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Author: Subject: Ayahuasca psychedelic tested for depression
Mesa
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[*] posted on 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]
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[*] posted on 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.
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[*] posted on 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.
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[*] posted on 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.
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[*] posted on 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.




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[*] posted on 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]
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[*] posted on 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.
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[*] posted on 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.




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[*] posted on 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.;)
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[*] posted on 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).




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[*] posted on 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]
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[*] posted on 25-4-2015 at 06:22
Classical hallucinogens as antidepressants?




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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[*] posted on 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.
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[*] posted on 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....




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[*] posted on 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.
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[*] posted on 25-4-2015 at 10:28
Treatments for Arthritis and dermatitis with MDA (3,4methylenedioxyamphetamine)





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]




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[*] posted on 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.



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[*] posted on 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]
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[*] posted on 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"?




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[*] posted on 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.
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[*] posted on 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?




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[*] posted on 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.
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[*] posted on 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.




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[*] posted on 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 126 times





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[*] posted on 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.
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