among non-lifetime classic psychedelic users, 85,601
(58.2% weighted) reported never having used any other illicit
drug.

Backs up my "opinion that they are different from other addicts who will huff gas to get a "high".

Psyc. users are different. Better off mentally IMHO

Edit... I read this wrong. I do not wish to remove my comments here because this finding surprises me. What I would like to see is complete data here. meaning how much of the other drugs were used.
Did these LSD users spend years shooting dope or did they try it once. Years smoking weed or a few times.
Reporting use, and the amount of use are two completely different factors.
This needs to be more concise to have any relevance.

Quote:
In fact, the self-reported cocaine use among the "lifetime classic psychedelic drug users" was 71.4%, compared to 7.5% for the "non-lifetime classic psychedelic drug users" (also, heroin use: 10.6% vs. 0.4%; pain reliever use: 46.5% vs. 9.5%; marijuana: 97.7% vs. 36.2%; and so on)

I would like to see these numbers related to the population in general. I imagine the curves would virtually overlap.

I believe they realize this, and backpedal here:

In fact, the self-reported cocaine use among the "lifetime classic psychedelic drug users" was 71.4%, compared to 7.5% for the "non-lifetime classic psychedelic drug users" (also, heroin use: 10.6% vs. 0.4%; pain reliever use: 46.5% vs. 9.5%; marijuana: 97.7% vs. 36.2%; and so on). It appears that the use of psychedelics is way more common among the users of stimulants, opioids, marijuana and other drugs (interestingly, data for alcohol users is not given!). At least partially, this might have to do with the prohibition laws, skewing the demographics as a factor limiting the use of psychedelics mostly only to those that are willing to ignore the prohibition as such, rather than reflecting personality connected drug use preferences. The lower difference in co-use of legal opioids and psychedelics could be an indication of such a prohibition based data distortion (those willing to use legal opioids, the use of which is still socially barely acceptable, might be more prone to use drugs in general, including psychedelics - those willing to only use alcohol, tobacco, caffeine and other socially acceptable drugs might be unwilling to use the socially unacceptable psychedelic drugs)



Quote: Originally posted by Zombie
What the study was comparing were apples, and oranges. Psychedelic users are generally more emotionally balanced (from my opinion but there may be studies to relate). I don't know IF Psychedelic users are less depressed as a result of the drug(s) or if they were better of in the first place.

Like the authors suggested, it is unlikely they were better of in the first place, given that they tend to use a lot of other drugs as well. If they were better in the first place, it would be unlikely they would be using psychedelic drugs in a country well known for its unusually repressive attitude toward drug offenders

We are talking about people that don't really care to much for "rules.
Actually I don't recall seeing any AA group for LSD users or support groups advertised on tv like the cocaine, and dope users have.
LSD users are emotionally better off IMHO. I don't need a fella in a white coat that lives in Bele-Aire to guess differently based on his 12 hours of reading questionnaires to tell me differently. I grew up w/ them. I didn't have to assume anything. My next post here kind of addresses this a bit more. Sorry if that sounded arrogant.


Quote: Originally posted by Zombie
I avoid coke heads, can tolerate heroin addicts, take pill freaks for face value (opiates), drunks (no offense Mr Aga) they are fun if I'm drinking but I'd prefer to be well away from them, trippers on the other hand... I admire many of them. Not so much for the fact that they like Tie Dye, and cookies but for the fact that simple things make them happy.

From the scientific perspective, your preferences toward disliking/admiring specific drug-type users could be just as much a consequence of your own personality traits, as is the personality involved in selecting one's drug of choice. You may have confounding factors here.

100% agree. It most likely is an opinion based on experience in my life.
I was never robbed by an LSD addict with a gun to my head nor have I ever seen a guy on LSD beating his family with a ball bat because they didn't have "dope money for them. Violence does not seem to be a part of an LSD users make up.
We all know what other drugs do to addicts. or what other addicts can do. Booze is probably the worst drug when it comes to violent behavior. Booze or coke... Tough call.

100% agreed... My opinion is most likely bred from my environment(s)


Quote: Originally posted by Zombie
I would much prefer to see non addictive persons with depression/anxiety whatever studied for comparative results vs. conventional treatment(s). Including relapse rates, and side effects.

Like it was mentioned several times in this thread, all this has already been done. For example this last article does a good review of the psychoterapeutic and physiological aspects of psychedelics use:

I will read the entire article.
This is where the real effectiveness of treatment can be found.
Comparing different "types of junkies may lead to great discoveries. I am not disputing what MAY come from any sort of research BUT stating you want to study junkies with Psychedelic drugs just doesn't have the kind of ring to it that would garner much backing.

Stating you want to end depression in elderly, and cancer patients sounds much better.
Let the junkies wait. They are self medicated anyway. Throw them some bongos, a tambourine, and a hand full of joints. They can wait.


Quote:
. For example, there is no such thing as "LSD addiction"

Physically, perhaps not. Mentally? see life long users.


I appreciate your taking the time to discuss this. The whole subject is fascinating, and I believe very valuable.

Perhaps what more of these researchers need is a real interest from the general; public. Like an add company... Tell the world that DMT CAN alleviate many human conditions, and anyone caught using it without the proper supervision will be thrown in the volcano.

People in general are scared of psychedelics Because of people like Leary, and all those damn hippies that walked around relieving themselves in yards, parking lots or wherever they happened to be. Free love, and F@ck tomorrow man. Peace!


Psychedelics have a bad reputation. As bad as tobacco IMHO, and it is unjustified. Valium is far worse, and far more deadly but you don't see tie died Valium shirts.

I respect you immensely Nickodem. You may have no clue how much.

I'm just sharing what I can. My opinion.







[Edited on 5-3-2015 by Zombie]

[Edited on 5-3-2015 by Zombie]

Nicodem - 3-5-2015 at 03:45

Quote: Originally posted by Zombie  
I see problems all over this report, and contradictions galore.
They do agree that demographics are not any sort of bias free basis, and personality testing is not included. In a sense it is because they ASSUME basic traits, yet they contradict their assumptions.

It is a multivariate analysis, so they did not have much freedom to assume much in the data treatment. In a multivariate analysis you look for correlations between the factors and the outputs by building a model with as little factor confounding as the data size and distribution allows. They did some operations in the merging and excluding data, but they described that in the article.
The problems arising from the data and its integrity are survey related and are obvious issues common to every questionnaire based survey (biased self-reporting, misunderstood questions, errors, etc.). They also expose the problem with the low numerus for certain psychedelic drugs. For example, for ayahuasca experience the N was only 26 which is 0.008% wighted. DMT was slightly better (N = 391; 0.1%) but still too underrepresented for a separate evaluation.
Quote:
I agree with this.
Not that I could ever claim fame here but a more defined set of parameters has to be established. How much money you pull down is useless data unless you are comparing rich to poor.

The authors of the study don't have anything to do with personality testing not being included in the National Survey on Drug Use and Health questionnaire (NSDUH). I assume it is not included because it would double the number of the the already numerous questions. It is a public health focused survey, so personality is not at its focus. The survey is conducted by a governmental agency: https://nsduhweb.rti.org/respweb/homepage.cfm
Quote:
Comparing a heroin addict to a LSD addict is like comparing a drunk to a tree frog. They are not in the same category.

LSD addicts do not exist, so there is nothing to compare with.
I think time ago there used to be some disorder classification in USA for naming people using psychedelic drugs, but it was most likely removed from the recent classifications as it made no sense. Even National Institute on Drug Abuse (NIDA), which is a USA governmental agency, does not recognize any such thing as addiction to psychedelic drugs. It does mention the abuse of psychedelic drugs, but from the context it is obvious they are actually discussing the normal use of illegal drugs as "abuse" rather than using the term "abuse" for destructive behavior ("a corrupt practice or custom" or "improper or excessive use or treatment" as per dictionary definitions).
Quote:

Quote:
Table 1 displays the characteristics of lifetime classic psyche-
delic users versus non-lifetime classic psychedelic users. Lifetime
classic psychedelic use was concentrated among 26–64 year olds
and rare among those aged 65 years and older. Furthermore, life-
time classic psychedelic use was more common among men,
non-Hispanic Whites and Native Americans/Alaska Natives,
those with greater educational attainment and income, individuals
who were divorced/separated or who had never been married,
those with greater self-reported engagement in risky behavior, and
those who reported lifetime illicit use of each of the other sub-
stances

Meaningless to what the mechanism of action is.

You cannot know which factors are meaningless until you analyze them. Particularly since the mechanism of action for reducing psychological distress and suicidality is unknown. You are trying to apply non-scientific methods to comprehend a scientific-statistical report. Such approach can only leads to misinterpretation. In science, a hypothesis comes before the experiment and conclusions come last. Reversing the order leads astray.
Quote:
Edit... I read this wrong. I do not wish to remove my comments here because this finding surprises me. What I would like to see is complete data here. meaning how much of the other drugs were used.
Did these LSD users spend years shooting dope or did they try it once. Years smoking weed or a few times.
Reporting use, and the amount of use are two completely different factors.
This needs to be more concise to have any relevance.

I agree that detailed stories from the users would have greater relevance. Unfortunately, you cannot get such data from a questionnaire-based survey only. Obtaining such data would require phenomenological methods which have fallen into disdain since researchers, particularly the most incompetent ones, realized the best way to obtain research grants is by limiting his skills to the scientific method only. Phenomenological studies are also difficult to publish in journals with an impact factor which is another problem.

Obviously, it is possible and likely that psychedelics are more often used by people addicted to alcohol, sedatives, narcotics or stimulants as some sort of a self-medication to change their life style. There are plenty of anecdotal reports that this is common practice among alcohol and heroin addicts. I don't know about stimulant users, but might be similar.
Quote:

Quote:
Quote:
In fact, the self-reported cocaine use among the "lifetime classic psychedelic drug users" was 71.4%, compared to 7.5% for the "non-lifetime classic psychedelic drug users" (also, heroin use: 10.6% vs. 0.4%; pain reliever use: 46.5% vs. 9.5%; marijuana: 97.7% vs. 36.2%; and so on)


I would like to see these numbers related to the population in general. I imagine the curves would virtually overlap.

You can easily calculate the numbers for the population in general. 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. The proportion of naive people (coded as "non-lifetime classic psychedelic drug users") is therefore 86.4%. Ponder the data in columns with these coefficients and sum it up to obtain the numbers for the overall population. The numbers will be somewhat higher than the ones in the "non-lifetime classic psychedelic drug users" column.

Quote:
We are talking about people that don't really care to much for "rules.
Actually I don't recall seeing any AA group for LSD users or support groups advertised on tv like the cocaine, and dope users have.
LSD users are emotionally better off IMHO.

Like I already mentioned, I believe it is the reverse. I think the "comorbidity" of LSD use with other drugs usage is probably just because people using drugs don't care much about rules (prohibition originating bias). Likewise, people in distress are also less likely to care about rules when it comes to self-medication. This is probably the reason why the study shows that "lifetime classic psychedelic drug users" have so much more troubles compared to "non-lifetime classic psychedelic drug users". They are demonstrating a survey based statistical fact. They do not make assumptions based on specific cases.
Besides, how do you make an AA group for LSD users? Maybe: "Hi, my name is John. I spend 12 hours every week tripping on LSD. This does not leave me enough time to take care of my family and business. I need help." Not really convincing. Even spending 2 hours per day in a traffic jam might a more convincing issue requiring a AA type support group.
Quote:
Stating you want to end depression in elderly, and cancer patients sounds much better.

You are not being innovative here. Such studies were already conducted and the reports published. However, there is almost nothing on the general population as an entity. This is why this last study is so valuable.
Quote:

Quote:

. For example, there is no such thing as "LSD addiction"

Physically, perhaps not. Mentally? see life long users.

I'm not sure you know what the term "addiction" means:
http://www.merriam-webster.com/dictionary/addiction
Quote:
People in general are scared of psychedelics Because of people like Leary, and all those damn hippies that walked around relieving themselves in yards, parking lots or wherever they happened to be. Free love, and F@ck tomorrow man. Peace!

That is not true. In Europe we did not have Timothy Leary and his movement and there was very little propaganda against psychedelics, yet most people are almost instinctively afraid of them. Some are fascinated, but too afraid to experience. Most chose to remain naive for the rest of their lives. I believe this is because they sense what a psychedelic experience is, could be, or have their own phantasm about it, and not because they would believe it is bad for their health, or a danger to the society. You can sense this by seeing how they try to cover the fears with jokes when it comes to the topic of hallucinogens in general. Rarely they resort to ideological arguments as a defense against the experience. The arguments are more commonly personal when they decide to share them at all. Maybe it is different in propaganda intensive countries like USA where the survey was conducted, but I don't know that.


There is another study using the NSDUH data, but from earlier yearly surveys (cited in the here disused article as the only other similar study):


Psychedelics and Mental Health: A Population Study
Teri S. Krebs, Pål-Ørjan Johansen
PLOS, 2013, 8, e63972
DOI: 10.1371/journal.pone.0063972

Quote:

Results
21,967 respondents (13.4% weighted) reported lifetime psychedelic use. There were no significant associations between lifetime use of any psychedelics, lifetime use of specific psychedelics (LSD, psilocybin, mescaline, peyote), or past year use of LSD and increased rate of any of the mental health outcomes. Rather, in several cases psychedelic use was associated with lower rate of mental health problems.

Conclusion
We did not find use of psychedelics to be an independent risk factor for mental health problems.

Nicodem - 3-5-2015 at 06:49

Regarding the survey based studies, there is this interesting web-based questionnaire where psychoactive drug users could report their perceptions on harm and benefit from their drug use. It kind of complements some of the conclusions made from the NSDUH data analysis. Being volunteered and web-based it is obviously highly biased in the sense of correspondents selection, but given the questions in the survey and the nature of the study, this lack is likely not so relevant (it might even be a positive bias, as the correspondents could be more familiar with various drugs and therefore giving more reliable comparisons).

User perceptions of the benefits and harms of hallucinogenic drug use: A web-based questionnaire study (article here)
R. L. Carhart-Harris, and D. J. Nutt
Journal of Substance Use, 2010, 15, 283-300.
DOI: 10.3109/14659890903271624

web_survey_drugs_mental_health.jpg - 84kB
web_survey_drugs_worse.jpg - 76kB

One of the authors, Robin Carhart-Harris, has a nice and comprehensive talk on how the psychedelics induce the psychedelic state of mind and how can this be used in psychotherapy. He tries to explain the mechanism of action on the brain-mind level (the neurochemical aspects were already covered in this thread), all based on his extensive fMRI studies on humans under the influence of psilocybin (see his publications).

By the way, Zombie, if you want other not too old studies of psychedelics done on "normal subjects", i.e., subjects without particular pathologies, or not "addicts" as you say, see the study done by Roland R. Griffiths: Psychopharmacology, 187, 268-283 and Psychopharmacology, 218, 649-665 (there is also a TEDx talk where he talks about it). Like I already said, there are several studies like this from the previous century, but some here objected the old methodologies. Rick Strassman's study on DMT is also similar, but somewhat older.

[Edited on 3/5/2015 by Nicodem]

Antiswat - 3-5-2015 at 09:56

man this thread is .. long
i 'believe' that there is a positive afterglow with many psychedelics, psilocybin has it and i have even heard 2c-b possess it aswell, up to a whole week
however for curing depression it almost sounds like just buying whatever nearest dealer can get you would work, i have seen ketamine, 2c-b, weed, MDMA, LSD and mushrooms suggested for curing depressions. too bad we live in a world where people seem to believe cocaine, heroine and amphetamine is your friend, and you have a future with it. no arms no cookies, you could say..

when thats said.. i dont think the problem is people being total idiots who cant think a minute into the future, i think the problem lays in the idea of limiting others.. just this night a bunch of coke addicts messed up my sleep, 3 past midnight, and many people i know do coke and they imagine it has actual benefits, they see it as a soft drug, for whatever reason, but this doesnt make me want to limit them or the drug either way

think about it.. how many problems arent based on one person trying to or succesfully limiting another?

bigpharma for sure knows the potential of some drugs, and they know those drugs wont get them customers, im as daring as to say that i see a pattern where bigpharma actually attempts to damage people, so that they can earn further credit by treating them with even more medicine, and then treating their sideeffects yet again with useless toxic shit

yeah, there is a future in psychedelics, but its a massive taboo, i dont imagine this being done before greed and the like is eliminated, and chances are everything goes to shit before we reach that point

Zombie - 3-5-2015 at 14:31

I do tend to generalize, and mis-use words. I know that makes it hard to follow my train of thought.


Quote:
Comparing a heroin addict to a LSD addict is like comparing a drunk to a tree frog. They are not in the same category.

LSD addicts do not exist, so there is nothing to compare with.
I think time ago there used to be some disorder classification in USA for naming people using psychedelic drugs, but it was most likely removed from the recent classifications as it made no sense. Even National Institute on Drug Abuse (NIDA), which is a USA governmental agency, does not recognize any such thing as addiction to psychedelic drugs. It does mention the abuse of psychedelic drugs, but from the context it is obvious they are actually discussing the normal use of illegal drugs as "abuse" rather than using the term "abuse" for destructive behavior ("a corrupt practice or custom" or "improper or excessive use or treatment" as per dictionary definitions).

I use the word addict quite liberally. It's like saying someone is addicted to kittens.

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.

That interconnects to the "does DMT physically change you or does it mentally change you.
Interesting question, and the answer is important (at some point) but if DMT can break either "type" of addiction, then the words I use are less important. It become a potato / potaato conversation.

I get the fact that for science all the words have to be exact. Just as in law because after all the two are bed partners, like it or not.


Quote Nickodem:

You can easily calculate the numbers for the population in general. 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. The proportion of naive people (coded as "non-lifetime classic psychedelic drug users") is therefore 86.4%. Ponder the data in columns with these coefficients and sum it up to obtain the numbers for the overall population. The numbers will be somewhat higher than the ones in the "non-lifetime classic psychedelic drug users" column.

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.



Quote:
We are talking about people that don't really care to much for "rules.
Actually I don't recall seeing any AA group for LSD users or support groups advertised on tv like the cocaine, and dope users have.
LSD users are emotionally better off IMHO.

Like I already mentioned, I believe it is the reverse. I think the "comorbidity" of LSD use with other drugs usage is probably just because people using drugs don't care much about rules (prohibition originating bias). Likewise, people in distress are also less likely to care about rules when it comes to self-medication. This is probably the reason why the study shows that "lifetime classic psychedelic drug users" have so much more troubles compared to "non-lifetime classic psychedelic drug users". They are demonstrating a survey based statistical fact. They do not make assumptions based on specific cases.

I really need to know the definitions here. Lifetime vs. non Lifetime.

Obviously a person that uses all sorts of drugs will have more issues as compared to a dedicated LSD user or any other single drug user for that matter.
I'm basing this on "functional" users. Those that keep a job, ect... vs the laying in the street user.


Quote Nickodem;
"Besides, how do you make an AA group for LSD users? Maybe: "Hi, my name is John. I spend 12 hours every week tripping on LSD. This does not leave me enough time to take care of my family and business. I need help." Not really convincing. Even spending 2 hours per day in a traffic jam might a more convincing issue requiring a AA type support group.

Lol... Hi I'm Ken, and I forgot why I'm here. You gonna eat those cookies?

I beats the crap out of ...

Yo! I'm Pete. I beat my kids, and drink 1 fifth of vodka for breakfast. I don't have a problem but the court sent me here. Anyone have a F'n problem with that?

LSD AA groups would be too much fun. In fact I think I do know of one. It's on PBS every week. The McLaughlin Group.


Quote:
Stating you want to end depression in elderly, and cancer patients sounds much better.

You are not being innovative here. Such studies were already conducted and the reports published. However, there is almost nothing on the general population as an entity. This is why this last study is so valuable.

You know what?
Focus on one group. Keep making them better. They don't even apply what they know works!
Why keep this "shotgun" style research going if they do not apply it where it is KNOWN to work?

Once Bob, and Ginny start talking about how much better their family life is due to Grandma taking DMT, and how much more comfortable Susan is with Chemo since the DMT treatments... It might get a foothold, and be considered a valuable tool.
Like I said... Let the junkies rot for a minute. They're not going anywhere.

Fix the contributing members of society first. Prove the research is correct, and the treatment is viable instead of studying everything else for a minute.
It's just wasting time, and allowing the hurt to continue.

They find that something does not work somewhere, and it's ammo in the chamber for the nay sayers.



Quote:
People in general are scared of psychedelics Because of people like Leary, and all those damn hippies that walked around relieving themselves in yards, parking lots or wherever they happened to be. Free love, and F@ck tomorrow man. Peace!

That is not true. In Europe we did not have Timothy Leary and his movement and there was very little propaganda against psychedelics, yet most people are almost instinctively afraid of them.

That's solely due to what happened here in the US. European kids fell into that hippy shit because it was a fad.
You didn't need Leary there. He did enough damage for the entire planet to share.

Granted he was correct on MANY levels. He was just overly zealous. The harm was done in the '60s, and the repercussions are still with us. IMHO.



Quote:

Results
21,967 respondents (13.4% weighted) reported lifetime psychedelic use. There were no significant associations between lifetime use of any psychedelics, lifetime use of specific psychedelics (LSD, psilocybin, mescaline, peyote), or past year use of LSD and increased rate of any of the mental health outcomes. Rather, in several cases psychedelic use was associated with lower rate of mental health problems.

Conclusion
We did not find use of psychedelics to be an independent risk factor for mental health problems.


We all agree on this. It's obvious.
It's the arguements against that are the "wall" that must be removed.


Another point that we are wandering away from is DMT is really what I believe is sort of the "wonder drug" here.
The others like LSD, Peyote, ect, are all similar but not the same.


DMT research is what I would like to know more about.

Thanks Nickodem for putting up w/ my lack of complex sentences, and simplistic manor. I believe you do understand we are on the same side in these matters.


Edit;

Thanks. I'm looking this up... Roland R. Griffiths: Psychopharmacology, 187, 268-283 and Psychopharmacology, 218, 649-665 (there is also a TEDx talk where he talks about it)

It's so hard to find all the time needed.

[Edited on 5-3-2015 by Zombie]

Zombie - 3-5-2015 at 14:41

Quote: Originally posted by Antiswat  
man this thread is .. long
i 'believe' that there is a positive afterglow with many psychedelics, psilocybin has it and i have even heard 2c-b possess it aswell, up to a whole week
however for curing depression it almost sounds like just buying whatever nearest dealer can get you would work, i have seen ketamine, 2c-b, weed, MDMA, LSD and mushrooms suggested for curing depressions. too bad we live in a world where people seem to believe cocaine, heroine and amphetamine is your friend, and you have a future with it. no arms no cookies, you could say..

when thats said.. i dont think the problem is people being total idiots who cant think a minute into the future, i think the problem lays in the idea of limiting others.. just this night a bunch of coke addicts messed up my sleep, 3 past midnight, and many people i know do coke and they imagine it has actual benefits, they see it as a soft drug, for whatever reason, but this doesnt make me want to limit them or the drug either way

think about it.. how many problems arent based on one person trying to or succesfully limiting another?

bigpharma for sure knows the potential of some drugs, and they know those drugs wont get them customers, im as daring as to say that i see a pattern where bigpharma actually attempts to damage people, so that they can earn further credit by treating them with even more medicine, and then treating their sideeffects yet again with useless toxic shit

yeah, there is a future in psychedelics, but its a massive taboo, i dont imagine this being done before greed and the like is eliminated, and chances are everything goes to shit before we reach that point



In the simplest f terms I agree with most all of what you say here.
In the '80s, coke ruled the day. It was then, and probably still is considered "soft" by most users.

Chemosynthises pointed out the Big Pharma problems, and yes, I fear you may be right... There may well be no more "Us" before they figure "Us" out.

Sometimes all of this discussing seems pointless but it beats sitting in the local bar talking about what car is faster, and why.

:cool::cool:

Chemosynthesis - 3-5-2015 at 17:17

The idea that competing pharmaceutical companies somehow collude to poison humanity on a mass scale with unparalleled precision rather than get exposed by competitors, academics, and regulators (any of whom would make their careers, land movie deals Erin Brokovitch style, and score talk circuit retirement laps over that alone), is not only detached from the reality of how drug discovery and design works (in public or private industry), but a gigantic risk of jail time and nonsensical in light of increased drug development costs.

Why diminish your profit margins on a short term gain, risk ruining your company and prison if just one person in a government, academia, another company, or your own company (formerly or current) decides to go public? It's not like disease itself is going away. Plenty of diseases out there people would pay just as much to treat or more to eradicate. You basically have to indict every single scientist in any biologically oriented field, and much of chemistry, to believe this, as well as assume they have no conscious or loved ones with an illness they would personally like to see treated or cured, then largely ignore how pharmaceutical medicine has advanced at some arbitrary point of conspiracy.

Zombie - 3-5-2015 at 20:38

Side effects. Ever see all those late night lawyers?

How about the newest must have allergy pill?

When they list Rectal bleeding , flu, , cancer, enlarged breasts as potential side effects just to help you stop sneezing... I get where Antiswat was coming from.

Like me... He could have worded that better but I get the idea.

Here 26 side effects that come with many prescription drugs currently on the market.

Drainage, crusting, or oozing of your eyes or eyelids
Swollen, black, or "hairy" tongue
Changes in the shape or location of body fat
Decrease in testicle size
Sores or swelling in your rectal or genital area
Blue lips or fingernails
Purple spots on your skin
White patches or sores inside your mouth or on your lips
Irregular back-and- forth movements of your eyes
Enlarged breasts in males.
Unusual risk-taking behavior, no fear of danger
Extreme fear
Hallucinations, fainting, coma
Fussiness, irritability, crying for an hour or longer
Paralysis
Thoracic Hematoma (bleeding into your chest)
A blood clot in your lung
Liver damage
Kidney damage
A lump in your breast
Decreased bone marrow function
Congestive heart failure
Shingles
Nerve pain lasting for several weeks or months
Bleeding that will not stop
Coughing up blood or vomit that looks like coffee grounds
One drug on the market, EvaMist -- a treatment for menopause symptoms such as hot flashes -- has possible side effects that include cancer, stroke, heart attack, blood clots, and dementia!

But this is only a partial list of the potential side effects of prescription drugs. There are, unfortunately, many more out there.

Chemosynthesis - 3-5-2015 at 21:24

You are seriously going to ask if I'm familiar with side effects of drugs? Do you know that drug companies often have to list suspected side effects with tenuous associations to drugs due to how clinical trial and side effect reporting is handled? Who bothers reading those information sheets anyway? Patient compliance, much less reading the booklet, is hard enough.

When someone says "i see a pattern where bigpharma actually attempts to damage people, so that they can earn further credit by treating them with even more medicine, and then treating their sideeffects yet again with useless toxic shit" they are insinuating that drug companies are purposefully designing flaws, presumably type A adverse effects, into drugs with such skill and precision to allow easy remediation, while still getting past approval and avoiding enough negative publicity to kill a company... and that on top of that, everyone is too stupid to catch on, much less a competitor? That is so patently ridiculous it's unbelievable, and that's being generous on my interpretation of the quote; they really said that companies are releasing drugs with zero efficacy, yet demonstrated toxicity at purportedly therapeutic doses. There is absolutely no evidence for this whatsoever.

Drug companies are competing with one another. Releasing a drug that purposefully has a higher incidence of expected side effects for actuarial purposes is one of the most mentally handicapped things a drug company could do! All a competitor has to do is float that hypothesis to the anti-vaccine Scientologist types, or a hungry reporter looking to break a huge story, and they gain conceded market sure. That also gives way too much credit to the omnipotence of pharmacological science. We can't even predict type B adverse effects well enough, as late stage liver problems are the largest reason for drug failures after spending fortunes on pre-clinical and early clinical testing. You would think a drug company would stop throwing money away before investing in a hair-brained scheme to physiologically hurt the public, possibly even themselves. No one with a clue would honestly believe that a company were capable of, much less willing to invest time, money and effort into, such a gambit. It's an incredible insult to anyone working in a pharmaceutical company, biotech, a regulatory agency, academic institution, or hospital involved in any aspect of research to suggest they are either morally bankrupt and complicit or stupid enough to be involved in that.

You don't see physicians or nurses poisoning patients just to sell them more services, do you? Sometimes you get a quack who kills patients, but that can be counterproductive to the whole make money spiel. What makes it so much more likely that a big evil, impersonal company bogeyman manages it on a mass scale without anyone noticing, yet there is no evidence of this? There can't be enough money in one company to buy off every government scientist at every level of government regulation, assuming all were evil. If there were, wouldn't it be cheaper to malign competition? What about the perpetrators who would presumably want safe drugs? Do you set up some kind of secret secondary synthesis and research apparatus? What about distribution? Suddenly you need what amounts to double the effort of just making a functional drug. Designing drugs with fewer adverse side effects would be a better sell because it could likely be taken by more people more frequently with easy marketing as super safe and patient friendly, and make a ton of money. Then you could push it on patients who are hypochondriacs, or think an antibiotic would help with their cold, etc.

[Edited on 4-5-2015 by Chemosynthesis]

Zombie - 3-5-2015 at 21:36

I wasn;t questioning you or what you know. It was a statement question.:o

Of course we all understand your point on this.

I'm just saying, I'd rather put up with watery eyes, than rectal bleeding.

if I meet a gal, and she tells me there is a one in one hundred chance I will bleed out my butt if I sleep w/ her... I'm going home alone.

Yeah poison drugs to sell you more drugs to take care of the poison is ridiculous... So is a bleeding but for hay fever treatment. That's all I'm agreeing with.

(i should have picked a better example):)

gregxy - 4-5-2015 at 13:21

Well one of those NSAIDs DID make me bleed out of my butt. Fortunately I had read the warnings knew to stop taking it.

I don't believe drug companies would market something harmful but the WILL pass up the best treatment simply because its not profitable.

Here is a case in point. Clomid, has been around so long it has lost patent protection. It is the best choice for treating low testosterone levels in men.
Yet no drug company will offer it since there is no way to make money on it.
http://shiramillermd.com/blog/clomid-men-testosterone-altern...
http://www.prohormonepodcast.com/prohormones/enclomiphene-ci...



Zombie - 4-5-2015 at 13:43

LOL... I bookmarked the links.

Chemosynthesis - 5-5-2015 at 13:45

Any NSAID with COX affinity can give a GI bleed or ulceration, which could could present in either fecal or vomit blood. The more selective ones are better are not causing this.

Enclomifene is actually in clinical trials for testosterone replacement therapy in men, and can always be written off-label at the whim of a physician. See clinical trial NCT01270841.

zed - 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]

Chemosynthesis - 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]

Nicodem - 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.

Zombie - 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.

zed - 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


Zombie - 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!

gregxy - 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

Zombie - 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]

zed - 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]

Chemosynthesis - 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.

Chemosynthesis - 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.

Zombie - 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.

Nicodem - 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.

Zombie - 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?

Chemosynthesis - 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]

gregxy - 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]

Chemosynthesis - 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.

Nicodem - 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!)

aga - 19-5-2015 at 15:18

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

OK. Experiment underway.

Zombie - 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

Chemosynthesis - 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.

Zombie - 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? ;)

Chemosynthesis - 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.

Zombie - 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]

Nicodem - 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.

Quote:
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.

Quote:
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]

Zombie - 21-5-2015 at 10:22

Quote: Originally posted by Nicodem  

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").



I have to look that up.
For whatever reason it is these "map" studies that I can relate to the best. It's most likely because I can put an image to an idea. Further on in that paragraph you also mentioned hormones. I have to read more on this as well.

What you stated for Vollenweider is what I believe I am most interested in. Making the connections between these combined brain scans, and other human sciences. There HAS to be a simple, demonstrable approach to seeing exactly what happens, and why. (mystical experience)


Quote: Originally posted by Nicodem  

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.




I think I was a little too far off the base here. I already knew the answer to this one...

I was married to a crazy gal. I mean REAL crazy. (bi-polar, paranoid, schizophrenic) Her doctor(s) kept switching/combining medications, and the girl went thru hell with all the changes. Physically, and emotionally.
I kept asking why the wouldn't do some simple brain scans to see what was happening physically to her. Not while they had her all doped up but when she was clean of all the drugs.
Not one of them ever had a satisfactory answer. One flat out said it was too expensive to run these sort of tests, and they might not be conclusive even if they were run.
My reply was "Is it any less expensive to keep treating her with different combos, and HOPE to find something that worked? Is it less expensive to have her committed 4-7 times a year due to episodes, and reactions? What about the peripheral costs? What about her children? Her family?

Point is since they know certain base line patterns, isn't it easier to SEE what is wrong before assuming what is wrong?


Quote: Originally posted by Nicodem  

Quote:
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]



Well what I mean here is what I addressed above. Does anyone really sit down, and think all of this thru logically? In my x-wifes case... A simple comparison of the known factors should easily point to a potential solution.
It seams to me that these issues have been studied for centuries yet there is no correlated solution.
We understand a rat will swim till it dies or just drown depending on what it's brain tells it to do. We know how to change what the brain tells it to do. We know the mechanisms... Why are there so many holes in this research?

I get the fact that ONE scientist can not possibly correlate all the known data. Hell, even entire institutes have enough combined data to stifle their own results. Something is always lost.
What about computer analysis? Has anyone developed a program to correlate all the know data to seek the commonalities? Sort of a code breaker for the brain. I get the fact that computers only do what they are programmed to do, and can not "think" but it would seem an easy task to at least search for commonalities.

I appreciate you fellas keeping this thread going. This is really the most interesting field in science IMHO.

Chemosynthesis - 21-5-2015 at 15:39

Zombie, I think part of the problem is that you may be conflating CSF and brain bloodflow chemistry with the neural connections themselves. If you want to measure the chemicals in the solution around regions of the brain, you use in vivo microdialysis. If you want to see what happens in each cell or neuron due to drug activity, there is not really a good way to do this now. Some techniques such as patch clamp techniques can show what electrical differences are occuring on various scales (single channel, multicell, etc.) but they have limitations. If want to look at what neuronal activity does in response to to a drug, which tells a lot about the pathways involved, you use MEG, EEG, fMRI, etc. To get a taste of how some of these techniques can work together, read what Nicodem has linked and the Riegel and Kalivas article on benzodiazepine addiction and dependence in PMID: 20148025. It's a fantastic article resolving what was, at once, a mystery in neuropharmacology and drug addiction.

These techniques all tell you different things. They have subtly different implications in terms of longterm effects. You can manipulate each of these by applying different drugs, transcranial magnetic simulation, electrical impulses. It is the context that is important, as gene expression, neural connections, hormonal chemistry, etc. all change in normal, healthy humans. They change on circadian rhythms to assist with sleep regulation (timless/period genes and per, tim, clock proteins). They vary in addiction, such as the imbalance in CRF/cAMP/NPY feedback loop in chronic alcoholic abusers.

Finding/knowing the exact right molecule you want to adjust in an animal of person is just not possible. Knowing how to specifically adjust it in one particular region of the brain is not possible. Being sure you don't affect other parts of the body is definitely not possible. Even knowing what was cause vs. effect is very difficult in these complex systems.

Zombie - 21-5-2015 at 18:04

Born a hundred years too soon I guess... It seems it should all be so simple.

Chemosynthesis - 21-5-2015 at 20:26

Zombie, part of the reason it is simple to you is that you don't understand the resolution or scope of the data, the difficulty in normalizing data to be quantifiably comparable to different experiments even with different equipment and parameters, and the fidelity of some of these experiments. Sometimes we just know what pathways interact, but not what they say, or where in the neuronal game of telephone a particular operation takes place. Reversible cryo-lesioning studies in animals can tell us more about what regions of a neuronal pathway actually do things, but these are not that precise, and again have their own problems.

You asked about some kind of big data analysis center. I knew a small agency that tried automated literature and data analysis for topics including these types of issues... and let's just say the tens of millions of tax dollars wasted could have bought a lot of real science. That is not to say a better implementation with more collaboration wouldn't work, but it is far from easy. Fortunes and lots of intellect has hammered away at it to little avail thusfar.

Chemosynthesis - 21-5-2015 at 20:39

Zombie, part of the reason it is simple to you is that you don't understand the resolution or scope of the data, the difficulty in normalizing data to be quantifiably comparable to different experiments even with different equipment and parameters, and the fidelity of some of these experiments. Sometimes we just know what pathways interact, but not what they say, or where in the neuronal game of telephone a particular operation takes place. Reversible cryo-lesioning studies in animals can tell us more about what regions of a neuronal pathway actually do things, but these are not that precise, and again have their own problems.

You asked about some kind of big data analysis center. I knew a small agency that tried automated literature and data analysis for topics including these types of issues... and let's just say the tens of millions of tax dollars wasted could have bought a lot of real science. That is not to say a better implementation with more collaboration wouldn't work, but it is far from easy. Fortunes and lots of intellect has hammered away at it to little avail thusfar.

Zombie - 21-5-2015 at 21:03

Well I kind of understand chipping away at large projects simultaneously. You keep at it until everything comes together.

Now isn't it similar in (I guess this is molecular medicine?) , and neuroscience? I do get the scope you are talking about. I thought that the tiny little things were all nailed down.
I mean I thought that the brain scan techniques described in the articles were real?

Is part of the problem in allocation to resources? Like who gets to play w/ the baseball but I don't want it getting dirty cause it's mine?

Yeah we did cover this, I just have a hard time accepting it.
Forget about things like dinosaurs, moon rocks, growing corn in space stations, WAR, and volcanoes for awhile. Work on medicine. I think it's a reasonable request.

Maybe it's an overall complacency in humanity... we're not going to survive this anyway. Why bother.

Nicodem - 23-5-2015 at 07:45

After doing some reading about it, I found out that the sub-threshold to threshold dosing of psychedelic drugs is quite popular among some people. They call it "microdosing" (named after the pharmacological method for safe pharmacokinetics probing of new drug candidates). This is not exactly the chronic microdosing that Zombie proposes, however there is some information that comes close to that. Apparently, it is possible to continously microdose using a protocol of 2 days at about 10-20 micrograms LSD, followed by a recovering third day and then all over again. This is supposedly enough to prevent tolerance. Interestingly, even though 10 micrograms is generally considered a sub-threshold dose in regard to the psychotropic effects (30 micrograms is the typical threshold), it was found to improve mood, performance, creativity and is is self-reported as generally beneficial. Until I see scientific results on a longterm study, I rather remain skeptical on how healthy this is supposed to be.

James Fadiman did some research on the application of microdosing in problem solving and creativity enhancement while it was still allowed 5 decades ago and then kept on researching by gathering information from psychedelics users. He has written about it in his books, particularly in the "The Psychedelic Explorer's Guide" and has a nice web site with all his interviews in video and audio formats:
http://jamesfadiman.com/watch-hear.html
For now, I have only listened to his interview for the "The Tim Ferriss Show", but I was seriously impressed.

In regard to interviews and other video materials, here are a few other suggestions:

The LondonReal interviews in relation to psychedelics. They managed to make some excellent interviews with interesting people (I highly recommend the interview with R. Doblin, D. Nutt and R. Carhart-Harris). They also have there several very interesting first hand accounts of ayahuasca and DMT experience. So far, all the episodes I watched were totally interesting.

Hear also the interview with David E. Nichols at Horizons'08.

TEDx: Roland Griffiths on psilocybin and his lecture "The Mystical Experience and Psilocybin Research". See also the account of two of the Johns Hopkins study subjects (participant 1 and participant 2). These are excerpts from the documentary "The Substance" which is an excellent film that I highly recommend (its torrent is easy to find).

BBC Horizon: Psychedelic Science is another excellent documentary.

Inside LSD is a National geographic documentary. Unfortunately it is made in a very lousy style. It looks like some documentary that is made specifically only for the USA public and therefore brings sensationalism in front of factuality, but might be worth seeing.

How do psychedelic drugs work on the brain? is a lecture from R. Carhart-Harris.

Neurobiology of Psychedelics: Implication for Mood Disorders is a lecture from F. Vollenweider about his Swiss group's work on psilocybin, MDMA, ketamine and other related compounds.

[Edited on 23/5/2015 by Nicodem]

Zombie - 23-5-2015 at 10:33

Thank you for posting all of those links.

I have seen 2-3 of them, and others are new to me.
Your statements about self reported improvements in creativity, problem solving, and an overall improvement in the quality of life (my term) are really spot on for my own experience with psilocybin.
I can only assume that others have realized that taking these drugs to threshold, and beyond is not needed unless you are only looking for recreational use. Same for most other mis-used, and abused drugs.

Getting back to DMT... Since it is so similar to psilocybin my hope is it can have similar effects if taken in moderation, and I again hope that the effect can be much more profound. Meaning it can help with MORE self reported symptoms.

The only drawback, and thing that prevents me from experimenting with it is the need for it to be smoked or injected for it to be active on it's own.
I have no use for needles due to all the potential complications, and smoking something off in a corner just feels wrong. That's a bad way to preface a "treatment"

I have considered extracting MAOIs, and DMT to experiment with oral dosing. My life long diet, and other potential complications prevent this.

I sort of feel like a poor kid that found the Sears Xmas book in the mailbox. All of this potentially life changing stuff out there, and you wind up in prison for trying to improve your quality of life yet crack, and dope slingers pay off patrol cops or entire prescient-s to hawk their wares. Please don't comment on that statement...

It's rather sad really... If your life is more comfortable then it only follows that others around you can not help but to reap the benefits. Why oh why is something so simple, so very complex.

I'm going to have a long night watching those vids.
Thanks Nickodem.

Nicodem - 5-8-2015 at 05:49

It appears that Jim Fadiman stirred quite some interest in "microdosing" with his latest study on self-reported effects of microdosing of psychedelics. It appears this topic become quite fashionable since the discussion in this thread. Several media reports talk about it:

Reset me, 21. May: Benefits Of Microdosing With LSD And Psilocybin Mushrooms

Raw Story, 17. June: Microdosing — a new, low-key way to use psychedelics

The Fix, 30. June: 'Microdosing' Psychedelics in Daily Life Shows Increased Focus, Emotional Clarity

Live science, 8. July: Short Trip? More People 'Microdosing' on Psychedelic Drugs

The Vice, 8. July: Can a Low Dose Go a Long Way?

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

As an interesting side note, at least one pharmaceutical company is considering a new application of ketamine for treating depression, however it appears they cannot figure out the mechanism of action and posted this problem as an Innocentive challenge. Ketamine is perfect as it is an already registered drug, so a company only needs to provide a final dosage form for use in a new therapy and skips the most expensive part of the development. But apparently they cannot figure out how this drug can cure depression upon a single application. Looks like their scientist never heard of neuronal plasticity.

Boehringer Ingelheim Challenge: Understanding the Antidepressant Effect of Ketamine

The challenge just got awarded (it was still active last month when I checked). I wish I could see the awarded solution. Ketamine is technically not a psychedelic. It is a dissociative, but just like psychedelics it is well known for facilitating the mystical state.

bereal511 - 20-8-2015 at 13:26

Nicodem,

Thanks for providing all these links. I've only recently returned to the forums after a 7-year hiatus, and it's certainly a breath of fresh air to see the interest in non-recreational uses of psychotropics.

Indeed, I've had a renewed desire to try these micro-dosing experiments after struggling with clinical depression in recent years, so all these discussions have a massive personal benefit for me. I've always been skeptical of the results though, despite the amount of research poured into exploring psychedelics as therapeutics in more controlled medical environments. I mean, you would think that someone would have been investigating low-dosing much earlier in the century...

But the question that tripping-level dosages brings about the changes that lead to long-term neurological/psychological improvement is something I've really hotly debated for myself in my experiences with psychedelics. The weeks and months after the high certainly FEEL like I'm doing better, but without sustained effort in some way, like better lifestyle or improved relationships, the brain certainly can't keep up the feeling. Since then, I've steered away from them - I've essentially associated my ecstatic experiences with the rise of my mood disorder. IMHO, and a subjective perspective, of course. For all I know, some laced substance wore away the neurological circuitry. Or just plain damn genetic luck. Now I'm rambling.

Zombie, I certainly agree with you on your perspective. As more and more information comes out, I feel like I'm just sitting here twiddling my thumbs before an actual full-blown therapeutic legally hits the market.

If you don't mind sharing, Zombie, what sort of dietary problems would you have to face if you wanted to go the gastro-MAOI route for DMT? Milk, bread and meat seem to be the major problem foods, if I recall correctly.

DubaiAmateurRocketry - 1-12-2015 at 20:56

Few month ago my velociraptor tried micro-dosing.

Some of you guys might have seen some articles about micro-dosing psychedelics recently.. and my baby velociraptor tried it out.

I dont know if the SCM community likes this, but i found my velociraptor's diary and here is what it wrote. I found it pretty interesting.


---------


11:00 am - my pet velociraptor took between 20-30 ug of LSD-25.

1:00 pm - my pet velociraptor told me it felt slight body high from the dose. it told me it might been too much of a dose for micro-dosing, it said a good dose is probably 15-20 ug. However no obvious visuals were experienced

2pm - my pet velociraptor finishes all his homework and was surprised that an hour passed. For a long time i saw my velociraptor sitting really focused on its work, it told me it felt like around 10 minutes.

4pm - my pet velociraptor really wanted to go out for a walk because the sun is setting and the world is beautiful.

5pm - my pet velociraptor had a meal and drank some coffee for its soccer game in a dinning hall, it told me it can clearly listen to multiple conversations even though it was really quite, as if its ears were enhanced.

7pm - my pet velociraptor played some soccer, it told me it forgot the outside universe existed during the event because it was too focused in the game. My velociraptor assisted on goal in the game and its team beat some other velociraptors 1-0. I was told the addition of adrenaline into its body made him feel very calm, and slight tunnel vision was experienced.

8pm - my pet velociraptor thought the effects were almost none.

My pet velociraptor said today was a good day, he suggests its a little over whelming for him because he felt over-dosed for daily activities and 10-20ug was probably enough. He would love to do it again once in a while, especially if he would go out side for a long walk, because my velociraptor kept thinking about its life and questioning its existence.

Makes you wonder what they're up to now

franklyn - 3-3-2020 at 02:19

www.yahoo.com/news/did-the-ci-as-notorious-mind-control-prog...


A mad scientist is one who experiments on himself.
A scientist who experiments on other people is called a pioneer.


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