Matrine

[Soul137]

So the 2 are not intertwined though? One could theoretically safely titrate the drug, marking hallucinogenic and depressant effects separately until it's more clear which way the receptivity leans, and design future doses based on that.

 

[sekio]

I think matrine has a rather broad pharmacological effect; reading around says it increases cardiac contractile force among other things, and has a 10 hour half life in humans.

I don't know if these are good things for a psychotropic drug...

 

[Soul137]

Too much cardiac activity is never a good thing. And I feel like it's pretty easy to say that this Matrine is not exactly gonna be a winner. I just haven't seen anything like it before, structurally or profile-wise.

I was wondering if anyone could even hazard a guess as to what a recreational dose might be?

 

[dopamimetic]

Philip Seaman reported that ketamine and PCP bind to D2 but no other labs have ever been able to replicate his findings.

Well.. not scientific, but it's dopaminergic for sure. Actually with tolerance ketamine begins to behave like a really clean, relaxed stimulant for me. Really nice and completely functional, but have to redose every hour or I'll get comedown, bit sad and tired ... is this unusual?

Think it's a DRI, not D2 agonist like memantine or MXE. Ketamine is like these combined with a little amphetamine.

 

[Soul137]

I think there is a tendency for all dissociatives to seem slightly "stimulating" at low doses / to those with tolerance. I wouldn't say that that really indicates dopaminergic action, though I'm no pharmacologist. My guess is that it would be more tied into the possible anti-depressant effects of NMDA antagonists; especially to users who find their niche in dissociatives. That mood lift I think is not universal.

 

[Cotcha Yankinov]

From what I have been told NMDA has a lot of input to inhibitory neurons, and it is thus that NMDA antagonists may induce seizures at high enough doses and release neurotransmitters and cause hallucinations at standard doses. So we might wager that even without an added DRI effect an NMDA antagonist could feel dopaminergic.

 

[dopamimetic]

Hmm... one point I forgot about is that there are probably auto receptors and antagonists actually cause an overall increase of glutamate. But NMDA and inhibitory - do you have a link for this?

What I've read is that in some area(s) of the brain the antagonism will cause less GABAergic activity and this can be bad, but it's pretty specific and unrelated to the action of e.g. benzodiazepines. I mean, in the end they all are anaesthetic at supra-recreational dosages. Don't know whether the seizures at even higher dosages are from, secondary activities or the glutamate.

But to come back to the topic, would be great if kappa was somehow connected to NMDA and we would have the possibility for a new generation of dissociatives.

Still wonder what kappa agonism plus little DRI would be like. There has to be a way to get around NMDA tolerance .... it is possible with opioids and stimulants now (by using dissociatives) but not for tolerance to themselves......

 

[Cotcha Yankinov]

I can't seem to find any studies about how NMDA antagonism leads to seizures (maybe Serotonin2A can enlighten us) but the other day I did find this study that would make me think twice about using NMDA antagonists long term http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856160/

 

[dopamimetic]

Well probably I'm far from being objective on this topic, but think there are some points to consider... If we have an actually overactive NMDA system, then antagonizing it to some degree won't hurt. Also there is definitive acute tolerance / change of effects happening, after a few days the dissociation fades away and there is more relaxed stimulation and overall normalization. I still don't know what to think about upregulation, my experience is that after some weeks of heavy ketamine use I'll get a bit of tremor and night sweating for maybe two days, then just back to baseline (thankfully and curiously no real mental symptoms besides that it's hard to accept that state again) - really nothing in comparison. The glutamate system is very fast in adjusting.

Wonder about the long term effects in general though. Probably it's too individual to be able to apply some general rules...

Noticed a weird thing about conception and memory in this regard - over time, things change in the way that without NMDA antangonism memory and recall gets worse rapidly, but this reverses when I'm on one again (including remembering seemingly forgotten events) and have the impression that they are really nootropics maybe through the increase in AMPA traffic... really don't know what's the reality, if I became dependent on the dissociatives or if I would just be in this fucked up state naturally.

Sorry for derailing the thread.

Am very interested in these kappa agonists though. Would be so great if we had the possibility for a whole new generation of dissociatives..

 

[serotonin2A]

I can't seem to find any studies about how NMDA antagonism leads to seizures (maybe Serotonin2A can enlighten us) but the other day I did find this study that would make me think twice about using NMDA antagonists long term http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856160/

In general, NMDA antagonists act as anticonvulsants.

http://www.ncbi.nlm.nih.gov/pubmed/2558775
http://www.ncbi.nlm.nih.gov/pubmed/8094234
http://www.ncbi.nlm.nih.gov/pubmed/2329567
http://www.ncbi.nlm.nih.gov/pubmed/2153806

But there are some exceptions, as follows:

Ketamine can induce seizures when given to epileptic patients:

http://www.ncbi.nlm.nih.gov/pubmed/4735460
http://www.ncbi.nlm.nih.gov/pubmed/4707578

After chronic of administration of ketamine to rats, there is a shift to proconvulsant effects, suggesting it may induce kindling:

http://www.ncbi.nlm.nih.gov/pubmed/4674053

Overdoses of PCP analogs can produce seizures in rats:

http://www.ncbi.nlm.nih.gov/pubmed/3964407

Basically, what is probably happening is that NMDA receptor activation contributes to seizure propagation, so blocking the NMDA receptor tends to be anticonvulsant. But NMDA receptor blockade can also increase Glu release and AMPA receptor activation, so the potential exists for NMDA blockade to be proconvulsant in situations where the seizure threshold is low.

 

[dopamimetic]

After chronic of administration of ketamine to rats, there is a shift to proconvulsant effects, suggesting it may induce kindling:http://www.ncbi.nlm.nih.gov/pubmed/4674053

Okay, now this worries me. Have to get the full text.

 

[Cotcha Yankinov]

Do you think that the matter of ketamine not being able to induce seizures in animals is just a matter of dosage, and that if the doses could be pushed higher without lethality we would see seizures with it? Also not to derail the thread but Serotonin if you have anything to contribute to this thread about the "voice in the head/audio hallucinations" I would be very curious http://www.bluelight.org/vb/threads...-inner-dialogue-quot-and-audio-hallucinations

But yeah dopa I definitely understand if someone is running high on NMDA then antagonizing it isn't nearly as bad, and also memantine seems to leave more normal physiologic NMDA alone and only address the faster firing NMDA too. But I do wonder if in the same sense that some people with major depression may benefit from increasing serotonin even though a serotonin deficit isn't their real problem, that some people that may not have overly large amounts of NMDA transmission benefit from decreasing NMDA. Part of what I'm wondering is that maybe whatever NMDA transmission we do have might be pathological, so don't get me wrong I'm not saying NMDA isn't the problem (we both have witnessed the magic of NMDA antagonists), but maybe it has less to do with the overall quantity of NMDA transmission (maybe we only have too much NMDA in a small part of our brain that's LTP dependent like the hippocampus or something). Or maybe one might propose that the amount of NMDA transmission is the same as "normal" people but that it is pathological in some sense, maybe "faulty wiring", for lack of a better term.

 

[Soul137]

The glutamate system is very fast in adjusting.

Am very interested in these kappa agonists though. Would be so great if we had the possibility for a whole new generation of dissociatives..

To point 1; isn't that quite the opposite? Tolerance to dissociatives builds so slowly and lasts (appreciably) forever. What part of the glutamate system is adjusting quickly? Is that in reference to how quickly dissociatives can lower tolerance to other drugs (I've experienced it with benzos, nicotine and weed, from Memantine more than anything else)?

As for a new generation of dissociatives– I mean, chemists are moving faster than ever to come up with new waves of chems as the last one gets banned. It's only a matter of time before someone takes a look at kappa-agonism, if for nothing other lack of options. I think it's just hard to market when the only commonly known kappa drug (Salvia) is— notorious for not exactly being a fun time.

I found experiments with Matrine on rats and they were using 50mg/kg, so unfortunately the scientific sample I theoretically could obtain would not be anywhere near enough to feel effects, without spending hundreds of dollars that is.

 

[Weltmeister]

Matrine seems to be a typical plant alkaloid along with Oxymatrine.

Sophora flavescens, the shrubby sophora, is a species of plant in the genus Sophora a genus of the Fabaceae family, that contains about 52 species, nineteen varieties, and seven forms that are widely distributed in Asia, Oceanica, and the Pacific islands.About fifteen species in this genus have a long history of use in traditional Chinese medicines. The root is known as Ku shen. is a typical traditional Chinese medicine.

Source : https://en.wikipedia.org/wiki/Sophora_flavescens

Oxymatrine (matrine oxide, matrine N-oxide, matrine 1-oxide) is one of many quinolizidine alkaloid compounds extracted from the root of Sophora flavescens, a Chinese herb. It is very similar in structure to matrine, which has one less oxygen atom. Oxymatrine has a variety of effects in vitro and in animal models, including protection against apoptosis, tumor and fibrotic tissue development, and inflammation. Furthermore, oxymatrine has been shown to decrease cardiac ischemia (decreased blood perfusion), myocardial injury, arrhythmias (irregular heartbeats), and improve heart failure by increasing cardiac function.

Source : https://en.wikipedia.org/wiki/Oxymatrine

Considering that it has been used in chinese medicine for so long i doubt it has any recreational value.

 

[Soul137]

The Sophora plant and it's medicines have been known for a long time. That doesn't mean that a purified chemical in much higher dosages wouldn't produce effects.

I mean, is it possible to act on ANY receptors in the brain (kappa opioid or otherwise) without as a byproduct getting you some type of high? I mean considering what I saw about dosages for rats for medicinal purposes (50mg/kg), it would stand to reason that it would take grams of the stuff to get one high, which in practice means it is unlikely to have any obtainable recreational value, but I don't think it can be said that it would inactive. Or am I misunderstanding your post?

 

[dopamimetic]

I'd though that the dosages for rats are somewhere between 10-12x higher than these for humans, so we would have around 35mg for a 70kg person and maybe somewhat like 135-205mg (just guessed) for recreational purposes. Or am I wrong?

 

[Soul137]

I don't know about how potency translates from rats to humans, but that math simply makes no sense. If doses were 10x lower for humans it would be 5mg/kg, 350mg for a 70kg adult. That still puts a recreational dose (probably) well over a gram, which is well over my budget.

 

[serotonin2A]

You can calculate the dose using allometric scaling. Note, however, that there can be pharmacokinetic and pharmacodynamic species differences that make allometric scaling inaccurate for some drugs.

 

[Soul137]

You can calculate the dose using allometric scaling. Note, however, that there can be pharmacokinetic and pharmacodynamic species differences that make allometric scaling inaccurate for some drugs.

For the less mathematically inclined can you say whether 10:1 ratio is an even somewhat accurate estimate from rats to humans?

 

[serotonin2A]

For the less mathematically inclined can you say whether 10:1 ratio is an even somewhat accurate estimate from rats to humans?

scaling by body surface area, the ratio is closer to 5:1. Multiply the rat dose by 0.16 to get the human dose, i.e. 8.1 mg/kg