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Mesa
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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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Chemosynthesis
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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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CrimpJiggler
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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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Chemosynthesis
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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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Nicodem
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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).
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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.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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Mesa
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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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Chemosynthesis
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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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Nicodem
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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.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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Chemosynthesis
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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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Nicodem
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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.
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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).
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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Chemosynthesis
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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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solo
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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.
Attachment: phpTIT0fS (1.1MB)
This file has been downloaded 406 times
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Chemosynthesis
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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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S.C. Wack
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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...
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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Chemosynthesis
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| 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.
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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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solo
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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.
Attachment: treatment fpr arthritis and cast dermatitis.pdf (271kB)
This file has been downloaded 484 times
[Edited on 25-4-2015 by solo]
It's better to die on your feet, than live on your knees....Emiliano Zapata.
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Metacelsus
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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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Chemosynthesis
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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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Nicodem
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Threads Merged
25-4-2015 at 12:34 |
Nicodem
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Threads Merged
25-4-2015 at 12:36 |
Zombie
Forum Hillbilly
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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"?
They tried to have me "put to sleep" so I came back to return the favor.
Zom.
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Chemosynthesis
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| 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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Zombie
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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?
They tried to have me "put to sleep" so I came back to return the favor.
Zom.
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Chemosynthesis
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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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Zombie
Forum Hillbilly
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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.
They tried to have me "put to sleep" so I came back to return the favor.
Zom.
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solo
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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 506 times
It's better to die on your feet, than live on your knees....Emiliano Zapata.
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Chemosynthesis
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| 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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