Sciencemadness Discussion Board - Ayahuasca psychedelic tested for depression

The other thing is that Big Pharma has been aware of these drugs for 50 years. In spite of their class 1 status, I'm sure they have researched the hell out of them. If there was a way to make them work for depression etc. I think they would have found it already.

Cannabis is another story. It is illegal because Big Pharma and Budwiser don't want competition from something you can easily grow in your yard.

Is the first paragraph your opinion or fact?
I'm not asking to be disrespectful.

To set a "buffer zone" in this thread... I am referring to a regulated dose, controlled fashion use of specific compounds.

You do not need to meet Jesus in order for a compound to have an effect.
while 60 Mg of Valium can be a hoot, I don't think that is what the prescribed use is intended to be.

N N-DMT in controlled / less than threshold doses is what I am talking about, and I believe that is where the research is.
I already mentioned we do not need more "trip reports". We need facts.
In this case the placebo effect is an accountable control for determining some of the effect.

As far as Weed is concerned...

My same approach applies. There is NO NEED FOR AN OUNCE OF WEED when a few Mg's of extracted compound will last a month in controlled doses.
Most people would suddenly get cured if it were only allowed as a 0.45Mg pill that had the same medical effect as 20 "Bong Hits", yet did not get you high.

I don't even care what ANY pot smoker says. It's about the high. Nothing more. Go bleed in the street. I don't care.
The fact is people have manipulated the use, and effects to the point they are doing the equivalent of 60mg Valium doses several times a day.

Did I mention I HATE stoners as much as any other form of drug addict? I should have.

Like much of YouTube... Addicts, or any sort of abuser help form the poor image of many useful compounds.

For hells sake, you can't even buy battery acid in many parts of the world. Did that happen because we don't need batteries? NO!

Abusers destroy everything in their wake.

This is the fate of Mushrooms, cactus, DMT,
Low controlled doses for specific uses have been shown time, and time again to be beneficial but stoners rule the day.

Find a way to get high on air. I'm tired of it all around me all the time anyway. Air is Soooo annoying :mad:

. I want it gone.

[Edited on 4-8-2015 by Zombie]

blogfast25 - 7-4-2015 at 17:12

Is the first paragraph your opinion or fact?

I could ask the same about your initial long ramble. Maybe (!) tomorrow I might make some time to rebut some of the points you've made so far.

On the positive side, I'm all for controlled research into psychotropic substances, on the 'sub-high' dosage level (for potentially therapeutic purposes). But substances that have potential hallucinatory side-effects will often not make it onto the 'to do' list of most licensed researchers. That has little, if anything, to do with 'hippies' or 'raping drug users' or 'stoners'.

By the way, without these 'psychedelic' effects, who would ever have heard of, say Ayahuasca? It's precisely their obvious effects that draw attention to them and might, potentially, make them interesting subjects of study as therapeutics.

[Edited on 8-4-2015 by blogfast25]

Zombie - 7-4-2015 at 17:34

Quote: Originally posted by blogfast25

Is the first paragraph your opinion or fact?
I'm not asking to be disrespectful.

I could ask the same about your initial long ramble. Maybe (!) tomorrow I might make some time to rebut some of the points you've made so far.

On the positive side, I'm all for controlled research into psychotropic substances, on the 'sub-high' dosage level. But substances that have potential hallucinatory side-effects will often not make it onto the 'to do' list of most licensed researchers. That has little, if anything, to do with 'hippies' or 'raping drug users' or 'stoners'.

By the way, without these 'psychedelic' effects, who would ever have heard of, say Ayahuasca? It's precisely their obvious effects that draw attention to them and might, potentially, make them interesting subjects of study as therapeutics.

[Edited on 8-4-2015 by blogfast25]

You usually call me out on my over dramatic flair. I will try harder to work on this.

It's akin to the issues with chemistry in general.
The bad apples tend to spoil things for the rest. I've only spent a few months researching this topic but I do have some very interesting information to date. Trouble is there is not much in the way of actual published research. I say not much but there is some...
Dr Robin Carhart-Harris is one of the better researchers in my opinion.
http://www.pnas.org/content/109/6/2138.abstract

David Nut works mainly on depression, and its treatment with Psilocybin.

Roland Griffiths works mainly with addictions, and treatment...
Quote: CNN
" Initial studies by Griffiths and his team to treat smoking addiction have found 80% success rates in people quitting the habit up to six months after their treatment. Their studies indicate that psilocybin-based therapy could potentially be quicker and more effective than long-term therapies such as nicotine "

Just a simple google search reveals thousands of pages on the subject.

https://www.google.com/search?q=psilocybin+depression+treatm...

blogfast25 - 7-4-2015 at 17:52

Harmine drug that restores beta cells seen as key diabetes treatment

Just a simple google search reveals thousands of pages on the subject.

Mostly MSM rehashes that feed the echo chamber known as 'the Internet', of course. But as always, it's the few gems that really matter. Will have a look tomorrow.

cyanureeves - 7-4-2015 at 18:14

i've always lived around dope haters,they will always be around also.the murder rate among coca leaf chewers is not high i bet but somehow we americans do kill for the coca product.i will always be a doper because the chemistry is awesome.i can swear by dmt but will stand by zoloft because i have to live among people.i'm feeling a bit depressed and will soon be dancing with chacmool,that scary son of a bitch!

mayko - 7-4-2015 at 18:15

In other recent ayahuasca-related news:

Quote:

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

cyanureeves - 7-4-2015 at 18:45

also got that! i should be a happy healthy mug according to latest studies and rats and such. gas is my problem and i swear it started when i used acid way back.any how i learned how to do acid/base extractions,bought ph meters and learned about none polar solvents,got many dirty looks at stores while purchasing most the stuff.i dont regret nothing and now i think quite a bit about how i might feel when i'm pumping my last drop of blood when i die.i think about my old man seeing all kinds of colors and crap he didnt understand when he died.our bodies release dmt when we expire and it is scary but maybe i will be familiar with all this stuff.i've seen the aztec gods and hope i dont see some weird nordic god when i die because then i'll know i'm really dead.

Chemosynthesis - 7-4-2015 at 22:21

Do all keep in mind that this was a study utilizing six patients, so there are very clear limitations with sample sizing alone, not to mention the type of study (open label). As a preamble to a larger double-blind trial (with pre-determined effect sizes and valid statistical testing), it's not useless, but still very limited.

a placebo effect would certainly indicate a troubled person or an imaginative individual with mind reading capability. a placebo that causes visuals and hallucinations could no way be a placebo unless maybe the patient is told about the drug's effects.

I'm not sure what you mean by this statement, as the placebo isn't measured against hallucination. Yes, it's difficult to test psychoactive substances with a placebo control because it is often readily apparent what the placebo treatment was, which un-blinds the subject, but this is where methodological critiques come into play (and I am sure I will have issues with the eventual paper, as will the authors publishing it). Placebo doesn't necessarily have to be totally inert. For example, in ahayusca, harmaline alkaloid MAOIs are administered to make DMT orally bioavailable to the brain rather than peripherally metabolized. Clearly MAOI drugs have been used to treat depression, so using an MAOI alone in a refractory patient cohort, or a mildly emetic substance with peripheral muscarinic antagonism and 5HT3 agonist effects may serve as a type of placebo. If the authors claim to have placebo controls, I want to see the paper they referenced to be published. They may be using an active placebo, which is not uncommon (even in analgesic studies, which may surprise you), but this would be difficult in such an uncharacterized substance as a plant extract, which is problematic.

Placebo and nocebo are very real and have to be discriminated against, even in psychopharmacology, which is less controllable than most other disciplines of pharmacology, including neuropharmacology. With some substances, this is clearly difficult to do, as marijuana is smoked, though oral dronabinol has had placebo trials (http://www.ncbi.nlm.nih.gov/pubmed/21310551). Trials are still conducted with inactive vs. high doses of caffeine or nicotine, and it is obvious which treatment group gets what drug. Some mitigation of placebo (at least on the part of the anticipatory or researcher driven kind) occurs.

Just because a patient received a treatment, psychoactive or not, doesn't mean the actual drug alleviated depression, that there were not confounding contributory effects from methodological flaws, nor does it necessarily apply for each patient group since depression is likely a heterologous disease since it's known that some patients respond better to some treatments than others.

the murder rate among coca leaf chewers is not high i bet but somehow we americans do kill for the coca product.

Steady state concentration is dependent on both dose and rate of absorption. Clearly a dilute, ingested leaf versus a purified and snorted/smoked/IV'd substance will have drastically different pharmacological profiles.

our bodies release dmt when we expire .

That's just an urban legend/potential hypothesis that has never been substantiated. I imagine that if you were acting is mercurial as your posting has been lately, that people did give quite a few looks.

Most biomedical research and drug development takes place in the US.
Much the medical research in pharmacology from 1962 onwards was spent re-testing medication in use but not tested for safety since the 1938 Food, Drug, and Cosmetic Act. The Controlled Substances Act has been law since 1970, and many countries mimic this regulation through the United Nations and International Narcotics Control Board, so research isn't necessarily as simple as you may believe.
A lot of paperwork goes into even working with these substances, as in DEA Form 225 approval on top of FDA and local/state compliance and is usually performed in academic hospital settings with additional funding sources (thus more paperwork, IRB panels, etc.). Additional security and records keeping is required for these substances, and they are in limited supply depending on the national quotas manufacture.

In order to argue for any clinical trials, you have to supply various pre-clinical sources of data, which are generally lacking for many psychoactives, and your experimental protocol to be separately approved at each clinical stage. Additionally, each schedule 1 narcotic to be tested requires a dedicated registered researcher for that substance, as well as a physician registered practitioner for dispensing purposes. These are special categories within DEA registration, not just any licensed person. Most of the literature with psychoactive substances stopped with animal model trials, not human ones. It takes an average of 12-15 years to go from optimized lead to completed clinical trials, so you could rule out many of the psychoactive substances being easily tested in humans before 1970.

Even at large medical centers with concurrent research and addiction treatment aims, there can be trouble enough just administering said substances to rats. This is a part of why studies on schedule 1 narcotic abusers don't supply the individuals with pure drugs for testing. Basically, no pharmaceutical company wants to try to invest billions in new drug testing only to then try to lobby to reschedule a drug. That is a losing game, financially. Not least of which due to the change in patent filing in the US. You either risk getting scooped by waiting until the drug is rescheduled to file... or you file and lose out on precious patent time lobbying, which might not even be successful.

Nicodem - 8-4-2015 at 13:41

There are many studies that demonstrate psilocybin, LSD other psychedelics reduce the symptoms of depression for long periods, sometimes after as little as one treatment. One of the latests reviews on the this topic can be found in Therapeutic Advances in Psychopharmacology, 2014, 4, 156-169 (DOI: 10.1177/2045125314527985). There is lately a renaissance of studies related to treatment of depressions, substance addictions, obsessive compulsions and other psychological conditions with psychedelics, but nearly all of these studies are just a reiteration of studies already done more than 50 years ago. At that time psychotherapists could still use psycholytic and psychedelic treatments with LSD and other psychedelics, with remarkable achievements (and misschievements when used in malicious or incompetent hands).

The use of placebo can compromise the results of a study with psychedelics, as it will have effects beyond the neutrality. In my opinion, the group that receives a placebo cannot be used as a control group. Due to the peculiar nature of these drugs, a placebo given group will have unpredictable consequences as a response to the "treachery" (stress, resentment, etc.) that will undoubtedly affect symptoms. Just imagine a placebo used in cancer patients, except that the patients immediately realize they received a placebo. Such a placebo will have undesired effects that could negatively affect the results of the study. A nocebo, or something that has perceivable effects, is more apt to such studies, but only to naive subjects (people who are not familiar with the psychedelic phenomenon). For example, Pahnke et al, successfully used niacin in the control group in their "Marsh Chapel Experiment" with psilocybin in the 60's.

For depression studies I would suggest neither a placebo or nocebo, just a large enough control group of randomly chosen subjects with the same diagnosis to monitor and compare. This is a problem because it means the treated group would better be a comparatively large group of randomly chosen subjects as well (founding such an expensive study would require a willing government agency - a no go with today’s attitude toward psychedelics). An alternative to obtaining founds is monitoring the health of religious groups that use psychedelic sacraments (e.g., Santo Daime, União do Vegetal, or Native American Church) vs. a comparative population that does not partake the rituals. Indeed, some such studies have been conducted, particularly on the Native American Church where the ritual use of peyote had a dramatic effect in preventing alcoholism. The drawback is that such a study cannot eliminate certain factors even if the control group is local and of same culture (effects of the community life, religious solidarity, faith induced effects, personal traits attracting toward such religions that could inhibit the researched illnesses, or other factors that are all church related).

These drugs are therefore nothing like the usual drugs amenable to the typical clinical study protocols. From the numerous studies conducted either long ago, or in the recent revival years, it could just as well be concluded that it is not the drug that is "active" in the classical clinical sense. Instead it appears that it is the psychedelic state of mind that causes the beneficial change. Even more, it appears that not even achieving a psychedelic state is enough and might not even be required, but it is just a state where mystical insight is facilitated.

Most psychologists, especially psychotherapists can tell you that a mystical insight can cause dramatic psychological and behavioural changes in the subject, particularly in periods of personal crisis (depressions, addictions...). It may therefore not be the psychedelic drug that has the healing activity, but it is the mind of the subject that does the work. For example, some non-psychedelic hallucinogens were also found to reduce depression symptoms, or help in treating addictions after single or few treatments (e.g., particularly dissociatives like ketamine and ibogaine). It can be argued that these non-psychedelics act by totally different physiological mechanisms to achieve the same effect (which might actually be the case for ibogaine). Yet it must be a strange coincidence that they are hallucinogenic as well. Unless this is further evidence that there is no exclusively physiological mechanism of action.

All this is in contrast with the classical concepts of pharmacology where the drug itself causes the improvement directly. It might just be the the mechanism of action of the drug on a cellular level is not what causes the therapeutic change. Hallucinogenic drugs typically provide their long-lasting effect by acute therapeutic applications, rather than chronic use like the majority of today's drugs. This might be another indication against a physiological mechanism of action (few drugs improve a chronic illness by acute application, and even these few are mostly some sort of toxins used therapeutically).

Obviously, with brains it is not easy to determine the cause and effect, because the mind can alter the neuronal physiology and the physiology can alter the mind. Does one have insight because of the physiological change, or does the insight cause the change in physiology of the neuronal networking? Obviously, scientists tend to be reductionists and avoid such complex models as long as it goes. For this reason they will be biassed toward seeing only a one way interaction. Most commonly among the psychopharmacologists is the tendency to assign all the therapeutic effects to the physiological change. Some psychotherapists will be biassed in the opposite direction. All are too biassed by their desire to obtain a simplified model.

In view of such a hypothesis, the psychedelic drug as such, given in the clinical setting, might have no direct connection with the medical improvement. Paradoxically, the drug itself could act as a placebo in some circumstances (providing the psychedelic state, but the mind of the subject still being unable to achieve insight). Today, there is good psychopharmacological knowledge on how to achieve the psychedelic state (dose, "set and setting"), but nobody has been able to reliably induce mystical insight (medical doctors are generally not skilled at playing the role of shamans or witches). Whoever would want to do such a study with such drugs properly, using the scientific method, will have to first give away with the classical clinical methods and modify the method to suit some hypothetical mechanism of action. There are a number of ways to do this. Groups can be divided by set and setting, guided or non-guided therapy, psycholytic or psychedelic therapy, and so on. If there are differences - and I suspect there will be, because studies performed in the 50's and 60's did show plenty - then there is much more to psychedelic drugs than there is to common drugs.

And there is not a slightest chance that an originator pharmaceutical company would go for it and ever register any such drug. Drugs that do not act as typical drugs have no business in their business. (Perhaps one little but notable exception is a particular mechanism of action of some psychedelic drugs, particularly DOI, that might be interesting to the big pharma: JPET 327:316–323, 2008, DOI: 10.1124/jpet.108.143461 and PlosONE, 2013, e75426, DOI: 10.1371/journal.pone.0075426)

A quote of Baumeister et al., Therapeutic Advances in Psychopharmacology, 2014, 4, 156-169 (emphasis mine):

Quote:

Hallucinogens have been employed entheogenically in human spiritual practice for several millennia, often in shamanistic approaches to healing or as a gateway for communication with deities. Despite, or perhaps in reaction to, this rich tradition, judicial processes in the 1960s and 1970s criminalized these substances without a clear scientific rationale, but more as a societal and political response to an emerged counter-culture. A historical legacy of the United Nations Convention on Psychotropic Substances [United Nations, 1971] has been significant obstacles and hurdles for scientific research using and investigating hallucinogens, whose neuropharmacology have remained incompletely understood [Vollenweider and Kometer, 2010]. Recently, it has been argued that the scientific community itself must lead the case for change in policies, as current drug laws severely limit scientific exploration of both neurobiological mechanisms and clinical effects that may prove valuable in the understanding of consciousness and mental illness, and offer novel therapies [Nutt et al. 2013].

For a more general and recent review on the potentials for psychedelics, see DOI: 10.2174/1874473708666150107114927 (and also a few other articles in the same issue of Current Drug Abuse Reviews).

solo - 8-4-2015 at 14:12

Psychedelics not linked to mental health problems or suicidal behavior: A population study
Pål-Ørjan Johansen1 and Teri Suzanne Krebs
Journal of Psychopharmacology
2015, pgs.1–10
DOI: 10.1177/0269881114568039

Abstract
A recent large population study of 130,000 adults in the United States failed to find evidence for a link between psychedelic use (lysergic acid diethylamide, psilocybin or mescaline) and mental health problems. Using a new data set consisting of 135,095 randomly selected United States adults, including 19,299 psychedelic users, we examine the associations between psychedelic use and mental health. After adjusting for sociodemographics, other drug use and childhood depression, we found no significant associations between lifetime use of psychedelics and increased likelihood of past year serious psychological distress, mental health treatment, suicidal thoughts, suicidal plans and suicide attempt, depression and anxiety. We failed to find evidence that psychedelic use is an independent risk factor for mental health problems. Psychedelics are not known to harm the brain or other body organs or to cause addiction or compulsive use; serious adverse events involving psychedelics are extremely rare. Overall, it is difficult to see how prohibition of psychedelics can be justified as a public health measure.

Attachment: Psychedelics not linked to mental health problems or suicidal behaviour- A population study.pdf (262kB)
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Chemosynthesis - 8-4-2015 at 14:32

There are many studies that demonstrate psilocybin, LSD other psychedelics reduce the symptoms of depression for long periods, sometimes after as little as one treatment. One of the latests reviews on the this topic can be found in Therapeutic Advances in Psychopharmacology, 2014, 4, 156-169 (DOI: 10.1177/2045125314527985). There is lately a renaissance of studies related to treatment of depressions, substance addictions, obsessive compulsions and other psychological conditions with psychedelics, but nearly all of these studies are just a reiteration of studies already done more than 50 years ago.

I do believe, personally, that there is reason to suspect efficacious treatment of psychological diseases or subsets thereof with some of these drugs, or at least optimized versions of them, but with respect, due in part to the lack of uniform FDA guidelines implemented from 1962 onwards that I mentioned, most of these studies are of dubious use, and the authors of your cited paper state

"The initial surge of clinical research that took place between the mid-1950s and 1960s in response to the synthesis of LSD and psilocybin produced more than 1000 studies, involving tens
of thousands of participants [Grinspoon and Bakalar, 1981]. However, as pointed out by Vollenweider and Kometer, there were difficulties with these studies [Vollenweider and Kometer, 2010]: the substances were little understood, their effects were difficult to control and different therapeutic approaches utilized them in different manners, and therefore the present review will refrain from considering evidence obtained in these studies." The abstract emphasizes with in "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."
(Emphasis mine).

Quote:

I believe you're slightly confused about the terminology I'm using. Active placebo, which I mentioned, has a physiological effect other than that which is being studied. This is different from, though arguably inclusive of a nocebo. Some of the possibilities I mentioned could conceivably serve to fool some patients, particularly if naive to treatment, by simulating the peripheral effects and some central nervous effects common to validated MAOI treatment. Patients don't need to be explicitly told what their specific treatment is (assuming no crossover in repeated measures) for informed consent, nor does it need to be a consistent treatment, so this can assist with the blinding of subjects. The largest risk to single unblinding in these instances is where a patient has experienced the drug before, and is currently on a drug treatment group.
Placebo control of varying kinds is hardly uncommon in psychopharmacology, though the type chosen does have various limitations, both scientific and ethical. This is part of why I was open to various designs (refractory to MAOI treatment, which is not a standard first line medication, and could be considered a last resort, etc.)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC161672/

If a patient suffers adverse effects from a placebo not being active, or being active and not treating their condition (which is a risk with any active drug as well), that is partly on the researcher for poor screening and patient briefing. Sham surgery has also been used as a placebo, and it could be argued that psychotherapy or religious iconography/theosophy could be utilized in the absence of the drug being tested as a form of placebo to determine the importance of the drug itself. Analgesic studies commonly use non-analgesic CNS depressants to give a form of psychotropic effect that mimics sedation with opioids. This is an active placebo. A nocebo is a substance that is physiologically inert but gives subjective deleterious effects, such as giving someone an inert powder, claiming it is monosodium glutamate, and then having a subject self-report an MSG allergy. Not that you would design a trial that extremely. Technically, I am sure one could refer to an active nocebo, as I implied way above, but this is still differentiated from otherwise unspecified placebo in that the subjective subject/patient response is considered undesirable in a nocebo, whereas any effect is unspecified for placebo.

In fact, the use of a placebo in the situation you describe (a true nocebo in this instance, where a patient suffers negative effects from placebo) is useful for the very purpose of demonstrating an otherwise unnoticed effect with treatment (a potential lack of negative effect), and can indicate adjunct therapies or novel targets for investigation that would otherwise be obscured, as well as demonstrating that current modalities of questionable efficacy may need such investigation to determine if they are harmful in some patient populations similar to the study placebo. It does raise philosophical issues of clinical vs. research equipoise, though. And actually, some cancer studies do use placebo, though this is usually relegated to those with no known alternative effective treatment to refer to.
http://www.cancer.net/navigating-cancer-care/how-cancer-trea...

Quote:

An alternative to obtaining founds is monitoring the health of religious groups that use psychedelic sacraments (e.g., Santo Daime, União do Vegetal, or Native American Church) vs. a comparative population that does not partake the rituals. Indeed, some such studies have been conducted, particularly on the Native American Church where the ritual use of peyote had a dramatic effect in preventing alcoholism. The drawback is that such a study cannot eliminate certain factors even if the control group is local and of same culture (effects of the community life, religious solidarity, faith induced effects, personal traits attracting toward such religions that could inhibit the researched illnesses, or other factors that are all church related).

We agree that observational studies are of more limited use than placebo controlled, double blind studied due to a variety of control factors. Anticipatory control, confounding variables, etc.

We'll have to agree to disagree on the validity of psychopharmaceutical testing, as I can't address psychotherapy as a non-science. As for mind/brain/body duality issues, my cognitive psychologist friend would probably debate you for hours just because he could, not necessarily because he even had an opinion on the matter. The pharmacological perspective would arguably be that there is no scientific rationale for said psychological treatment being contingent on specific regulated substances, though they may in fact be of benefit. This could be very important in allowing freedom of choice of psychoactives with specific pharmacokinetic profiles to reduce polydrug interactions, at-risk reactions in some patient groups (age, blood pressure, etc.), or simply allow for substitution with drugs of a tailored half-life to meet with patient/researcher time schedules. If no drug at all were necessary, this would lead to decreased fixed costs of treatments and reduced risk of pharmacological interaction (ex. DMT analog active without an MAOI, the latter of which is kind of a poster child for interactions) all while simplifying patient histories (important in a medical situation to allow more focus on relevant historical details).

As far as your Nutt quote on scientific regulation with neuroscience/neuropharmacology, that particular part of the quote is a very different matter from psychotherapy, though the two are both mentioned there. Neuroscience/neuropharm normalizes data in the same way as a placebo. Both could arguably be advanced with diminished regulatory controls, or at least diminished bureaucracy, since filling out those DEA forms takes time, and even with non-schedule I substances, can require multiple filings for subtypes of schedules, as I learned much to my chagrin. (Ex. Schedule 3 doesn't necessarily cover 3A, please submit a new form and wait.)

As far as toxicity concerns with psychedelics that Solo brings up, determining/ruling out adverse cardiac fibrosis risk would top my list rather than behavioral issues, as one is predictable whereas the other is arguably not. Much like the potential for serotonin toxicity syndrome, it would not only be beneficial for patients to be studied, but would open the door for additional types of studies, in my opinion.

[Edited on 9-4-2015 by Chemosynthesis]

cyanureeves - 8-4-2015 at 14:36

mercuric twice then shame on me! next time i will buzz first before i do any purchase.i think the banesteriopsis(MAOI) is the actual chemical that is effective in the ayahuasca study.dmt works without the MAOI but with the banesteriopsis i get stomach contractions just like when i drop acid.dmt alone is very disassociating but changa(dmt infused MAOI) is not and neither is acid. both changa and acid do give me a calm non worrying feeling for days afterwards.about that native american church though:i read that a group of natives took peyote and were sitting next to a horse carcass.all the natives not just one,saw the horse carcass fly to the sky.WTF?skip the placebo AND nocebo and go just straight to satan i think.power of suggestion maybe?if a person was to read all my crap in this here post and smoke changa then all his findings could be suggested?

Chemosynthesis - 8-4-2015 at 14:42

Testing against an MAOI might allow some form of quantification of efficacy and/or additive/synergistic effects. Serotonin agonism is usually what is associated most strongly with such GI interactions due to the strong role of enterochromaffin cells, though other receptors also play a role (muscarinic possibly being of relevance here).

Motility is usually 5HT4 mediated, whereas nausea and visceral sensitivity is 5HT3 mediated. Do note that nausea has several known mechanisms of activation prior to integration in the brain's nausea center, and that motion sickness is completely different.

solo - 8-4-2015 at 14:54

Reference Information

Cardiovascular toxicity of novel psychoactive drugs: Lessons from the past
Patrick Dawson, James D. Moffatt
Progress in Neuro-Psychopharmacology and Biological Psychiatry
Volume 39, Issue 2, 3 December 2012, Pages 244–252
doi:10.1016/j.pnpbp.2012.05.003

Abstract
The long use of ephedrine, amphetamines, cocaine, LSD and more recently 3,4-methylenedioxy-N-methylamphetamine (MDMA; “Ecstasy”) allows us to predict with some confidence what cardiovascular risks are likely to be associated with novel psychoactive substances (NPS). Once the probably multiple biological activities of a compound are known it is possible to define the likely risks of cardiovascular toxicity. Agonists of 5-HT2A receptors or alpha-adrenoceptors may cause vasoconstriction and tissue ischemia. Drugs which have agonist affinity for 5-HT2B receptors will probably promote heart valve fibrosis leading to heart failure. Compounds that interfere with uptake of dopamine or 5-hydroxytryptamine (5-HT) are likely to also have effects on noradrenergic neurotransmission and lead to sympathomimetic effects on the heart and vasculature. Drugs that cause dopamine release, or inhibit uptake are likely to be addictive and lead to chronic use. Other drugs (particularly the so-called empathogens) are associated with weekly usage in social settings; over time such use can lead to cardiovascular harm. Defining which of these effects NPS have is an important element of predicting the harm they may cause and informing those appointed to introduce regulations to control them.

Attachment: Cardiovascular toxicity of novel psychactive drugs-Lessons from the past.pdf (350kB)
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[Edited on 8-4-2015 by solo]

solo - 8-4-2015 at 15:02

Reference Information

Drug Abuse and Cardiac Problem
Mohammad Shafiqur Rahman Patwary
Medicine Today
2013 Volume 25 Number 02

Abstract
Drug abuse has reached epidemic proportions in many
countries including Bangladesh and threatens to overwhelm
economic, social, and health care systems. In addition to
their effects on the central nervous system, many of these
agents induce profound changes in the heart and circulation
that are responsible for a significant proportion of
drug-related morbidity. Drugs that can affect the
cardiovascular system are cocaine, heroin, inhalants,
ketamine, lysergic acid diethylamide(LSD),
marijuana,3,4-methylenedioxymethamphetamine(MDMA),
methamphetamine, nicotine, phencyclidine (PCP),
prescription stimulants, steroids .This article reviews the
cardiovascular problems associated with drug abuse.

Attachment: Drug Abuse and Cardiac Problem.pdf (179kB)
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Chemosynthesis - 8-4-2015 at 15:02

Solo, the problem with current toxicological research in that regard is that there is very little in terms of quantification of risk. Yes, I can look at a drug and use various SAR techniques to flag a compound for further toxicological study, but without actual toxicological data in a controlled setting, determining what patient groups are most at risk or what kind of interactions are possible but unlikely to be of clinical concern, they are limited. Particularly with regard to chronic use, a better understanding of these issues would allow for better drug selection, safer dosing schedules, or even concomittant administration of prophylactic or "rescue" compounds to reduce harm.

solo - 8-4-2015 at 15:06

Solo, the problem with current toxicological research in that regard is that there is very little in terms of quantification of risk. Yes, I can look at a drug and use various SAR techniques to flag a compound for further toxicological study, but without actual toxicological data in a controlled setting, determining what patient groups are most at risk or what kind of interactions are possible but unlikely to be of clinical concern, they are limited. Particularly with regard to chronic use, a better understanding of these issues would allow for better drug selection, safer dosing schedules, or even concomittant administration of prophylactic or "rescue" compounds to reduce harm.

......I only provide references to evaluate choices and decisions, and i agree with you as to the controlled studies, with today's street drugs one doesn't know what one is consuming, hence its best to make your own or grow your own for safety and long life with colorful perspectives......solo

<a href="http://www.freeimagehosting.net/commercial-photography/texas/dallas/"><img src="http://i.imgur.com/jCIaVSs.jpg" alt="Dallas Commercial Photography"></a>

[Edited on 8-4-2015 by solo]

cyanureeves - 8-4-2015 at 15:18

oooh, i so suspected that.what i didnt describe was that feeling of being catapulted into space which is very,very physical and not psychological at all.blasted into space then all of a sudden time stops and colors explode or so it seems.hell my heart could be doing 100 mph for all i know.of sound mind but of a dying body also maybe. the study does say in small dose though and i believe that ayahuasca if thrown up can fail to give visuals.maybe the people who throw up do feel better afterwards than those who dont.all the videos i have seen of ayahuasca experimenters seem so calm afterwards.i have also read of 10 hour long nightmares and some split 50/50 paradise and hell. i bet all were feeling better in the long run though.

Zombie - 8-4-2015 at 18:02

All of the compounds you mentioned in your posts Solo contain stimulants.

This is a different class of drug.

In the past 5-6 posts I have seen one commonality.
The question... Do psychedelics work via direct chemical interaction or do they work via allowing a built in reaction.

You fellas used more big words than I have room for in my pea brain. I did understand all but one... Mercurial. I kind f proud of that.

I work on intuition, and I have the gut feeling that the effects of psychedelics are not a direct chemical action. I do not believe these compounds cause audio / visual / or any other tactile distortion of reality. Nor do I believe they create any spiritual awareness.

My instinct tells me they bind receptors that open pathways we already have. All of the effects are waiting within us, and are dormant (for lack of a larger word).
These compounds simply allow us to be us.

This, in a simple way explains how so many seemingly un-explainable results can occur.

You can say that spiritual awareness will help cease addiction or you can say that a balance of priorities will do the same.
Look at rehab groups... Many of them use religion as a tool. Self help groups use re-examining your goals...

So does the chemical "trip" make your brain change, and allow a "chemical balance that allows people to think clearly or does the "chemical balance occur due to the psyche?

Nicodem addressed these questions without including an opinion.
I am offering my opinion... The compounds allow a part or parts of our brain to activate. This activation allows us to chemically balance ourselves, release us from mundane false priorities, give us a buffer between nonsense, and reality in a time based fashion, and generally lets us accept the onslaught of sensory input we have to deal with without constant chemical input or receptor firing in the brain.

Take a fella that works in any high stress job. Constant adrenaline, and lactic acid build up...

Put the same fella back at that job but remove the stress effects,ie: adrenaline, lactic acid...

In which case do you "THINK" he will be healthier, live longer, make better life choices daily.

You fellas justifiably mention placebo, no-cebo, cebo cebo...

Once again I have to add, A Trip is not needed to gain certain results. You don't need to pee brown to acquire the needed effect from vitamins.

A placebo control is 100% as valuable if NO ONE was expected to "trip", see aliens, or run down the hallway naked.

15-25mG of psilocin does not alter reality in any detectable way but it does fire receptors. The effect of lessening anxiety, and depression are documented at low dose studies.

http://www.gizmag.com/johns-hopkins-psilocybin-study-finds-o...

I can NOT say this often enough... Take tripping out of this!
Use any of these compounds in the minimum dosage required to fire synapsis', and trigger receptors.
There is no need to use a cannon to kill a deer.

cyanureeves - 8-4-2015 at 18:33

zombie i might try a tiny bit next time and not go for the abuse thing in my smoking and i do believe i will get the same end results.just intuition also and also no big words because i had to google mercurial.when i take one big hit all kinds of elfs.aztec gods in color etc.. come out ,BUT when i then go for a second high something strange happens.i see all visuals except in my brain i get locked in a loop and start to panic because i feel like i am trapped in a millenium.it appears like i am reliving a book story that has been played out over and over for centuries and i can only live it out.something occurs in the lobe where deja vu is played out.the place where information received from hearing and seeing is transmitted to the perception part of the brain and processed back as confirmed info.during this transmitting there is a delay and messages that have already been received gets processed again creating deja vu.i heard johnny carson describe deja vu this way on the tonight show and johnny never lied.this chemical also is like acid in which one builds tolerance because i have to smoke within minutes of each hit or else i will not see hardly zip.this tells me in can be used as an antidepressant one day because they have at least these similarities, not the creepy loopy thing.oh my lawd i think i just described an instant "flash back?" not good!

[Edited on 4-9-2015 by cyanureeves]

solo - 8-4-2015 at 18:37

Quote:

All of the compounds you mentioned in your posts Solo contain stimulants.

.....i just provide the reading stuff, each person decides what they consume, my effort is to provide the information for the reader to make an informed choice as to the drug he /she might indulge in .....also, as someone pointed out many of this studies are not controlled, hence the findings may not be as one sided as they conclude.....so stay with the natural stuff or make your own ....solo

Chemosynthesis - 8-4-2015 at 20:33

While both of Solo's articles contain information on stimulants, some of the compounds are psychedelic, both as chemically substituted amphetamines and simple indoleamine/substituted tryptamine compounds, and the implications are broader than for just stimulant drugs as there are even some examples of dissociative NMDA antagonists with CNS depressant activity.

Solo, I do want to say I have always appreciated your promulgation of scientific literature as paywalls annoy me, even in the cases they don't apply to me.

I do think it's important to note that there is still risk with synthesizing your own own chemicals for the purpose of ingestion as it is virtually impossible for an individual to maintain the quality control inherent in current Good Manufacturing Practice, and that natural substances aren't inherently any less dangerous than synthetically produced, though they may prove so in circumstances such as those being discussed.

Some possibly interesting examples of PTSD medication results often double blinded placebo controlled, for kicks and giggles. Lots of investigation in that area.
http://www.onu.edu/node/27553
http://emedicine.medscape.com/article/288154-medication

MrBlank1 - 10-4-2015 at 05:27

Maybe I've missed the point of this discussion, and if so I apologize for derailing, but here goes :

Regarding N,N-DMT and psycho-pharmacology, surely one cannot go without mentioning the work of Rick Strassman, specifically his book "The Spirit Molecule".

If anyone would like a copy of the documentary of the same name, I am willing to upload it to a file hosting service, just u2u me or post here to let me know, and I'll upload it and reply with the link.

[Edited on 10-4-2015 by MrBlank1]

solo - 10-4-2015 at 06:03

Reference Information

DMT: the spirit molecule: a doctor's revolutionary research into the biology of near-death and mystical experiences
Rick Strassman MD

[Edited on 10-4-2015 by solo]

Attachment: DMT_the_spirit_molecule.pdf (3.3MB)
This file has been downloaded 719 times

MrBlank1 - 10-4-2015 at 08:08

The Spirit Molecule 2010 (699 mb, 1:13:46, 640x352) - Hosted on Uploaded.net

http://ul.to/htk7ti0x

Loptr - 10-4-2015 at 09:55

Psychedelic Information Theory
http://www.amazon.com/Psychedelic-Information-Theory-Shamani...

I found this as an interesting read, especially with my work with automata-based information processing systems. It takes the psychedelic experience and starts to break it down in terms of systems, system interactions, and the balance needed in order for them to work optimally. You skew the balance, and weird things start to happen.

It's been a few years since I read it. You will read about dynamical information processing systems, which isn't a typo, and is actually based on a theory aptly named dynamical systems theory (http://en.wikipedia.org/wiki/Dynamical_system).

For the more chemistry and biology inclined, it might be deemed rubbish, but the overall theory was very interesting to me from a perspective of how do you build such a system in terms of software.

[Edited on 10-4-2015 by Loptr]

Zombie - 10-4-2015 at 10:58

Here is the documentary on YouTube... https://www.youtube.com/watch?v=ewdWBHh8hY8 (The Spirit Molecule)

I have been reading / studying EEG (Electroencephalography), and MRI (Magnetic resonance imaging) results of people under the influence of N N-DMT for comparators.
The issue I have with all the testing I can find is the same as the issue I have with the entire conversation about the compound.
The tests are all run during moderate to high dosages.
I have not (to date) found any tests run at low dosages.

That being what it is... There are consistent test results in both genres.

This could get long winded so I will try to keep it brief.

Taking the most commonly read frequencies in EEG testing, (Delta- Theta -Alpha- Beta- Gamma- Mu) The EEG test consistently show:

Delta, Normally low activity is increased w/ DMT

Theta, Normally low activity is Not increased w/ DMT

Alpha, Normally low activity is decreased w/ DMT

Beta, Normally high activity is decreased w/ DMT

Gamma, Normally high activity is decreased w/ DMT

Mu, Normally low activity is increased w/ DMT

To put these results into context,
Mu is rest-state motor neurons. They are read when a person is at rest

Gamma is cross-modal sensory processing (perception that combines two different senses, such as sound and sight).

Beta is active thinking, focus, hi alert, anxious.

Alpha is associated with inhibition control, relaxing, deep calm thought.

Theta is found to spike in situations where a person is actively trying to repress a response or action or in drowsy adults attempting to fight off sleep.

Delta is found during boring tasks, light sleep.

The main commonality is the higher functions are decreased, and the lower functions are increased.
In essence you can say that N N-DMT is flattening the brain wave graph or balancing the electrical activity to a flatter curve.

This is where I am focusing. What exactly does this "flattened curve" do?

Is it better for us? Is it worse?

My thoughts are it is better to have a balance. This really does apply in almost everything in nature. Too much of any one thing is always bad. Same for too little of any one thing.

My thought is combining low dose amounts of many of the compounds listed as Class One Drugs, along with other compounds that are indeed healthy, into sort of a multi-vitamin for the brain.

We all know those "good days" where the flipping house could burn down, and you just couldn't care less. The days where you know everything will be taken care of, and there is NO reason to get upset.
Those are the days you are in balance. Now imagine a tablet that will allow this to be everyday.

Some of you will come back with reality on this ie: Govt:, unknown effects, poison, propaganda, ect... but the reality is... It can be done. WE can do anything.

[Edited on 4-10-2015 by Zombie]

Chemosynthesis - 10-4-2015 at 12:09

It's important to remember that nearly anything can be said in a book or a movie regardless of the burden of evidence as these have no peer review. If any of you are interested in neuroscience, I could recommend some classic texts. From Neuron to Brain and Kandel's Principles of Neuroscience are both great starting points. Unfortunately, our current ability to model neural systems is very, very crude.
It's also important to specify fMRI in some MRI studies. Great tool, but there are quirks to dealing with them; enter the Dead Salmon Study.
http://blogs.scientificamerican.com/scicurious-brain/2012/09...

Zombie - 10-4-2015 at 13:40

I appreciate the direction Chemosynthesis.

I would have provided some citation to what I posted but I can not find the links at the moment.
What I have seen so far are models of the brain maps compiled from many studies.

Sort of an overlay of the results. I can't even remember the terminology used.

Basically what I am finding is base line brain activity is more or less consistent, and predictable in study groups. You see colored areas similar to thermal imaging where a color denotes the level of activity.
They then compare the same size sample groups to other drugs, and stimuli. These "maps" are again predictable.

The promising aspect (IMHO) is the fact that none of the "maps" are as balanced as the N N-DMT maps.

Inactive areas of the brain become active, while hyperactive areas lower in intensity.

I'm fairly certain it was in an article by Andrew Newberg that I found the images, and this information...

If this thread continues I will keep trying to find the links. I have hundreds of them to sort thru, and I'm not much for a "system" to keep it in order.

I'll look for the books you mentioned. Thank you!

smaerd - 10-4-2015 at 17:34

So I'm not a stoner or a drug taker, user, whatever... I can't really say much about counter-culture, philosophy, or spirituality with stuff like this. I personally believe if someone wants to do something with themselves they should have that right so long as it harms no one else. Anyways I don't have really much to say about psychedelic drugs or Ayahuasca personally. I am still very interested in this research and the legal issues. I feel comfortable enough with the community here to share my perspective which is probably very seldom heard... I really hope at least one of you interested in this research takes time to read this...

Edit - Nicodem shared the most likely in my opinion hypothesis for the therapeutic effects associated with psychedelics. We can talk therapy, I think there's probably merit to that. I'm not one who would benefit from such therapy, but I have a mental health disorder which is believed to be related or at least treated by antagonizing adrenaline, serotonin, and dopamine receptors. I'd rather talk about literal chemical imbalances and physical structure of the brain.

Let me give you a personal story, very brief but to the point. The diagnosis I got was the psychological equivalent to cancer and receiving medication that on the bottle literally stated "Warning may cause sudden cardiac death" was no less reassuring... One medication I took made me gain 30 pounds in 2 months, then develop a temporary movement disorder. Unlike many, I was blessed in that it was temporary and not permenant... The current scientific models used in animals involve the substances LSD, PCP, and amphetamines and trying to downregulate their effects (pharmacologically or behaviourally).

That's really the best thing we have, rats on LSD swimming, going through mazes, etc... Hold on, keep in mind it's very hard to administer LSD to a rat without years of paper-work and likely rejection by the government.

Needless to say the availability of these substances in scientific communities is INTEGRAL to progress towards the disorder I have and other similar ones. It is and has historically been integral to nueroscience. Funnily enough I did a report on Lysergic acid derivatives and their medical uses and found that the discovery of LSD's psychological effect basically founded modern nueoscience, psychology, etc... That's not really where the line stops for me though...

I have in the past researched serotonin, and dopamine agonists just out of structure activity relationships, and what substances hit where, what do those substances do, and maybe "why". Also cannabis was of interest to me because supposedly cannabidiol can function as an anxiolytic and as an antipsychotic (rather peculiar really).

I recently did a medication change to a newer compound reported to be the most free of side-effects in it's class. Was a warm welcome. Nausea, verses things such as cognitive dulling, akathesia or tardive dyskenisia? HAH - any day of the week. Anyway's, this new medication actually serves as partial agonist at certain serotonin and dopamine receptor sites. Not particularly the psychedelic ones, so no abuse potential but still VERY interesting. This mode of activity is unlike it's predeccessors which are full antagonists ("amygdala labotomy").

Infact a new theory states activating only ONE serotonin site has proven to be successful in one model for treating such disorders. Will it make it through the FDA? Who knows... Maybe in two decades that will be decided... Imagine that though, an agonist (speculated cascade mechanism) verses a complete biochemical blockade...

So should psychedelic research be allowed? Without question. We have a mental health crisis world-wide. Not just depression, or anxiety, or I guess ADD/ADHD (those are all valid disorders and I think anyone who has experienced such states can empathize). People can argue that those are over-medicated and over-diagnosed disorders, whatever. We have 1% of the population(seems small, but take 1% of 7 billion, that's surreal) fighting for their 'sanity' and wanting to live a fulfilling life, some other odd percent bouncing from manic to depressive states.

I support anyone and everyone here or elsewhere who has taken an interest in legitimizing such research. I just hope that the message of mental illness is not over-shadowed by people wanting to get high. Don't get me wrong, again, I will say, do what you want but don't hurt anyone. For all I know getting high could be the most important thing any single person can do. Just remember psychedelic research is integral into taking a leading edge in serious mental health disorders. It has been a bit of a travesty that our efforts as human beings has been haulted in that avenue for so long by childish legal impediments.

That's really all I had to say... Blessings

[Edited on 11-4-2015 by smaerd]

Chemosynthesis - 10-4-2015 at 18:51

Smaerd, I am happy to hear you were able to transition to a new medication that has worked well so far. I hope that this continues, as transitioning from something like an antipsychotic can have difficulties that no one in the medical community can easily predict. I am close to someone with a debilitating psychosis that destroyed their ability to function "normally" in society, and they have chosen to largely avoid taking medication due to side effects they experienced.

I definitely believe a large part of the problem with psychological diseases, despite our knowledge of associated imbalances, is that they are very much heterologous diseases. As with 'cancer' or even albinism, many molecularly distinct issues can present similarly or identically, and determining cause from effect in such complex systems as the brain, which we still have yet to map out on a systems level or comprehend well from an intra-neuronal perspective.

Adding to this the difficulty of attempting to diagnose an individual largely based off of self-reported symptoms rather than quantifiable clinical signs, and the risk for miscommunication increases. I expect that future generations will be able to combine novel imaging techniques and genetic screening with new therapies (be they small molecule chemicals, macromolecules, implants, transcranial magnetic stimulation, or other) to tailor treatments to better serve patients. It's my opinion that serving in any validly designed research, whether as a researcher or subject, is likely to lead to advances in medical treatment.

Some of you may choose to donate your genome (note: these may be de-anonymized based on new studies) or take a new medication. Even healthy controls can participate in phase 1 safety profiling, so if someone you care about has an illness, you may still be able to directly assist with the advances associated with that.

Zombie - 10-4-2015 at 19:01

What I find to be almost unbearable is the fact that almost every slightly intelligent person on this planet will agree with your sentiment yet a tiny handful of lawmakers will die trying to block access to research.

What on Earth could be wrong with finding solutions people need for their problems?

My mother had a complicated cranial "bone spur" surgery in 1982, at a well respected NYC hospital.
During this procedure she bled. They had to pump blood into her to keep her alive. The blood was un-tested (1982), and bore the HIV virus.

For 14 years she reported symptoms, and was tested / treated for perhaps a dozen disorders, disease s, conditions. Everything except HIV because she did not fit "the profile".
She spent tens of thousands on medications, and in her last 2 years she found Marijuana as the only relief she could tolerate. It did not cure anything but it allowed her to live comfortably, and accept what was coming.

6 weeks before her death she was pulled over for a faulty light on the car, and arrested for possession of said relief. They found her tiny pot pipe in the ashtray of her AMC Gremlin.

We had to bail her out of JAIL! She of course died before ever appearing in court.

My sister wrote an essay on this story that won her The NY Chancellors Award. It was titled Living a life of AIDs

This comes back to my point about raping stoners, and tripped out hippies. Perhaps you can see why I am adamant about proper use of any chemical or really anything for that matter.
The difficulties researchers face are due largely to abusers, (IMHO)

I come from a family of addicts. Some used random street drugs, some booze, some legal pharmaceuticals. Every member of my family on both sides except for my mother, and my fathers father. There were generation of this behavior. Honestly I am surprised I made it out of there alive.
I did not mention that both sides of my family come from MONEY! No one ever wanted for anything. It was all brought to us so it was not social depression that brought this on. It was nothing more than boredom with life.

If people like mine helped to set the miss-conception that certain compounds are useless in medicine, I apologize for all of them.
Does that make it all better now? can we get on with helping people instead of wearing blinders?

I hope so.

I know where you are coming from Smaerd! So far everyone that has posted in this thread does.

szuko03 - 11-4-2015 at 13:50

I suppose I could see how an extended DMT trip could make you happy to be who you are and that the effect isnt forever.

pneumatician - 11-4-2015 at 17:33

Here I read some time ago the same with hembane & co.

"new" studies for the same!!!

of course all this is for keep up appearances that something is done

the same case with MMS (miracle mineral) used by the us army, in water purification, meat industry, etc, etc, etc. and the "experts" saying is very very dangerous, placebo, etc, etc, etc...

http://unesdoc.unesco.org/images/0007/000747/074776eo.pdf#74...

-------------
The forms which you see, that which you touch, this is in reality images created by consciousness, likened unto the images which you see in your dreams, yet in those dreams you believe them to be real forms.

cyanureeves - 11-4-2015 at 17:55

indeed szuko10 and even the chemist who invented L.s.d. felt great after his trip but during the tripping he prayed to God.many people have felt a sense of being protected by someone during a dmt trip including myself.i perceived that it was my mother who intervened in my welfare but that she also had to let me find out the unpleasant.i think we have a chemical in our brain that we subconsciously feel and comes to the rescue(intervenes) and alerts us of danger.life and all it brings IS the greatest trip and every day sobriety has the best visuals.depression though can trick the brain into seeing nothing but gray and doom and despair.depression is horrible and can make people kill themselves for nothing.my mother during her depression state would worry about not knowing where the strangers on board airplanes flying overhead were going.depression is way worse than drug addiction.

Zombie - 11-4-2015 at 21:00

depression is way worse than drug addiction.

I Very much agree.
Depression in many cases leads to self medication, and more often than not this creates more issues, and prolongs the depression. Quite often for a life time.

There are commonalities in the reported experiences of DMT "trips" that seem rather curious. The reports of protective beings, aliens, whatever...

I have this feeling that DMT just may open a door to a common conscious among people or souls.
As per usual there is nothing scientific about this theory but the idea has nagged at me for some time. Now I understand that this idea may just be akin to BigFoot or wide eyed aliens in that people are creatures of suggestion.
If ten people say that God looks like Cookie Monster, then the eleventh person is very likely to see the same.

I base my idea on the fact that DMT does have a positive effect on almost ALL users. (not including abusers in this statement).
Lets say that one person goes on a month long retreat to some isolated location. There are one hundred people there that have never smoked tobacco or drank alcohol. During this month it would be quite easy to accept the fact that you really do not need either of these, and cessation of the addiction would be an easy, conscious choice. Most likely permanent because you made the decision.

Now whether DMT does link us to others or we perceive it to, the effect is the same. We accept ourselves because we realize WE have the power to make the changes that we need to make.

This comes back to, does N N-DMT actually change us or do we make the changes?

This alone is worth the research. Perhaps it could be discovered that we really don't need anything but ourselves.

Nicodem - 14-4-2015 at 12:01

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).

Then there are also the irresponsible idiots who think psychedelics are like any other drug to get high with and end up doing stupid things. These people are too disconnected from themselves to even realize what is going on, so there is no chance for any beneficial effect. For them the psychedelic state can be as shallow as watching a Hollywood movie on TV. I'm not sure this even counts as drug abuse. It is more like self-abuse. In general it is quite difficult to abuse psychedelic drugs. It takes a lot of effort to use them and there is a natural opposition in most people against the experience (even if ignoring the days long tolerance prevents regular use). It is kind of like school. Nearly nobody likes it, but still nearly everybody goes to school to learn what needs to be learned.

Is DMT any different in this regard? Maybe for a few reasons. It is inactive orally, so you need to either smoke it or block its enzymatic degradation to get it to work. Smoking DMT has its peculiarities. The experience lasts only about 5 minutes (that can subjectively appear an hour long). There is also practically no low dose effect. You either break trough or you don't get anything. Most orally active psychedelics have some perceivable effect in the dosage between the threshold and the psychedelic breakthrough levels (a most common problem with the psychedelics is that people tend to take too low a dose). As far as I know, DMT does not have such levels. Even orally, activated by beta-carbolines, you either get over there or you feel nearly nothing (or worse, you get only nausea). Yet, smoked DMT or ayahuasca are very different experiences. Smoking it is so intense that you cannot humanly interpret the experience as you go. Even though it has no detrimental effects on cognitive abilities (aside the informational overload), it is just not possible to comprehend it (hence the mystical experience). It is like being flooded with data and all you can do is to awe at it all. Ayahuasca has a slower tempo, giving more possibilities to process the experience and incorporate the message. So, I think there can be no generalization on the therapeutic properties between the two methods of DMT use.

(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)

Zombie - 14-4-2015 at 12:32

You know... You are correct. I tend to forget about all the non willing "subjects", and the lunatic friends that have been pretty much permanently damaged from psychedelics.

The same example can be made for most things too. It does depend on the level of understanding that the user has. If you don't understand laxatives... You're gonna have a crappy day.

I see your point in "threshold" dosages. Low dose psilocybin, for example really can not be compared to low dose DMT (thanks for sparing me the extra typing).
What I am trying to find out is IF low dose DMT will allow the receptors associated with the compound to activate. If the receptors are working, the synapses are firing. If the synapses are firing then the positive effects should be taking place, ie: balanced brain activity.

Perhaps the "trip" is integral to the effect. Perhaps not.
To my knowledge there are no long term low dose studies. This is what I would like to see.

They put people on psychotropic meds for decades and this is acceptable? I don't see how.

Whether we create the changes needed or the compound creates the change... Either way, the change is made.

I'd rather see better meds developed than see people suffering simply because something is "not in vogue".

Perhaps this is all explained in the same fashion as political elitist's, war, poverty, ect... we ALL realize that these issues SUCK yet we allow it to happen. Most days I am ashamed to be a Human.

Nicodem - 14-4-2015 at 13:34

What I am trying to find out is IF low dose DMT will allow the receptors associated with the compound to activate.

There can be no low dose activity from DMT as it is degraded in mater of seconds unless the monoaminooxidaze A enzyme is overloaded. DMT is as easily degraded by this enzyme as serotonin, the endogenous ligand. You would need psilocybin, LSD, DOB or other such metabolically stable 5-HT_2A agonists to experiment with threshold levels of activity.

Quote:

If the receptors are working, the synapses are firing. If the synapses are firing then the positive effects should be taking place, ie: balanced brain activity.

The 5-HT_2A receptors activation does not lead to synapses firing. These receptors are neuromodulatory. Their activation by agonists activates a few second messenger systems that alter the membrane potential, therefore facilitating or inhibiting the firing caused by glutamate (they modulate the firing, but do not induce it). Currently, it is not even certain which second messenger system(s) is/are involved in the induction of the psychedelic phenomenon (agonists can be quite discriminatory toward the second messenger system activation). If you are interested, David Nichols and his group did most of the discoveries that led to the current understanding of the mechanism of action of psychedelic drugs and the 5-HT_2A receptors in general, so check his review articles.

Quote:

To my knowledge there are no long term low dose studies. This is what I would like to see.

There were people who experimented with daily threshold doses of LSD, or so they claim. Supposedly, a level can be maintained with an equilibrium against tolerance building, but it must be a very narrow dosage window. As for what they experienced and achieved on long term, I have yet to find a useful report. I doubt it was that beneficial, or else such self-medication would become more popular.

Quote:

They put people on psychotropic meds for decades and this is acceptable? I don't see how.

Yes, bur these psychotropic pharmaceuticals do not cause the psychedelic phenomena. It is acceptable to sedate or stimulate the mind with sedatives, tranquilizers or stimulants, or to narcotize it with opioids. Even dissociative hallucinogens and deliriants found use in the medicine (ketamine, scopolamine, atropine, antihistaminics, etc.). They are socially and politically acceptable, but the regulators do not find the psychedelic phenomenon equally acceptable. As far as I know, there are only two psychedelic drugs used in the medicine, ergonovine and methylergometrine, but they are used at considerably sub-psychedelic doses. There is also a similar bias against entactogens, but it appears that that there is more will to accept entactogenic drugs than psychedelic ones. Maybe it is because entactogens were found extremely useful in psychotherapy, or maybe there might be simply less (political) fear toward them.

aga - 14-4-2015 at 13:50

Ordinary people with induced mind-states beyond 'normal' ranges are disallowed by law as their responses to standard control inputs are unpredictable/unreliable.

That is the main reason that most 'drugs' are illegal.

The notion is founded on a Good idea, in that without control of any sort, people do all kinds of nasty things to each other, and generally produce less Work, and therefore Taxes.

Booze & Cigarettes were established and massively powerful before the whole Control thing got properly started, and therefore Won.

gregxy - 14-4-2015 at 15:46

Going back to my argument on Big Pharma. No they could not sell DMT or any of the other psychedelic drugs "as is". But if there is a working mechanism there, they can study it in infinite detail and develop a profitable, patent-able, schedule 4 analog that works as well or better. Its happened with all the other drugs. Look at the variety of benzos, steroids, barbituates etc. Once one company announces a new drug, the others all have copycats. The key is finding the mechanism, and they have had 50 years to study these.
Who knows maybe the current SSRIs etc are the "grandchildren" of psychedelics.

My feeling is these are too unpredictable for practical use. But who knows, they could be helpful to some individuals. Its stupid to jail someone for trying.

I remember reading and article saying many drug companies had given up on developing new psychiatric drugs.

Chemosynthesis - 14-4-2015 at 16:11

Zombie, generally for both toxicity and efficacy profiling, one uses an escalating dose to determine maximal plasma concentration, therapeutic window, etc. Just using a low dose isn't necessarily useful.

Going back to my argument on Big Pharma. No they could not sell DMT or any of the other psychedelic drugs "as is". But if there is a working mechanism there, they can study it in infinite detail and develop a profitable, patent-able, schedule 4 analog that works as well or better. Its happened with all the other drugs. Look at the variety of benzos, steroids, barbituates etc. Once one company announces a new drug, the others all have copycats. The key is finding the mechanism, and they have had 50 years to study these.

The development of the drug classes you mentioned took place before the CSA, and schedule 1 drugs are difficult to work with, bureaucratically, so it's not really the same.

Quote:

Who knows maybe the current SSRIs etc are the "grandchildren" of psychedelics. [

SSRI drugs were actually among the first rationally designed drugs, so we do know what they were derived from. "Dr. Arvid Carlsson was the first one to develop the antidepressant compound, zimeldine, which was the first selective serotonin re-uptake inhibitor (SSRI). The precursor of this drug was brompheniramine."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136031/

Quote:

My feeling is these are too unpredictable for practical use. But who knows, they could be helpful to some individuals. Its stupid to jail someone for trying.

Another concern is that as long as you are using a plant extract, you have concerns about availability. Just look at Taxol. You had a botanical extract where demand exceeded total world supply. Scientists determined the active ingredients, synthesized it after much trouble in the lab, then optimized it for different pharmacological profiles.

Zombie - 14-4-2015 at 16:17

What I am trying to find out is IF low dose DMT will allow the receptors associated with the compound to activate.

Quote:

To my knowledge there are no long term low dose studies. This is what I would like to see.

I am kind of confusing to follow at times.

When I describe "low dose" dmt, I am also including an MAOI as part, and parcel of the treatment. More similar to Ayahuasca in an oral form.

Low dose LSD has been studied fairly well as you pointed out but it is hard to find credible research. Without knowing enough about the entire subject I dare to say that LSD, and DMT are so far removed from each other that any research on LSD will have limited value as to what DMT is actually doing.

The 5-HT2A receptors that David Nicholls (I am reading "Effects of 5-HT-releasing agents on extracellular hippocampal 5-HT of rats. Implications for the development of novel antidepressants with a short onset of action") has studied so well may be a common link between the two compounds but as you pointed out it may well be the secondary receptors that differentiate the two.
What LSD does appears to be a very different ball of wax compared to DMT.

Exactly what that difference is??? I think it is important to know.

Quote:

They put people on psychotropic meds for decades and this is acceptable? I don't see how.

I very much appreciate the fact that people in a hallucinatory state are not really what we need working at the bank or even at a gas station.
Fact is I know plenty of people sooooo messed up on their prescribed drugs that I don't allow them near my home or my dogs. A potential side effect of "False sense of well being" (Adarol) does not mix with a Presa Canario. The dog will quickly remove that false sense, along with a limb or most of a face.

Perhaps high dose treatments will work to alleviate physiological/ psychological disorders. Perhaps short term treatment is all that is needed to complete a task. Maybe the Big Hammer theory does apply.
I have almost always chosen to chip away at a project with a small hammer first. Perhaps that has always been a fundamental flaw in the research? You can easily drive a nail with a sledge hammer but you can not always see what is happening along the nails route. Too much too fast...

I really do appreciate your participating in this thread Nicodem. This is essentially the subject that led me to find your site. Yes indeed my horizons are broadening but learning more about the physiology of the human brain is my main goal, and your insights are more than helpful. They are leading me in the right direction to learn the correct methods to learn more.

Here are two very helpful videos. One from Nicholls, (LSD Neuroscience), and one from Carhar- Harris (Brain Imaging Studies with Psilocybin and MDMA)

These are both rather long lectures but they contain a lot of info that applies to this thread.

https://www.youtube.com/watch?v=CNR4o5JZEi0

https://www.youtube.com/watch?v=LbUGRcuA16E

Mr. Aga... I know all those people. They all live here in Carrabelle.

Chemosynthesis - 14-4-2015 at 17:15

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

MrBlank1 - 14-4-2015 at 18:00

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

+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?

blogfast25 - 14-4-2015 at 18:07

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]

Chemosynthesis - 14-4-2015 at 19:34

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]

Zombie - 14-4-2015 at 20:01

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.

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

Chemosynthesis - 14-4-2015 at 22:49

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...

Zombie - 14-4-2015 at 23:05

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...

Chemosynthesis - 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.

Zombie - 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.

Nicodem - 15-4-2015 at 11:56

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)
This file has been downloaded 538 times

Chemosynthesis - 15-4-2015 at 17:58

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]

Zombie - 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.

MrBlank1 - 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

Chemosynthesis - 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.

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]

Zombie - 15-4-2015 at 21:01

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?

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?

Zombie - 15-4-2015 at 21:14

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

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?

Chemosynthesis - 15-4-2015 at 21:55

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.

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]

Zombie - 15-4-2015 at 23:31

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.

MrBlank1 - 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]

Chemosynthesis - 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.

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.

gregxy - 16-4-2015 at 11:04

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

Zombie - 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.

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]

The MAOI part I understand. Nicodem also helped me realize that there are other properties to the active plants/sources of the MAOI(s).
I sort of knew this but did not realize it.

That's what led to the square peg/round hole comment.

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

I just read the description in the link. I'm going to have to follow up, and find as much more info as I can.

Now I have to ask... What on Earth gave you the impression that adding a link to a supplier of said compound would in any way interest a fella such as myself?

I'm lost, flabbergasted, and appalled!

I have NO interest in personally trying any of these compounds!

Jeez!

Honestly... I have issues. I'd like to see the work happening.
Mega/multi/over the top ,Uber vitamin. That's what I need.

turd - 16-4-2015 at 14:17

Quote:

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

That has already been done by nature and the result is gifted to us in the form of mushrooms growing on cow dung.

Quote:

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

Well, it's not peer reviewed but if you want, you can cite "turd, private communication":

In a small group of enthusiasts it became tradition to finish off remains after a session (2-3 full voyages) in rounds of small sub-psychedelic tokes. It's good fun. Brings back memories of the experiences, is soothing on the body, calming on the mind. But there is no reason to believe that it would be particularly efficient at treating psychological problems.

DMT is a very special and wonderful material - at effective levels. But due to the idiosyncratic nature of the trip I don't think it is very valuable for therapy. And I'm also not sold on ayahuasca - poisoning yourself to make the DMT orally active? I would just go with the mushrooms. They're benign and easily dosed if treated with respect and generally well accepted.

An important point is that one size does not fit all. Whereas for example some people love the uplifting merry nuttiness of 2C-B, others will find the push very disagreeable. Therefore, should therapy with these kind of materials ever become acceptable, the therapist will have to carefully select the material and be intimate with it. One reason why I don't see a bright future for this. Every fool with training can adjust SSRI dosage - but how many people would do trust enough to trip with them?

PS: I'm too tired to read the whole thread. Sorry if I'm just reiterating something that has been said before.

gregxy - 16-4-2015 at 15:35

The anti aging site has hundreds of items, nootropics, thyroid stuff etc. I have bought stuff from them. Since they are in the UK it takes a while.

I take 15mg selegiline/week, dissolved in the mouth, trying not to swallow
it. My "neurotransmitter profile" is that dopamine is low while norepiniepherine is high GABA and serotonin were normal. An "anxiety" profile. (there are tests you can get to test your profile, although I think the science is questionable). I think it helps my mood, I know it increases my sex drive. An SSRI makes me worse since it also depresses dopamine.

IMO Someone with depression should always evaluate thyroid, cortisol, the sex hormones etc. before messing with neurotransmitters. My Dr says the "healthy ranges" for some of these things are wrong, since they are determined from mainly from sick people.

Zombie - 16-4-2015 at 16:20

Quote: Originally posted by turd

Quote:

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

That has already been done by nature and the result is gifted to us in the form of mushrooms growing on cow dung.

PS: I'm too tired to read the whole thread. Sorry if I'm just reiterating something that has been said before.

I am a firm believer in psilocybin. Especially it's low dose usage. It does take off all the rough edges of daily life, and allows you to see clearly what is important, and what is rubbish.
From my own experience I can say the most profound effect is a fairly complete removal of anxiety. I'm unsure if this is due to psychological or physiological action but I know the effect is real.
I would very much like to see further research into the compound. It actually may be more realistic than pursuing DMT research but going by my instincts... DMT may be much more important in the long run.
As is often said... There is a reason it is so prevalent in nature. Much like the Earth revolving around the sun, we just don't see it yet.

Quote: Originally posted by turd

In a small group of enthusiasts it became tradition to finish off remains after a session (2-3 full voyages) in rounds of small sub-psychedelic tokes. It's good fun. Brings back memories of the experiences, is soothing on the body, calming on the mind. But there is no reason to believe that it would be particularly efficient at treating psychological problems.

DMT is a very special and wonderful material - at effective levels. But due to the idiosyncratic nature of the trip I don't think it is very valuable for therapy. And I'm also not sold on ayahuasca - poisoning yourself to make the DMT orally active? I would just go with the mushrooms. They're benign and easily dosed if treated with respect and generally well accepted.

This is the important part of my questioning the legitimate use of DMT.
Does a person NEED the trip or is the compound useful without the trip. I personally would like to take a legit tablet that sorts out the imbalances, and go about my day.

I don't really see a use in tripping balls, while riding a 1970 hard tail on Interstate 95 heading to work. :cool:

(we need a Not Cool emoticon)

Ps... Don't sweat catching up. My head barely fits thru the front door from all of this.

The anti aging site has hundreds of items, nootropics, thyroid stuff etc. I have bought stuff from them. Since they are in the UK it takes a while.

I take 15mg selegiline/week, dissolved in the mouth, trying not to swallow
it. My "neurotransmitter profile" is that dopamine is low while norepiniepherine is high GABA and serotonin were normal. An "anxiety" profile. (there are tests you can get to test your profile, although I think the science is questionable). I think it helps my mood, I know it increases my sex drive. An SSRI makes me worse since it also depresses dopamine.

IMO Someone with depression should always evaluate thyroid, cortisol, the sex hormones etc. before messing with neurotransmitters. My Dr says the "healthy ranges" for some of these things are wrong, since they are determined from mainly from sick people.

There is a site I found that sells many different compounds like Glucosimine, ect. http://www.xarealin.com/_d269029703.htm

I am interested in developing a custom tailored Uber vitamin for myself but the potential for disaster is overwhelming.
It is also very difficult (if not impossible) to find a doctor that is 100% on board or even knowledgeable enough to determine what is needed, what could potentially interact, ect.
I'm not much for living to 109 but I wouldn't mind being healthy in mind, and body right up to the time to stop.

I do know one thing that all the dietitians tend to forget... Exercise, and diet only work due to the chemistry of the body. When I worked out as a younger fella I knew everything I needed to know about myself to supplement with the right compounds, at the right levels. I could eat granite, and crap roses.

I'd like to get back to that point in my life but my mind is so screwed up from decades of worry that the list of needed supplements has grown beyond my comprehension.

I can still learn tho.
That's why I'm here.

Chemosynthesis - 16-4-2015 at 18:12

Selegline, as opposed to MAO-A inhibitors, had diminished risk for food related toxicity. Ex. J Clin Psychiatry. 2003 Feb;64(2):208-14.
This is thought to be due to the vastly preferential affinity of MAO-A to tyramine, which induces norepinephrine secretion when inhibited.

Neurotransmitter profile tests are completely unscientific. Unless you are taking spinal taps or getting a brain shunt for in vivo microdialysis, which is localized to specific regions, there is zero science behind it in any test I have ever seen, and are articles against them online.

Zombie - 16-4-2015 at 18:37

Is it known exactly which MAOI is in the P. Harmala or the Banisteriopsis Caapi? (MAOI-A or MAOI-B)

Chemosynthesis - 16-4-2015 at 20:16

The harmala alkaloids are the predominant components discussed in previous posts by Nicodem and me, mostly page 3.

Zombie - 16-4-2015 at 21:03

I knew it was covered but could not find it.

I'm trying to keep as much of this organized in my mind as I can.

Reviewing I can see where the entire topic can lead to difficulties, or worse even for an expert.

Discussing options such as modified DMT to avoid metabolism, isolating potential psychoactive / interactive compounds from secondary sources, doses, duration's, registered effect, ect. MAOI's , no MAOI's, smoked, oral, injected. Mice, rats, dogs, monkeys.
Fat people who drink, skinny people who eat rats, mice, and monkeys...

Yeah I think I am seeing the bigger picture here.
One thing for sure, Ignorance is truly bliss. One other sure thing, you really can't go backwards once you learn something.

This thread (to me) is like looking at baby pictures of yourself.
I'm gonna sleep on all this, and see what comes to me in the morning.

Wow!

[Edited on 4-17-2015 by Zombie]

Chemosynthesis - 16-4-2015 at 22:12

Important to my post on selegiline is that gregxy is using it sublingually, which is similar in many regards to transdermal administration. Oral use has a different pharmacokinetic profile. Additionally, diminished risk is not eliminated risk, to be clear.

Do note my response below the selection you quoted as well. I have citations urging caution and I cross compared some relevant binding affinities along with exposition on the importance in distinguishing between affinity/type of bonding vs. potency and toxicity with regard to harmala alkaloids from a pharmacological/toxicological perspective. The post above my exposition on hepatoxicity risk indicators.

gregxy - 17-4-2015 at 11:01

The bioavailbility of selegiline is 5X greater sublingually. The prescription form is Zelpar, for treatment of Parkinson's. For depression there is the Ensam patch. Up to 5mg/day should be safe (without the cheese effect). Still, I don't take things like pseudaphed with which it interacts. It can also give a false positive on a drug test for methamphetamine. It takes up to a month after you stop taking it for the MAO to regenerate. Likewise it takes a couple weeks to take full effect.

Chemosynthesis - 17-4-2015 at 14:18

Not sure where you get your numbers. Would like to see because what I have reported seen generally corresponds to "In summary, by reducing the opportunity for first-pass metabolism, the absorption of selegiline from Zydis Selegiline was more efficient and less variable than from conventional selegiline tablets. Compared with conventional selegiline tablets 10 mg, Zydis Selegiline 1.25 mg yielded similar plasma concentrations of selegiline and degree of MAO-B inhibition, but markedly reduced concentrations of the principal metabolites. Thus, the lower but equally MAO-B inhibitory dose of selegiline in Zydis Selegiline 1.25 mg, which is associated with lower concentrations of potentially harmful metabolites[.]" PMID 14628189

Zombie - 17-4-2015 at 14:52

The bioavailbility of selegiline is 5X greater sublingually. The prescription form is Zelpar, for treatment of Parkinson's. For depression there is the Ensam patch. Up to 5mg/day should be safe (without the cheese effect). Still, I don't take things like pseudaphed with which it interacts. It can also give a false positive on a drug test for methamphetamine. It takes up to a month after you stop taking it for the MAO to regenerate. Likewise it takes a couple weeks to take full effect.

Mr. Chemo... Your post above (regarding brands, and doseages) is important information. Good stuff to know.

You also questioned Mr Gregxy's numbers...
I have a question that I can easily look up but I prefer to see it here for everyone. Besides potential serotonin build up (toxic?) what other need is there in the body for MAO(s)?

Let's assume long term use of MAOI. In an otherwise healthy individual what harm can or will be done?
I am asking from the perspective of a long term, low dose DMT "patient". (assuming it was a viable course of treatment)

I used assume a few times... That can't be good.

gregxy - 17-4-2015 at 15:15

The 5:1 number comes from here:

http://www.zelapar.com/more-about-drug-delivery/pk-charts-of...

They do recommend a max of 2.5mg/ day to maintain MAO-B selectivity (for Parkenson's). 3X/week I just chew up a regular 5mg pill and keep it in my mouth. (tastes awful) I don't know if there is something else in Zelapar to enhance adsorption.

This site http://www.drugs.com/pro/selegiline.html says the max oral dose to avoid dietary restrictions (the cheese effect) is 10mg/day.

So for depression, to inhibit both MAO-B and some MAO-A, 5mg/day seems like a good dose.

Chemosynthesis - 17-4-2015 at 16:17

The 5:1 number comes from here:

http://www.zelapar.com/more-about-drug-delivery/pk-charts-of...

Thanks! Hmm, interesting. I'm wondering if their reference in the footnote has indications on the pharmaceutics of their formulation.

Mesa - 17-4-2015 at 16:52

Note that MAOI's differ not only by their selectivity towards one or another specific enzyme(or by their non-selectivity.) They will also differ in their site selectivity. Selegine, for example, was developed as an MAOI that selectively inhibited MAO-B in the brain with the goal of minimizing any enzyme inhibition in the liver/other areas. This is the reason why user's are often excluded from the dietry restrictions generally applicable to prescribed MAOI's.

A few of the statements I've seen in this thread lead me to believe this isn't common knowledge to people in the discussion. It's actually pretty interesting to go through the older studies and see the progression of research in that area. For example, I noticed a trend in that many of the compounds developed for medical treatment via the MAOI mechanism will often be metabolized to another biologically active compound(or a close analogue of one), which is unrelated in terms of mechanism of action. These metabolites tend not to accumulate in any significant amount. Not enough to have a detectable psychoactive effect in most cases anyways.

I had a fleeting idea of looking into possible novel prodrugs of DMT that were sufficiently resistant to metabolism not to be affected by first pass metabolism in the liver, but not so much so that it will result in a significant amount of DMT being released by the time it gets to the brain.
I even saw a similar alternative in a patent, whereby they created a co-crystal containing both the target drug, and some unrelated compound. Supposedly the co-crystallized compounds take a significant amount of time to separate AFTER dissolution, allowing some degree of targetted drug delivery. I'm still kinda confused on the "how" as my understanding is that they exist as separate ionic species the entire time, dissolution should result in instant separation I thought.

Chemosynthesis - 17-4-2015 at 18:42

Quote: Originally posted by Mesa

Note that MAOI's differ not only by their selectivity towards one or another specific enzyme(or by their non-selectivity.) They will also differ in their site selectivity. Selegine, for example, was developed as an MAOI that selectively inhibited MAO-B in the brain with the goal of minimizing any enzyme inhibition in the liver/other areas. This is the reason why user's are often excluded from the dietry restrictions generally applicable to prescribed MAOI's.

This is an excellent point, but I don't think allosteric binding is in effect here at normal compartment concentrations if at all. Because the harmala alkoids are described as competitive, this strongly suggests occupying the canonical binding site, and when looking at selegiline, without calculating Tanimoto coefficients, it look extremely similar to phenelzine, just with steric differences likely to account for MAO-A antitargeting.

Mesa - 17-4-2015 at 19:30

Yeah, I only started looking into this area when I learned one of the major alkaloids in kava is a selective MAOB inhibitor. I'm Fijian and have drunk kava regularly as a recreational/traditional type of thing since I was a kid without ever thinking about how it works.

An interesting thing here is that there was never any form of ayahuasca developed by the native tribes of Fiji or neighboring pacific islands despite being home to the plant species containing the largest reported concentration of DMT(Acacia Simplex, 2-3% of the dry weight of some sections contains alkaloids, mainly DMT.)

The plants themselves are very common, I figure once kava was discovered by the natives, it was too much effort to try to mix it with anything else

Zombie - 17-4-2015 at 21:30

The 5:1 number comes from here:

http://www.zelapar.com/more-about-drug-delivery/pk-charts-of...

They do recommend a max of 2.5mg/ day to maintain MAO-B selectivity (for Parkenson's). 3X/week I just chew up a regular 5mg pill and keep it in my mouth. (tastes awful) I don't know if there is something else in Zelapar to enhance adsorption.

This site http://www.drugs.com/pro/selegiline.html says the max oral dose to avoid dietary restrictions (the cheese effect) is 10mg/day.

So for depression, to inhibit both MAO-B and some MAO-A, 5mg/day seems like a good dose.

I went out drinking tonight so I may misinterpret what you said.

If I can ask, and if you feel it appropriate to answer... Exactly where did you get the information that an MAOI coud / will help you?

I'm not being a smart ass... Trust me.

I have never tried DMT. Sort of want to but ...cool.

I have a history of crazy fucks in my family. I posted this.
The history of mental disease goes back for more generations than I really know.

To lay it bare my family name is McLaughlin. As far as I know we are the FIRST recorded name in history. 2454 bc is the furthest back we know of.

Look it up if you like because this thread is not about us.

My mothers family name is McKinnon. They are the crazy f@ckers. Every woman on my mothers side as far back as I can trace (1642) has died of "mental disease".

If you think I am joking or full of crap...; Guess why I am posting,

I thought long, and hard last night about this entire thread,
Life sort of sucks for a fella that has Kings on one side, and lunatics on the other.
From the age of FIVE I knew I was "different".
No problem... Deal with it. After 51 years of dealing with it I am nothing but TIRED!

So... As I posted, I have tried every friging drug I could find. None of them solved the problem. NONE!

That is why I believe I have an addictive gene yet I never became addicted to anything. I have the mind set to avoid addiction.

Sooooo again, I am focusing the last remaining years I have to solving the problem(s) that I, and many others share.

Granted I may not be able to help anyone else but I intend to try.
That is the SOLE REASON I am posting on the open net.

I'm not here to fool anyone, and ask for formulas. I could care less about producing worthless drugs BUT if something triggers a real response in my mind I WILL ask more.

I (like I said) believe that DMT has a commonality in all things that create it. I have to believe that there is a common thread between all living things or else I would be as F'd up as the rest of the family I came from.

I said it before... DMT "MIGHT" be the radio that links us all. The "trip part is the exaggeration of this. Without the trip I PRAY it is the compound that allows us to be us.

Yeah... I have been at Fathoms tonight but all that did was allow me to be more up front about why I am interested in this topic.

I won't go back, and edit because this is me.

Just for fun... I'd like you to meet my Buddy Jonny...

The kid is cool. https://www.youtube.com/watch?v=jN_K2Raznzo

Ok I had to edit...
That kid is not into any sort of drug culture (Mulbray) BUT he is very much into spiritual energy. He has a map of the original pyramid alignments. the Masons temples, the Aztec temples, and some of the crazy peoples temples... Guess what... They all align. Magnetic lines converge.

I'll let you all figure out if either of us are worth a damn.
Please watch the videos if you want to form an opinion...

https://www.youtube.com/watch?v=xI59Pe4Fv5w

[Edited on 4-18-2015 by Zombie]

CrimpJiggler - 19-4-2015 at 08:56

I can vouch for this. It helped my depression quite a bit. Its like years of psychotherapy packed into a few hours. They were some of the roughest experiences of my life though, you need to be ready to face your inner demons head on. Some temporary suffering is a small price to pay. I went into it with the primary intention of becoming a better person and thats what I got.

Is it known exactly which MAOI is in the P. Harmala or the Banisteriopsis Caapi? (MAOI-A or MAOI-B)

Harmine, harmaline, and tetrahydroharmine are 3 alkaloids that I know of, they all bind to MAOI-A (hence why p. viridis and b. caapi stop DMT from being metabolised, MAOI-B inhibitors don't do that). Harmaline is the most potent one (at least it has the most potent reported psychedelic effects when taken alone).

[Edited on 19-4-2015 by CrimpJiggler]

blogfast25 - 19-4-2015 at 09:22

That kid is not into any sort of drug culture (Mulbray) BUT he is very much into spiritual energy. He has a map of the original pyramid alignments. the Masons temples, the Aztec temples, and some of the crazy peoples temples... Guess what... They all align. Magnetic lines converge.

Align in what way?

Mesa - 19-4-2015 at 09:50

Quote: Originally posted by blogfast25

Align in what way?

A really long one. If you go around the earth enough times it'll eventually figure itself out.

blogfast25 - 19-4-2015 at 10:01

To lay it bare my family name is McLaughlin. As far as I know we are the FIRST recorded name in history. 2454 bc is the furthest back we know of.

Look it up if you like because this thread is not about us.

2454 BC??? That's Bronze Age! AFAIK, the practice and recording of surnames started WAY, WAY much later than that. More like 10th century or so...

I mean, you do know that Fred Flintstone was just called Fred, right? Fraudulent archaeologists later added Flintsone because it sounded so good!

[Edited on 19-4-2015 by blogfast25]

Zombie - 19-4-2015 at 11:31

Yes Fred was our g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,gg,g,g,g,g,g,g,g,g,g,g,g,g,g,g,g,gg,g,g,g,g,g,g,g,g,g,g,great grand uncle.
Wilma was actually his second wife.

I have researched our family. Just a quick link. It flows back much further than this...
http://www.surnamedb.com/Surname/McLaughlin

Quote:
"Recorded in many forms including MacLaughlin, MacLoughlin, McLaughlin and McLauchlin, this is an ancient Irish surname. It derives from a pre 10th century Old Gaelic name borne by two entirely distinct clans. The first was originally called the O' Maoilsheachlann' and in the 17th century assumed the name MacLoughun. The territory of this sept lay in the central plains of Ireland, especially in County Meath. The prefix O' indicates male descendant of, whilst "maol", describes a "tonsured one", a follower of a religious order. The original nameholder or chief was called Maoilsheachlann and he was better known as Malachy 11nd, the High King of Ireland from 980 a.d. to 1002. The second sept belonged to Innishowen in County Donegal. Here the name meant the "son of Lochlann", the latter being a Norse-Viking pre 7th century compound of the elements "loch", meaning a lake or fjord, plus "lann", land. The great leading men of this sept are frequently referred to in "The Annals of the Four Masters".

Edit:
We come from the second sept. The Norsemen recorded their blood lines very well.

As for the magnetic convergence thing. I don't know much about it but apparently there are areas on the planet that are reported as ":high energy" centers. Something about the pyramids, certain capitols. Something called "Ley Lines"

http://holeinthedonut.com/2009/05/26/coral-castle-energy-med...

One of these centers is right here in Florida. I have been there, and I can tell you that you do know something is there. For days afterwards I could almost feel what people were thinking.

There are maps that show these lines. If you want to take this a step further... One of the axisis or convergence points is in a direct line to that "face" looking formation on Mars.

I know, Open door for Blogfast... I believe in spirituality, and I believe that people have interactions on many different planes than most of us realize. What if anything is involved in these lay line things I do not know.

Coral castle does have some "thing" that happens there. A walk thro tour won't allow much in the realization of this but 24 hours in the pinnacle room there... It changes.

Mr. Blog... If you wish to research my family further you will find the same as I did.
Lay lines??? I don't know what you will find because I never looked.

CrimpJiggler,
I appreciate your input. Demons don't scare me. Inner or outer. I have dealt with them for decades.
In fact we play Golf on Tuesdays, and Sundays.

I have come to realize that dealing with, and letting things go are not the same.
I sort of get that my personal issues are not really a chemical imbalance so medications are really worthless at best, and harmful at worst.

I'm leaning toward opening new doors toward a more "spiritual" understanding of time, space, humanity.
Knowing religious methodology is not what I mean either. awakening some of the "sleeping" parts of the brain is.

Perhaps one day I will "trip out" but I'd much prefer to know exactly what, and why things are before I tamper with "imperfection".

[Edited on 4-19-2015 by Zombie]

cyanureeves - 19-4-2015 at 12:10

calea zacatechichi is an herb that is a very,very mild sedative but tastes like a burnt goodyear rubber tire.taking calea just before bedtime will cause the most crazy dreams but so will jalapenos sometimes.on calea i dreamt of walking with a sky blue eyed girl and way after i awoke i remembered the dream.when i remembered the dream, i closed my eyes and saw her bright deep blue eyes imprinted inside my eye lids about three times repeatedly.the dream was a little on the nightmare side in which i was being accused of vandalizing.i think calea is an irritant of sorts and creates wild dreams but it is just like a valium pill in strength.no hallucinations while awake with calea and is very relaxing but the taste is unbearable.i think the aztecs pulled all their carvings and paintings from crazy dreams.because of dmt visuals i always feel like i am the one who breeched some space where color and strange beings live and not THEY who came into my world.that's as spiritual as i get.

blogfast25 - 19-4-2015 at 12:49

I have researched our family. Just a quick link. It flows back much further than this...
http://www.surnamedb.com/Surname/McLaughlin

Quote:
"Recorded in many forms including MacLaughlin, MacLoughlin, McLaughlin and McLauchlin, this is an ancient Irish surname. It derives from a pre 10th century Old Gaelic name borne by two entirely distinct clans. The first was originally called the O' Maoilsheachlann' and in the 17th century assumed the name MacLoughun. The territory of this sept lay in the central plains of Ireland, especially in County Meath. The prefix O' indicates male descendant of, whilst "maol", describes a "tonsured one", a follower of a religious order. The original nameholder or chief was called Maoilsheachlann and he was better known as Malachy 11nd, the High King of Ireland from 980 a.d. to 1002. The second sept belonged to Innishowen in County Donegal. Here the name meant the "son of Lochlann", the latter being a Norse-Viking pre 7th century compound of the elements "loch", meaning a lake or fjord, plus "lann", land. The great leading men of this sept are frequently referred to in "The Annals of the Four Masters".

For the most part I don't trust genealogy sites as far as I could throw'em. Here that site may be roughly right but "pre 10th century Old Gaelic " doesn't equate to 2,500 BC.

The oldest Gaelic inscriptions (NOT manuscripts) date back to about the 4th century and recorded Scottish history starts about the Roman period. That leaves a gap of about 3,000 years! Additionally, one then would have to assume that Gaelic hadn't evolved much over that period (ever tried to read William Shakespeare - died 1616 - in the language he wrote in?)

Even the 'Norsemen' only go back to about 500 - 1000 AD.

As regards 'holeinthedonut.com', I think you're pulling my leg but in any case I much prefer astral gateways!

Whatever makes you happy, I guess (now where did I file that cross-eyed emoticon???)

[Edited on 19-4-2015 by blogfast25]

CrimpJiggler - 19-4-2015 at 14:04

CrimpJiggler,
I appreciate your input. Demons don't scare me. Inner or outer. I have dealt with them for decades.
In fact we play Golf on Tuesdays, and Sundays.

I have come to realize that dealing with, and letting things go are not the same.
I sort of get that my personal issues are not really a chemical imbalance so medications are really worthless at best, and harmful at worst.

I'm leaning toward opening new doors toward a more "spiritual" understanding of time, space, humanity.
Knowing religious methodology is not what I mean either. awakening some of the "sleeping" parts of the brain is.

Perhaps one day I will "trip out" but I'd much prefer to know exactly what, and why things are before I tamper with "imperfection".

[Edited on 4-19-2015 by Zombie]

I should mention that I did ayahuasca not too long after I quit dexedrine which I'd been on for 6 years. The low dopamine levels were a big part of what made my experiences so rough, the serotonergic activity of the ayahuasca without dopamine activity balancing it out caused extreme bodily discomfort. This happened me with all serotonergic psychedelics during that time period. Most people don't have that issue. You're right, letting go is a whole other skill. I'm still learning that one myself. Another powerful entheogen which I've been blessed with discovering is iboga. Treating depression with ayahuasca is a gradual process that doesn't happen overnight. With iboga on the other hand, its very possible that it might cure ones depression in a single ceremony.

For opening doors to a new spiritual understanding of time, space and consciousness, salvia is another powerful one. Like ayahuasca and iboga, its really in a category of its own. Strangely enough its mechanism of action is kappa opioid agonism. Its a good one for seeing first hand the subjectivity of time. You can be gone for what seems like days, but only minutes pass on the clock. You see mechanisms of reality that have been right under your nose the whole time, but you never cared to look because your logic tells you that theres nothing there. It breaks your consciousness out of your ordinary system of logic so you can directly see whats beyond it. I saw through the illusion of separation first hand during a salvia trip. What happened was I got stuck in the second dimension for what seemed like days, I had no memory of where I had come from so for all I knew I had always been in that limited 2D reality. The only way out was to realise that I was not actually separate from my external environment, we were in fact one in the same and with that realisation, I found myself back transitioning back to the 3D world. I realised that this principle applies to the 3D world and during that transition period I experienced this state of oneness that spiritual people describe. It was the funniest thing I'd seen in my life because it implied that the bulk of my psychological suffering was the product of an illusion. I remember having a list of things that I would try in order to transcend that 2D world and the one that worked was the very last thing I tried because it was the one I least expected to work, since I had the preconception that I was separate from my external environment. I don't think it was coincidence that the trip ended at the exact moment I discovered the key to transcending that 2D world.

Before jumping into an ayahuasca ceremony, one can familiarise themselves with the effects of B. caapi by making tea with it. Due to its harmala alkaloid content, it has its own psychedelic effects.

Also, if you haven't yet started, I recommend exploring lucid dreams. The things one can learn by observing the dream state (especially the transition state where one goes from being "non lucid" to lucid) is phenomenal. While practicing techniques to attain lucidity, it might be beneficial to take a mild acetylcholinesterase inhibitor like galantamine.

[Edited on 19-4-2015 by CrimpJiggler]

CrimpJiggler - 19-4-2015 at 14:32

i think the aztecs pulled all their carvings and paintings from crazy dreams.because of dmt visuals i always feel like i am the one who breeched some space where color and strange beings live and not THEY who came into my world.that's as spiritual as i get.

Thats exactly what I think. I experimented with the combination of zolpidem and 5-MeO tryptamines and I kept getting these direct (as opposed to peripheral) visuals in which everything I started at morphed continuously at distinct time intervals into patterns that looked exactly like Mayan or Aztec artwork. Everything looked absolutely mindblowing but it seemed very familiar, like I'd seen it all before. These alpha subunit selective BZ agonists combined with sleep deprivation causes very interesting effects, its almost like one begins to dream while still awake. Adding tryptamines to that makes everything Aztec/Mayan like. My theory is that these ancient cultures were naturally in psychedelic states, its only our dumbed down modern societies that don't perceive these spiritual aspects of reality. Australian aboriginals have this thing called "dreamtime", its like they can literally dream while they are still awake. I wish society would end their absurd demonisation/fear of consciousness alteration and realise that the ability to explore ones consciousness through neurochemical alteration is as important as meditation, lucid dreaming or any other spiritual practice known to man. Western society is only recently become reacquainted with spirituality, its just a matter of time before the masses accept entheogens for what they are. Similarly, everyone will realise that theres a lot more to dreams than the current concensus would have us believe. A lot of people think alchemy is just the primitive beginnings of chemistry, but in reality I think chemistry will become a whole lot more alchemy like when the reconciliation of science and spirituality happens. Spirituality is right brain science, contemporary science is the domain of the left hemisphere. Alchemy is actually a stegonographic representation of spiritual phenomena which often seem to have a physical counterpart. Or more accurately, for every physical phenomenon, there is an underlying spiritual dimension (like how every particle has an underlying wave). I believe transmuting lead into gold is also a metaphor for the illumination of the mind which occurs when the two hemispheres of the brain are reconciled. I can't really explain how I gained this understanding, it came to me on entheogens. It comes from "sleeping" areas of the brain.

[Edited on 19-4-2015 by CrimpJiggler]

Chemosynthesis - 19-4-2015 at 15:32

Quote: Originally posted by CrimpJiggler

]Harmaline is the most potent one (at least it has the most potent reported psychedelic effects when taken alone).

Source? This is disputed by the literature according to McKenna et all. (see my posts on page 3) as debunked.

[Edited on 20-4-2015 by Chemosynthesis]

Zombie - 19-4-2015 at 19:22

There is a lot of first hand (experience) info there Crimp.

It still begs the question, how much is influenced by suggestion, and how much is actually created repeatedly in the mind (removing influence / suggestion factors).

Really my entire curiosity in these compounds revolves wholly around the research into the mind, and body. I find it hard to believe that the most important thing that should be known is one of the least understood mechanisms.
I liken humans to machines in my concept of them. It's so very easy to diagnose a machine. Logic tells you where the flaw is, and you correct it.

I think I just answered my own question(s). Look at the level of machine(s) we understand... internal combustion, hydraulic pumps, pistons, vanes, basic electronic switching... I finally got it.
There is another thread here about the evolution of science... The evolution goal is to create life. If we could build a human we would have already learned how to fix what's wrong with the existing ones.
In all fairness I now believe we are still in pre-school playing with blocks, and producing random "cool" shapes.

I might be a few centuries ahead in my "wish list".

[Edited on 4-20-2015 by Zombie]

CrimpJiggler - 20-4-2015 at 06:31