Sciencemadness Discussion Board - Ayahuasca psychedelic tested for depression

posted on 14-4-2015 at 18:07

I base my idea on the fact that DMT does have a positive effect on almost ALL users. (not including abusers in this statement).

Psychedelics in general are not beneficial to all users. It really very much depends on the person and the setting. Some people, particularly excessively neurotic persons, will try to fight back the psychedelic state. On some psychedelics this can be done up to a certain limit, but if the dose is high enough, then there is no way, and fighting it back instead of accepting it can make the experience horrific. If you open the door, you better walk trough. The problem is that it is very difficult to explain a neurotic person that all he needs to do to stop the horror is just to stop resisting. It takes an experienced sitter or a therapist to manage such situations, or better yet just giving it up and stop it with diazepam. Unless properly managed the experience can only be traumatic to them. This was evidenced during the 50's and the 60's when LSD, DMT and other psychedelics were abused by certain incompetent physicians who thought that any "research" involving these drugs is an easy way to get funding and publishing articles. So they would dose schizophrenics, prisoners and other willing or unwilling people in totally inappropriate settings causing them a lot of suffering. Needles to say, that most of these researchers never even experienced the psychedelic state of mind themselves. There were proper researches done as well, but at the end, it is mostly malpractice that remains in the history (and this was even before the perverts from the MKUltra project got their hands on LSD).

(Zombie, the correct acronym is N,N-DMT as for N,N-dimethyltryptamine, but you can skip the regioisomeric assignations when using the acronym as other DMT isomers are inactive anyway)

+1
The whole "induce a model of schizophrenia" thing probably doesn't help in terms of public opinion when discussing psycho-pharmaceutical benefits of classic hallucinogens.

Also, I can confirm a dose a mirtazapine will also fairly quickly "shutdown" almost any 5HT2A type "trip" (LSD,DMT,etc). IIRC, this is due to it being both an antagonist and inverse-agonist at said site. Additionally, I will claim that at about 300mg or over, the effect of smoked N,N-DMT increases no further in intensity, only in length, which I found to be curious.

The big problem in using N,N-DMT for medicinal purposes in my opinion would be it's interactions with other ingested substances (MAOI's etc). I'm of the understanding that coffee, cigarettes and alcohol consumed before a vaporized dose all affect the experience, specifically in potentiating the actions of said substance.

Finally, unless I've missed something, wouldn't down/up regulation of receptors make any positive effects of repeated dosing short-lived(4-8 weeks), therapeutically speaking?

AAAAA = Australian Association Against Acronym Abuse

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posted on 14-4-2015 at 19:34

See the first video, slide with the Andrews-Hannah data? 21:37? I don't mean to libel the authors, as the inference may be valid, but look at how poor that correlation is, and no coefficient is shown in the slide.

Starts at 21:27. That's one BAD correlation. Never mind R<sup>2</sup>, had they calculated confidence intervals for predicted values, I doubt they would have had any appetite for showing that graph! Hard-to-define measurands are part of the problem.

Well spotted...

[Edited on 15-4-2015 by blogfast25]

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Chemosynthesis

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posted on 14-4-2015 at 20:01

Finally, unless I've missed something, wouldn't down/up regulation of receptors make any positive effects of repeated dosing short-lived(4-8 weeks), therapeutically speaking?

Receptor regulation is very complicated. It depends on the specific drug, for one thing, dose and the dosing regimen. You may run into tachyphylaxis, or short-lived tolerance, which can be overcome with a different dosing schedule (though may leave gaps in treatment), or you may run into longterm tolerance. Just depends. These are separate mechanistically, by the way.

As an aside, your point is intellectually valid (though importantly anecdotal, so not confirmatory), but generally we refer to inverse agonists as separate from antagonists.

Quote: Originally posted by blogfast25

Thanks. I stopped watching there for now, so there might be more. I did mean to insinuate the CI being left out (it's probably buried in the text, removed from the figure itself). With the caveat I didn't go find the original publication, I point a lot of this kind of thing out at work because think it's sloppy to do so, even when the result 'sucks' and a bit disingenuous in presentation, but that might well have been the only way to slip it past a reviewer. I know I've been panned for going against the grain in presenting data in what I felt was more honest (i.e. showing overlapping values rather than just the non-overlapping deviations).

Piggybacking on the link I had up above, effect sizes are a huge pet issue of mine. I wish they were published more. Sometimes reviewers ask for them to be removed (a sin in my book, but I have done it) for clarity. They are especially important for large n work. The risk of low n publications is typically demonstrated with type II false negatives, but you can absolutely get type I errors/false positives. I see it all the time. With high n studies, you detect much smaller differences, so statistical significance increases. Sometimes this points out variations which are not clinically significant. This is where effect size and a good understanding of the physiology of your target come into play. General public is oblivious about the former, but anyone not in the sub-field being studied are going to have issues with the latter aspect.

My philosophy is that I would rather trust that the difference is real and read up on/quibble over the tangible physiological, scientific aspects of significance, rather than worry about both. Edit:
This is not to say that smalls studies are without merit, though. Scientific inquiry has very real limitations. The amount of people with an illness that are able to be studied can be small. Human subjects can move or die before you reach a primary endpoint, invalidating their data. Money can be tight. It makes no sense to blow all your funding on a one-shot deal. It's smart and necessary to test on a small scale and move from there, but it's not smart for someone to take those initial steps as definitive. All a low n study shows is that something may be worthy of more investigation in that particular setting. It might not translate to a useful discovery for a number of reasons.

[Edited on 15-4-2015 by Chemosynthesis]

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Zombie, I definitely recommend textbooks and statistics prior to or during investigation into the primary lit. There are issues with neuroscience as a field that are still being ironed out. See the first video, slide with the Andrews-Hannah data? 21:37? I don't mean to libel the authors, as the inference may be valid, but look at how poor that correlation is, and no coefficient is shown in the slide. Some of this is just how neuroscience is, unfortunately. The unavoidable nature of the data. That may be reason for skepticism. Without experience or serious reading on the methodologies, it's hard to say.

Also, there are questions of what statistics are valid. This is a problem in all aspects of science, but recently neuro has been the subject of more criticism for 'hard' sciences: http://www.nature.com/neuro/journal/v14/n9/full/nn.2886.html

I have to also thank you for your guidance.

I find myself googling words more than I spend time comprehending what I am reading, and I am finding that many of the texts I am reading, and lectures I am watching either contradict each other or themselves.

It sort of reminds me of the way I look at things that are accepted in many of the sciences. I tend to put the large pictures into frames or context, and when the smaller images do not line up I attempt to fill in the blanks with my own version of logic.

I see this repeated everywhere in these neuroscience papers, and lectures. We assume, as far as we understand, the current belief is, It is uncertain how, ect..I appreciate this as it is but I have a VERY hard time believing that some of these brilliant people are as brilliant as they like to think.

I might come off as arrogant sometimes but for good reason (IMHO) LOL There has to be a pun in that...

Open mind, Big picture, logical thinking, no presumptions. these are I believe the most important qualities for a researcher.
I read something that got my attention. Maybe it was Nicholls... It stated that researching what LSD does to snowflakes is a way to open the door to further, incidental research.
It could be argued that a snow flake made of LSD the subject of research but the effects it had when it landed on a rat needed to be followed up.
Where the rat came from is anyone-s guess but the point is we need more snowflake studies.

Again maybe not LSD (done to death) but DMT. It's in us, and most other mammals, and plants for a reason.

I'd like to believe it is the common bond, and means of communication we all share. Not very "sciency" but perhaps... Just maybe, that common form of communication IS the God we all seek. Wouldn't that be a game changer.

Quote: Originally posted by Nicodem

posted on 14-4-2015 at 22:49

Mr. Blog,
From what I understand so far you are right. A specific diet must be followed when taking any MAOI. I have not completely familiarized myself with it but I believe I get the "jist of it.
The same can be said of many medications, and conditions tho so that alone should not be a deter-int to trials or research.

The dosing qualities I also find to be of substantial interest. It does appear to be a safe compound. No one has ever over dosed or had problems returning to reality on DMT. I am SURE there are jack-asses out there that have tried. I am assuming this is similar to Marijuana, LSD, Mescaline, Peyote, Psilocin, ect.
This is another factor that tells me it is a preferred substance to research.
You can kill yourself on most anything found in almost any store (when taken in excess) but not these compounds.

I've been holding a card below the table here... This is NOT a SWIM statement but it is a fact as I state it.
I know a young couple with a couple kids. Both parents work, and the kids are kids.
We all know the stresses of daily life as a new family... They started cultivating Psilocybe cubensis approx 2 years ago, and rather than "tripping out", and escaping reality, they began low dosing "cubes" daily instead of the Doctor crap they could have sought (and been given).
The average dose to see threshold results is 4-5 grams dried.
They each take 1 gram in the morning, 1 at lunch, and one at night. 3 grams total per day.

The kids are happier, the parents are happier, and the family is thriving. He has gone from some local restaurant "trainer" to regional manager, and she has opened her own business as a Debt Collector.
They increased their income by 3 times in 3 years, bought their own home, 2 cars, boat, dirt bikes...

They introduced me to their "regime", and I did follow it for 30 days. From the first day I understood why it works.
I am what you call a closet overachiever. I could care less for notoriety but I thrive on creating things that have never been done before.

Right now, at this very second, I have a second 50cc race scooter I am building, a 1970 Triumph hard tail I am building from a frame, and an engine case, a full blown Legal lab I am building with all the equipment being designed, and built by me (and help here), a 1957 Chris Craft 28' sedan I am restoring, a line of hydrofoil sport boats I have designed, and am planing to build, my concentric fuel column I am attempting to patent, raising Presa Canario dogs (seven of them), and running two businesses (boat repair / restoration, and a small engine shop). Add to this my new interest in chemistry... Trying to develop better polymers, and or epoxies, and my interest in this subject.

Combine all of this, and you have a PERFECT candidate for Valium.
I forgo the Big Prarma drug, and prefer the "cube" regime. I am not on this now nor have I been for about a year BUT I can see it in my future.
Some people drink, some take the sedative, some take a mistress.
My choice just so happens to carry prison as the only side effect I know of. How is that for a fine F.U.?

Sorry for the long rant. It's the only way I know to make my point.

Much love! Z

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Chemosynthesis

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posted on 14-4-2015 at 23:05

The big problem in using N,N-DMT for medicinal purposes in my opinion would be it's interactions with other ingested substances (MAOI's etc). I'm of the understanding that coffee, cigarettes and alcohol consumed before a vaporized dose all affect the experience, specifically in potentiating the actions of said substance.

No, as I said, for a psychotropic, psychedelic effect you NEED an MAOI to inhibit MAO degradation of DMT prior to effect. It's the MAOI interaction that is problematic.

MAOI drugs do require specific restrictions in diet to prevent dangerously high blood pressure, potentially fatal serotonin syndrome, and interact with a large number of medications... even those one might not expect, including birth control. It's a complete different order of magnitude than most other drugs, which is why I made a big deal about it earlier. It's a last resort drug for a reason, as I noted. This is why it's so important for medical personnel and trained researchers to determine what is going on, and for in-patient, supervised treatments of any untested medications, and a thorough understanding of pharmacology with treatments.

There is a reason many of these ethnic MOAI therapies require dietary restrictions days in advance.
http://ayahuascaprajna.com/ayahuasca/ayahuasca-ceremony-prep...
http://www.mayoclinic.org/diseases-conditions/depression/exp...

Possibly relevant ahayusca death with few details:
http://newsfeed.time.com/2012/09/14/u-s-teen-dies-after-taki...

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I have seen the first site, and the advice given there is consistent with medical use of MAOI's.
I have not delved into it much further than that but I do understand the basis.

The second link surprised me. I was unaware that a MAOI could be or is used as an anti depressant.
That will take some looking into for me to understand how this works or why it is thought to work. Interesting...

The third link is any-ones guess as to what happened. I can accept the kid died from an MAOI created issue, or they just plain killed him.
The fact that they allegedly buried the kid says a lot. Nothing positive for sure.

I do certainly agree that oral use of DMT MUST be done in a clinical setting. Brewing up your own ahayusca from Ebay finds in unknown ratios / concentrations is rather risky to say the least.
I'm also on the fence with smoking DMT. Perhaps a registered dose in a vaporizer style "prescription could be a useful tool.

Of course you would have to know the time line of the activity inside the body before the compound is broken down.
This is part of something I was reading where they do now have urine tests to determine the compounds of DMT as a whole, and as it breaks down.
The work is not complete but it is a begining. The article is titled AYAHUASCA CHARACTERIZATION,
METABOLISM IN HUMANS,
AND RELEVANCE TO ENDOGENOUS
N,N-DIMETHYLTRYPTAMINES

There is a complete PDF format report, and an on line lecture. The work is being done by Ethan McIlhenny, PhD. I have both D'loaded but lost the links.

This one has the lecture... http://www.psychedelicscience.org/18-conference-workshops/11...

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Chemosynthesis

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posted on 15-4-2015 at 00:04

Smoking is often a self-regulatory administrative route in that one can easily exhale and stop smoking once they have achieved a desired effect. Without requisite monitoring, either at the administrative end or from the plasma concentration, it's scientifically useless as measurements are ignored, but it's relatively difficult to OD or anything from smoking alone.

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posted on 15-4-2015 at 07:58

I am thinking in terms as if it were used as a prescription drug.

Thinking that a low dose could be useful, I am still uncertain if prescribing "vaporizers" is a good idea.

This brings it back to oral dosing, and the real need to deal with MAOI's.

This could be one of the more important aspects of studying DMT. Finding a viable means of administration.

Perhaps something similar to asthma inhalers... The dose would be a little more controlled than smoking.

Interesting topic, with lots of issues involved.

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Nicodem

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posted on 15-4-2015 at 11:56

posted on 15-4-2015 at 17:58

The harmala alkaloids that are the crucial component of ayahuasca are competitive reversible and selective monoamineoxidase A inhibitors. The severe diet restrictions valid for irreversible and nonselective inhibitors used, or having been used as APIs, like the old phenelzine or tranylcypromine, or even the MAO-B selective selegilline, do not necessarily pertain to harmala alkaloids. It is wise to be cautious, but not very clever to make conclusions based on deduction only. Most of the MAOI fears from ayahuasca originate from internet hysteria (reproductions of myths), rather than actual experiments or traditional practice. A lot of the traditional diet restrictions among the South American tribes is mostly part of a fast (a sacrifice), or purely practical in order to reduce the nausea.

As far as I know, there is no general adverse reaction to specific foods from these alkaloids even though ayahuasca is regularly used by tens of thousands of people, many of them regular users. Furthermore, DMT containing plants are not the only admixture used. Many tribes add scopolamine and atropine containing plants (mainly to reduce nausea, but also to modify the effects), or even tobacco or many others. Shamans used to learn about the properties of herbal medicines, by adding the herb to ayahuasca, a terribly dangerous practice if the harmala alkaloids were irreversible MAO inhibitors. In addition, several shamans tend to use the harmala alkaloids containing Banisteriopsis sp in large amounts as the single component for brewing their potion. In fact, the harmala alkaloids alone are hallucinogenic, though they are not psychedelic. Their hallucinogenic effects are actually very peculiar and cannot be classified among the known types of hallucinogens. It is particularly interesting that they give vivid cartoon like closed eye visions, but only in experienced persons, as it requires the cooperation from the mind to bring up its full effect (a closed loop must be established). It is for this reason that apprentice shamans in some tribes used such a basic ayahuasca (without DMT) for training and vision seeking. There is evidence that Peganum harmala seeds, the plant material richest in harmaline, harmine and other harmala alkaloids was also traditionally used as a single component drug to attain visions or mystical states in parts of Asia.

The mechanism of action of harmala alkaloids is still not fully known, but it apparently involves the build up of serotonin due to MAO-A inhibition. Yet this cannot be the whole story as other MAO inhibitors don't give the same phenomenon. These compounds also have a strong affinity toward imidazoline I₂ receptors (DOI:10.1016/j.ejphar.2005.06.023), but what role this has is anyones guess. I'm telling this so that there is no misconception about the harmala alkaloids just activating DMT for oral use and nothing more (some posters appear to see it this way).

Attached is JPET, 2003, 306, 73–83.

Attachment: Human Pharmacology of Ayahuasca.pdf (254kB)
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Chemosynthesis

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Quote: Originally posted by Nicodem

The mechanism of action of harmala alkaloids is still not fully known, but it apparently involves the build up of serotonin due to MAO-A inhibition. Yet this cannot be the whole story as other MAO inhibitors don't give the same phenomenon. These compounds also have a strong affinity toward imidazoline I₂ receptors (DOI:10.1016/j.ejphar.2005.06.023), but what role this has is anyones guess. I'm telling this so that there is no misconception about the harmala alkaloids just activating DMT for oral use and nothing more (some posters appear to see it this way).

Attached is JPET, 2003, 306, 73–83.

Could you clarify as to other MAO inhibitors not giving the same phenomenon? I haven't heard this stated so definitively before, though I am aware that they have only modest 5-HT2R affinities and this isn't/wasn't considered to be their primary mechanism of hallucinogen induction. It's unsurprising if true as different pharmacological profiles have nuances in effect, often of potential clinical relevance, which is part of why I find it so important to have RCT trials and cross-comparisons with different treatments to determine the relative importance of receptor affinity profiles to more specifically target these and reduce off-target side effects potentially resulting in toxicity. It's interesting to note that harmala alkaloids such as harmaline and harmine have shown benzodiazepine receptor affinity, so this may not be accounted for in trying to replicate the exact pharmacological profile with less promiscuous MAOIs. (J. Med. Chem. (1983) 26 p499-503). Opioid binding is noted further below, as is dopaminergic activity in J Ethnopharmacol (2010); 127(2): p357–67and Pharmacol Biochem Be (2003); 75(3): p627–33.

Of course, if your previous hypothesis on the potential irrelevance of pharmacology bears out, and the importance of a psychedelic or psychotropic state is prime in psychotherapy, this is likely an irrelevant point.

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). As MAO inhibitors, ß-carbolines can increase brain levels of serotonin, and the primarily sedative effects of high doses of ß-carbolines are thought to result from their blockade of serotonin deamination. The primary action of ß-carbolines in the ayahuasca beverage is their inhibition of peripheral MAO-A,which protects the DMT in the brew from peripheral degradation and thus renders it orally active. There is some evidence, however, that tetrahydroharmine (THH), the second most abundant ß-carboline in the beverage, acts as a weak 5-HT uptake inhibitor and MAOI. Thus, THH may prolong the half-life of DMT by blocking its intraneuronal uptake, and hence, its inactivation by MAO, localized in mitochondria within the neuron. On the other hand, THH may block serotonin uptake into the neuron,resulting in higher levels of 5HT in the synaptic cleft; this 5-HT, in turn, may attenuate the subjective effects of orally ingested DMT by competing with it at post-synaptic receptor sites (Callaway, et al.,1997)." I see no reason moclobemide or brofaromine could not substitute. They have demonstrated diminished hypertensive crisis risk, though not eliminated risk as well as sharing some of the attributed effects in the above paper. They may well not, and I am interested if this is the case.

Quote:

Respectfully, I don't see what "cleverness" has to do with toxicological risk assessment, but there is more to base concern over than merely deduction. Two non-fatal cases of toxicity attributed to harmala alkaloids are reported in IJPT(2002) vol.1, no. 1 p1-4
Confounding pharmacological factors may be at play, but there is obviously indication of potential risk. The applicability to ayahuasca in certain patient groups (i.e. medical tourists) should be studied, since toxicity can vary among different populations (such as some benzodiazepines showing increased plasma concentrations in a proportion of Asian patients, similar to alcohol/adehyde toxicity, etc.)

Your source itself notes "Interestingly, harmine and harmaline, and, to a lesser extent, THH, are potent MAO inhibitors (Buckholtz and Boggan, 1977; McKenna et al., 1984)."
Reversibility of inhibition may mean little if the inhibition itself is very potent. In fact, Hoffer and Osmond claim harmine and harmaline were 100 times as active as iproniazid with shorter duration in regard to MOA inhibition. Source: The Hallucinogens, (ISBN9781483261690) p479 This is where pharmacokinetic profiles on absorption and elimination come into play, as harmala alkaloids may reach a peak plasma concentration and begin tapering off prior to reaching the peak concentration of DMT. This could result in synergistic or additive dose-dependent drug-drug toxicities, or be masked by the pre-emergence of a harmaline toxicity. In the latter case, this may or may not lead to the design of more effective treatment protocols. In either case, it could still present problems with diet or other drugs. We know that MAOI's, including MAO-AI's, reversible or irreversible can exhibit toxicities.

Your attached source is an excellent pharmacological piece (love ASPET, by the way), but it uses standardized doses in healthy volunteers. This is scientifically important and valuable, but may not apply to uncontrolled formulations or different at-risk populations. Just because a certain geographic/tribal patient cohort has not shown noted incidence of toxicity does not mean that genetically diverse individuals with different diets and co-morbidities will have the same toxicity incidences. The same applies with screened applicants to these treatments centers.

There is reason to believe that high doses of DMT may prove fatal with otherwise typical doses of harmala alkaloids based off of fatalities with the more potent analog 5-MeO-DMT. Ex. Journal of Analytical Toxicology, (2005 ) Vol. 29, p838-841 http://jat.oxfordjournals.org/content/29/8/838.full.pdf
These factors are both relevant in my second point below the quote.

Potential uninvestigated dangers, though possibly not of clinical relevancy in formulation, are the downstream insulin secretion effects (glucose/I3R mediated), and mutagenicity/comutagenicity of harman and norharman alkaloids, or their metabolites. These were included with likely less relevant neurotoxic and mutagenic/carcinogenic b-carbolines described as "very dangerous" in their discussion in Current Medicinal Chemistry, 2007, Vol. 14, No. 4 p479-500
There are also additional toxicological factors that have yet to be thoroughly investigated aside from those mentioned above (ex. noradrenergic toxicity implicated in PMID: 986992). Also "interactions with benzodiazepine, serotonin, opioid, and imidazoline [receptors and] with enzymes such as cytochrome P450" also have toxicological implications. Food and Chemical Toxicology 48 (2010) p839–845

Quote:

As far as I know, there is no general adverse reaction to specific foods from these alkaloids even though ayahuasca is regularly used by tens of thousands of people, many of them regular users. Furthermore, DMT containing plants are not the only admixture used. Many tribes add scopolamine and atropine containing plants (mainly to reduce nausea, but also to modify the effects), or even tobacco or many others. Shamans used to learn about the properties of herbal medicines, by adding the herb to ayahuasca, a terribly dangerous practice if the harmala alkaloids were irreversible MAO inhibitors.

The reversibility of reaction is secondary to potency. Small doses of low potency irreversible inhibitors may not be dangerous. Moderate doses of high potency reversible inhibitors may be dangerous. Don't be confused as to the mechanism of binding or even efficacy with regard to a dose-response curve. Neuro Endocrinol Lett. (2010); 31(5): p645-56 lists IC50 values as 1.55±0.12 and 1105±101μmol/l for iproniazid and moclobemide in pig brain mitochondrial isolates, respectively. While this is a homology model, it does imply that the standard reversible MAO-AI drugs such as moclobemide may not be easily comparable to harmala alkaloids given the Hoffer and Osmond claim. Reversibility is more important in pharmacological "rescue" situations. While not common (we usually assume surrogacy in drug discovery), there are still examples of low affinity/high efficacy drugs (Br. J. Pharmac. (1985), 85, p783-786), so using the affinity of a compound to quantify the efficacy, even with a good grasp of the competitive kinetics, is not always easy to estimate without hard data.

It's exactly the unstandardized nature of ayahuasca that makes it of particular concern for me, since dose is the predominant factor of toxicity incidence.
"The DMT alkaloid has been reported as ranging from 0.1% to 0.66% dry weight in P. viridis leaves [14]. Surprisingly, the DMT in leaf samples from a single P.viridis plant has been shown to vary from approximately 3 mg/g to 9.5 mg/g dry weight in the course of one day. The concentrations of the b-carboline alkaloids in B. caapi have been reported as ranging from 0.05% to 1.95% dry weight [15,16]."
This is a lot of relative variability without additives, and should be investigated further to determine therapeutic windows for different patient risk categories.
Addiction (2007) Vol.102, Iss. 1, p24–34

These kind of issues are exactly why I think further pharmacological/toxicological inquiry is important.
This is supported by:
"Furthermore, because of its potent effect on MAO, the ingestion of P. harmala might result in the interaction with the metabolism of dietary biogenic amines, and particularly tyramine, resulting in hypertensive crisis as a secondary effect. Then, precautions should be always taken avoiding foods containing tyramine or other dietary amines. Nevertheless, results obtained here indicate that MAO inhibition by seeds extract is reversible and highly selective for MAO-A over MAO-B, which is the main isozyme involved in the metabolism of tyramine. These facts could lower the possibility of hypertensive crisis."
Food and Chemical Toxicology 48 (2010) p839–845

Additionally, as to foods, this is an excerpt from Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants by Donald G. Barceloux p53: "Potentially, the ingestion of tyrosine-containing foods along with the MAO-A inhibitors in harmala-containing plants may cause hypertensive crisis similar to monoamine oxidase inhibitor toxicity. Additionally, serotonin syndrome is a potential complication of the concomitant ingestion of selective serotonin reuptake inhibitor (SSRI) antidrepressants with monoamine oxidase-inhibiting harmala alkaloids in ayahuasca." This is in keeping with advised ayahuasca diets.
Additional recommendations supporting my previous non-scientific advisory for ayahuasca pre-therapy diets:
http://www.ayahuasca.com/science/what-foods-and-drugs-need-t...
http://www.herbalandwellbeingsanctuary.com/pre_ayahuasca_cer...
http://www.elmundomagico.org/ayahuasca-the-magical-brew-of-a...
http://raiseyourvibration.com/ayahuasca-safety-precautions-b...
http://www.neurosoup.com/ayahuasca/

These dietary restrictions, and even restrictions on concomitant drug use may be overly burdensome on patients if otherwise non-necessary (be it through use of standardized formulation, drug analog optimization, or both).

[Edited on 16-4-2015 by Chemosynthesis]

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posted on 15-4-2015 at 18:44

How the hell do you two know all this stuff?

I consider myself as a pretty smart fella but I feel like a complete ignoramus reading all these perfectly logical, sensible posts containing dozens of words I have never seen strung together before.

I mean I grasp exactly what you are saying but I have no idea how to express what you have said. I "feel" all the answers, I understand the definitions, but I have NO way to express them.

Perhaps I should have stayed in school a few more days. I think I missed this part.

They tried to have me "put to sleep" so I came back to return the favor.
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MrBlank1

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posted on 15-4-2015 at 19:09

You're not alone there, two "heavy-weights" going back and forth.

I think a very simple, yet often overlooked fact (by others, not here) is that Ayahuasca and DMT smoked are two very different entities.

On a different, unrelated note, DMT's can do wonders for anxiety

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Chemosynthesis

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posted on 15-4-2015 at 20:45

Thinking that a low dose could be useful, I am still uncertain if prescribing "vaporizers" is a good idea

Check out nebulizers. They're used for all kinds of drugs.

posted on 15-4-2015 at 21:01

How the hell do you two know all this stuff?

I don't recall every particular detail from memory. I prefer to be secretive about my background, and mine is unusual, but I do have an advantage over most of the public in this context, so don't feel bad. By chance is this dissertation the article you mentioned one post above? http://etd.lsu.edu/docs/available/etd-06252012-143806/unrest...
I haven't read through it, as it's long... but one thing that jumps out to me is that metabolites are measured in terms of urine excretion. This has limitations. There's more than one way to measure urine concentrations, and you are essentially only measuring the end products excreted, not any intermediates. The method of collection may also have experimental artifacts.... But this looks like an excellent read. I'll have to set aside time to give it the reading it deserves.

To expound on further potential risks of harmala alkaloids, specifically with regard to CYP450, the European Journal of Pharmacology 613 (2009) p119–127 notes that "It is estimated that less than 20% of these [drug toxicity] cases [in the United States] are due to genetic polymorphisms that result in altered metabolism: the vast majority of the adverse reactions are due to individual host or environmental factors such as age, nutrition, or disease state (Ingelman-Sundberg and Rodriguez-Antona, 2005)."
CYP450 isozymes are considered the major metabolic enzyme for xenobiotics. Numbers can vary somewhat, but PMID: 19651758 estimates 75% of all known drugs undergo CYP metabolism.

"The prevalence of NAFLD [non-alcoholic fatty acid liver disease] is estimated to be between 14%and 24% in the world population[.]" Source: European Journal of Pharmacology 613 (2009) p119–127 again.
Note that is is ignoring both cholestatic liver disease and alcoholism induced liver disease for simplicity, so expect this to be even more significant. Both of these ignored groups are likely more prevalent in developed countries with access to large quantities of alcohol, high fat diets, and bowel resectioning surgeries. Longer average and modal life expectancies, which I assume relevant to wealthy medical tourists, will not only increase the incidences of these, but also carry additional age-related risks.

NAFLD and harmala alkaloid use have differing effects on CYP expression, but both commonly inhibit CYP2D6, and CYP2E1 expression (PMID: 19651758 again with PMID: 20041830). The effects of the two do not appear to be studied in humans, unsurprisingly. This could represent a distinct subset of patients seeking treatment with increased risk of some form of associated toxicity. Of particular import may be the fact that CYP2D6 metabolizes harmine, and thus forms a metabolic feedback loop (PMID: 16149329)

Great care must be taken not to exaggerate the following, as they are not human data, nor have I bothered looking into performing FDA suggested interspecies dose conversions because of that. This may have zero clinical relevancy, but it is worth being aware of. Some studies indicate with mouse data that chronically-administered alcoholic extracts of harmala alkaloids may cause hepatoxicity and nephroxicity, in contrast with a previous IV study, but in accordance with cited studies on sheep, horse, and cattle.
The article ends: "In conclusion, these results, suggest that peganum harmala exerted a potent toxic effect on tissues of liver and kidney at dose of 100 and above. In view of its toxicity, harmaline may not be used in food of human and other animals." (Journal of Scientific & Innovative Research 2013; 2 (3): p585-597).

Similarly, in Journal of Animal and Veterinary Advances(2009) Vol. 8, Iss. 8, p1535-1538, notes "Although the P. harmala and B. undulata leaves are commonly used in Jordan and other countries for the treatment of various ailments, toxicological information on chicks or rodents is unavailable. The results of the present study indicated that 10% P. harmala and 10% B. undulata or 5% mixture of two plants in the diet were toxic but not lethal to chicks when fed for 2 weeks. Inappétence as well as the damage to the liver could explain the depression in growth.

It has been suggested that the susceptibility of chicks, rodents and livestock to plant material is at least dependent on the type of active constituents and concentration in the amount added as well as the rate of their metabolic conversion to metabolites and consequent excretion (Barri et al., 1983; Bakhiet and Adam, 1996a; Adam et al., 2000)."
I don't know enough about non-human liver enzyme serology levels to give a personal assessment of the article, but it notes "There was mild fatty change in the liver of the chicks in groups 3 and 4. Hepatic fatty change was marked in group 2 with congestion of the blood vessels or hemorrhage especially in the heart. On microscopy, fatty cytoplasmic variolation and individual-cell necrosis of the centrilobular hepatocytes were observed."

It is possible that these changes do not occur in humans, that the dosing schedules are not comparable to psychotherapeutic use, that the changes do occur in humans at a mild extent and transient duration, and/or that the effects would only be of clinical relevance in predisposed populations, be they idiosyncratic (not uncommon for drug induced liver problems) or co-morbid. Ex. "Simple steatosis is characterized by micro and macrovesicular steatosis and predisposes the liver to the more severe non-alcoholic steatohepatitis (NASH) (Koteish and Mae, 2002)."
Source: European Journal of Pharmacology 613 (2009) p119–127 again.

[Edited on 16-4-2015 by Chemosynthesis]

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How the hell do you two know all this stuff?

I prefer to be secretive about my background, and mine is unusual, but I do have an advantage over most of the public in this context, so don't feel bad.

To expound on further potential risks of harmala alkaloids, specifically with regard to CYP450, the European Journal of Pharmacology 613 (2009) p119–127 notes that "It is estimated that less than 20% of these [drug toxicity] cases [in the United States] are due to genetic polymorphisms that result in altered metabolism: the vast majority of the adverse reactions are due to individual host or environmental factors such as age, nutrition, or disease state (Ingelman-Sundberg and Rodriguez-Antona, 2005)."
CYP450 isozymes are considered the major metabolic enzyme for xenobiotics. Numbers can vary somewhat, but PMID: 19651758 estimates 75% of all known drugs undergo CYP metabolism.

.

I don't feel particularly bad about being ignorant in certain areas but I do feel bad about not being able to simply fix the issues that bother me in life.

I can fix a toaster or a space shuttle. They are both mechanical and everything has a systematic function. Easy stuff.

The human physiology is exactly the same but with organic components, so why is it that I don't see the answers in the same way?
I assume it is because there are soo many nonsensical names for all the systems. (plus you're not really allowed to take people apart, and try to put them back together...)

That being that, I don't understand what role CYP 450 plays.
As I understand it CYP 450 is a gene that dictates what a specific enzyme does.

"The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into the aliphatic position of an organic substrate (RH) while the other oxygen atom is reduced to water:"

Is this the reaction that would normally metabolize DMT or is this the reaction that prevents the metabolizing of DMT?

posted on 15-4-2015 at 21:14

By chance is this dissertation the article you mentioned one post above? http://etd.lsu.edu/docs/available/etd-06252012-143806/unrest...
.

Yes That is the article.

All the rest of your post goes a long way toward opening my eyes on the simplicity of many of my arguments regarding my assumed benign nature of the MAOI's used in conjunction with oral DMT dosing.

Point taken.

As you point out the existing animal studies may / may not apply so of course more needs to be learned.
As the thread is about Ayahuasca these conversations do apply. Albeit somewhat distracting (for me) they are important aspects.

Now to get simple again for a moment... Since there are some psychotropic qualities to the inhibitors, yet there are some risk factors... Why not separate the two?
Why not break the compound down, and do away with whatever acts as the MAOI.
Same goes for DMT. Why not modify it in such a way that it is not reactive in the metabolic system?

Combine the best from both, and there you have it.

Is this unreasonable to assume this can be done?

They tried to have me "put to sleep" so I came back to return the favor.
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posted on 15-4-2015 at 21:55

Did not mean to pass this up... The method of administration does obviously make a huge difference in the effect the compound has.

It is easily understood that oral dosing creates a gradual onset, longer duration, and slower return to "base line".

Most of the arguments I have read supporting oral administration are logical. This method allows the user to adjust to the new "psyche" or state of being. The increased duration allows for a better sense of acclimation or understanding of what is happening, and why.

I can imagine this more in tune with taking a long walk in a strange reality.

Smoking on the other hand must be more in tune with falling from an airplane into the same reality. There is no time to adjust. Just deal with it.

Now this again comes to what is really happening?

They tried to have me "put to sleep" so I came back to return the favor.
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Oh, and I forgot to mention that CYP450 2E1 is the minor metabolic pathway for alcohol metabolism (vs. ADH's). One can imagine this could affect patients consuming alcohol, depending on validity, onset and duration of effects... particularly if they have alcoholism-induced fatty livers or cirrhosis. In this case, it might even be beneficial if relevant because this pathway creates free radical reactive oxygenative species, and down-regulating it might be beneficial in that regard, but may induce other problems (shunting more alcohol to aldehyde). It may depend on individual enzymatic kinetics, which I am not an expert on.

posted on 15-4-2015 at 23:31

The human physiology is exactly the same but with organic components, so why is it that I don't see the answers in the same way?

My take: 1) you don't have the training. This training is perishable as methodologies and techniques change. If I don't know how to use an ampmeter, or never learned Kirkoff's law, Ohm's, etc. I would be completely caught offguard with a circuit diagram. Instead, I am just passingly familiar with them. Actually an area I would like to be more proficient in.
2) It's hard. Small scale: Cells are tiny, and it's hard to see what happens inside of them without destroying them or altering their function. This can be clumsy.
Intermediate scale: Yes, dissecting people or implanting them with in vivo microdialysis tubes or whatever is medically unethical.
Big scale: Getting volunteers, especially who stay the course, is troublesome.

Quote:

I assume it is because there are soo many nonsensical names for all the systems. (plus you're not really allowed to take people apart, and try to put them back together...)

Uh, yeah. It certainly doesn't help that there are multiple competing names for enzymes. If two people start characterizing it at the same time, you can form little political camps who rally behind their buddy, vying for a Lasker or Nobel prize. People are petty.

Quote:

That being that, I don't understand what role CYP 450 plays.
As I understand it CYP 450 is a gene that dictates what a specific enzyme does.

"The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into the aliphatic position of an organic substrate (RH) while the other oxygen atom is reduced to water:"

Is this the reaction that would normally metabolize DMT or is this the reaction that prevents the metabolizing of DMT?

Close. With DMT it's a similar overall reaction with oxidative deamination, rather than hydrolysis.

Further phases of metabolism can occur. It would be interesting to compare PMID: 2251412 with the dissertation you found.

Quote:

Now to get simple again for a moment... Since there are some psychotropic qualities to the inhibitors, yet there are some risk factors... Why not separate the two?
Why not break the compound down, and do away with whatever acts as the MAOI.

This is what I would have done in an ideal study. The problem is getting enough patients. Varying orders treatments and doses to include different combinations of an MAOI of choice, MAOI+DMT, harmala alkaloids alone, and harmala alkaloids+DMT may be part of a good trial, but it's logistically difficult. You have to make sure the order of administration doesn't impact the effects secondary to the currently observed treatment, for one thing.

Quote:

Same goes for DMT. Why not modify it in such a way that it is not reactive in the metabolic system?

Combine the best from both, and there you have it.

Is this unreasonable to assume this can be done?

There is no reason at all not to do this, and it is a good idea (as well as something I would love to see studied). It's actually something I hinted at previously and is a common technique in drug optimization to tailor the half-life of a drug by altering it in a manner which doesn't affect the target receptor affinity significantly (how much varies) but diminishes metabolic enzyme affinity. Extending the n-alkyl groups does this in DMT (ex. diethyltryptamine/DET), but there are steric limitations.

Dose-response is also still important. According to the original article, it may very well be sub-psychedelic doses (or even future analogs) that could be therapeutic:
"AYA administration did not produce statistically significant sensory, cognitive, or affective modifications as assessed by the BPRS and YMRS scales. Although nonsignificant, in the present study these effects were observed during a period ranging from 80 to 140 min after AYA administration, which is the time point when the subjective effects of AYA are peaking, as are DMT plasma levels.8-12The absence of statistically significant effects on BPRS-TD scores could be explained by the DMT concentration found in our AYA batch (0.08 mg/mL), which is lower than DMT doses used in previous studies that reported significant psychotropic effects of AYA (0.53 mg/mL DMT).9,12 The nonsignificant effects of AYA on the BPRS-TD subscale suggest that changes in sensory perception and thought content may not be essential for therapeutic effects."
Rev. Bras. Psiquiatr. (2015) vol.37 no.1

This remains to be seen more definitively, but possible explanations are functional selectivity, alternate receptor binding, signaling integration differences, etc. If it is the case, it is possible a drug company would get a waiver/exclusion/scheduling judgment for a non-psychedelic analog, roughly similar to how cabergoline is structurally related to LSD, yet is legal.

[Edited on 16-4-2015 by Chemosynthesis]

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All of this I easily understood. Thank yo!

I had to look up "steric limitations" but that also makes sense (considering the scale).

So basically what you are breaking this down to is a "mechanic or fabricator" with no medical training can understand the issues associated with medicinal molecular chemistry, find potential routes to solutions for issues caused by whatever compound (fit a square peg in a round hole by modifying the peg), YET 1000 years of trained medical professionals are not allowed to do what they do because politicians don't understand any of this?

In a nut shell, political issues are determining what is best for humanity, and the medical scientists are there for, ?????

I mean really now. Sure there are important things like preventing warts with vaccines or making Tums work better but mental health? This takes a back seat?

I sort of get it. If you look at all the damage medicinal / medical studies have done in the past, and combine this with Big Money Pharma, and political lobbyists it paints a very dark picture.
Sooner or later you have to trust that research is both valid, and needed. I now see however that limited amounts of "product", patients, research space, time constraints, research field constraints, all set by people that have no need for the resultant product, it's easy to see what is happening.

So. Just like in political issues I will ask the same question.

What can a single person (ME) do to help change the way things are?

Is this entire conversation a masturbation of the mind? Too many of them are. I get tired of finding flaws that have no method of repair.

They tried to have me "put to sleep" so I came back to return the favor.
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MrBlank1

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posted on 16-4-2015 at 00:01

Zombie :

It's worth noting that smoked DMT does not need to combined with an enzyme inhibitor to be psychoactive. It's only oral use that requires a MAOI compound (harmala,etc) to decrease the rate at which DMT is broken down, thereby enabling it to become active.

This being said, the common reason for dietary/drug considerations when smoked (amongst 'psychonauts') is due to (perceived) pronounced differences in effect/experience with seemingly trivial (at first) variations of diet/drugs.

Since there are no actual studies (that I know of) measuring the relationship between inhaled dmt + diet/drug factors = variation of DMT-only clinical response, there is some valid cause for concern/caution in this regard (to the non-learned) when one looks at the pharmacodynamics and kinetics of DMT.

As for the question : In the short term, that will have a directly noticeable effect, within the bounds of the law, speaking strictly in terms of psychedelic-hallucinogen treatments? Very little, unfortunately. The current view on 'drugs' held by the global majority will likely exclude any significant research/approval of these compounds for decades yet.

Unfortunately, more focus is on prohibiting access to illicit drugs, rather than identifying factors that reduce demand.

[Edited on 16-4-2015 by MrBlank1]

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posted on 16-4-2015 at 02:53

Had a response typed up and lost it. I also noticed my autocorrect somehow saved "ahayusca: rather than the correct ayahuasca. How annoying. Edited a couple previous posts to add additional information, for the curious.

posted on 16-4-2015 at 11:04

All of this I easily understood. Thank yo!

You're welcome. I am glad I was comprehensible.

I can only really give my opinion, and am not fully comfortable doing so, as it's fallible, of limited perspective, and probably more suited for Whimsy (where I do not go). I will reluctantly post below hoping not to derail the thread, and that it answers what you asked (as it's kind of vague).

I can't speak as to peoples' motivations, and there are plenty of scientists in government regulation. If you are sure you want different restrictions, I am not sure how to achieve that, politically. The only thing I can think of is to non-belligerently push for more scientific funding. This will take money from other areas.
From a private industry perspective, if the government is not restrictive, and marginal profit is appealing, pharmaceutical companies will look into it. It's difficult with analogs of class 1 drugs now, and psychological illnesses are so poorly understood, that it may make more financial sense to invest elsewhere.

With government, decisions are made according to who writes the best grants, and politicians', lobbyists' advisors' (science and othewise) and regulators' values or their perception of voter values. This includes funding for some diseases which disproportionately affect minorities, or have no treatments available (as opposed to those with poor treatments). Whether you agree with the funding decisions will vary. Just as most clinicians don't perform science, most administrators don't perform their own science anymore either. Some do, but it is rare as they are divergent fields and require different personal qualities. I won't lie... some investigators are not necessarily high quality or honest either, and I have often found myself less than impressed by politicians I have known in passing.

With private industry, money talks. The marginal profit per project over some arbitrary timepoint is how they view value. The underlying assumption here is that people who provide more societal value tend to make more money, and so whatever group offers the highest marginal profit tends to be proportional to the highest societally-valued need being met, or the need of the most societally-valued individuals, per the cost of research. Some blend thereof.

That is my perspective, at least. Ultimately, the decision to fund one issue over another is kind of arbitrary. I could just as easily say "I don't personally believe group X deserves funding" because of any reason. I could have personal bias for my own issues (such as my insomnia), hold a grudge, or falsely believe another disease is easier to cure/treat than it is. Just as with any scientific study or experiment having flaws... every value system will exclude some people, even if they are internally consistent, because they may contain aspects that are mutually exclusive.

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MAOIs can be used for depression and Parkinsons disease

Selegiline is selective for dopamine at low doses. It also makes lab animals live up to 30% longer.

http://www.ncbi.nlm.nih.gov/pubmed/16804014

You can buy some here http://www.antiaging-systems.com/

Beware, since it disables the MAO its effect lasts for 30 days!
At low dose it lowers blood pressure instead of raising it like most MAOIs

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posted on 16-4-2015 at 12:33

Quote:

I forgot to address this. Getting a little off track so I hope I don't get lost, again.

I keep trying to find any form of literature detailing sub psychedelic dosages of DMT but... cannot.

This again relates to is the compound chemically active or physiologically active?

I still have not located the "brain maps" that showed the activity centers while the patient(s) were administered psychoactive doses. They are in fact very similar to the psilocyben maps I linked earlier but more profound.
I would very much like to see comparative mapping in low dose studies. This alone would go a LONG way toward opening new doors in research. Just as you stated Chemo.

This is actually the main focus of what I would like to know.

It's kind of the same thing for the marijuana arguments I have. People shouldn't have to get "stoned" to see the benefits of marijuana. In fact it make ZERO sense to me that states would allow people to get high under the pretense that they are taking medicine.
Perhaps the obvious is the unseen in this case. I deal with people from all stations in life daily. Some Doctors, Lawyers, politicians, cops, clerks, jobless bums, millionaire business owners, ect... A common thread for all of them is I will guess that 6 out of every ten, in each group uses weed at least a few times a year.

The same can not be said for DMT. In fact I will guess that two in ten has heard of it, and one in ten actually knows what it is. For the rest if you attempt to tell them it is a psychedelic compound found all over nature, and is inside them right now... They'd most likely knee jerk, and the present issues with research would never end OR we would face a new wave of "hippies", again compounding the problem.

Rant done. I forget where I was anyway...

Oh yeah... If low dose brain images verify the compound is working on the receptors, then the results in the therapeutic models (depression, anxiety, ect.) would easily provide the answer to the "Is it a psychological or physiological process." question.

Now how about this...
They have these "churches" that are allowed to use DMT/ Ahyauska. Wouldn't the common sense move for ANY researcher truly interested in finding these answers become a member of this "church, establish a fund raising campaign to set up shop, and use volunteers from this group to complete these studies?

I only see two issues.
One) Who's gonna pay this guy/team, before, during, after. There goes a career eh?

Two) gray area in the law I assume...

Now IF I were educated enough in this field, I would chomp at the bit to get this started.
Do the research,Patent the new wonder drug, and have that "church open the Pharma company that manufactures the best thing that has happened since Penicillin. Why not?

It seems a simple solution to the complexities you posted answering why politics gets in the way.
Over simplified? Heck yeah.
Could it be done? Why not???

As always, in just a few pages of posts decades of arguments are laid bare. Really the only large hurdle is money. I am CERTAIN there is a benefactor out there that could alone fund such a project.