Health - Dissociative neurotoxicity prevented by psychedelics

[Hyperreal]

I came across this study published in Nature:
Serotonergic Agents That Activate 5HT2A Receptors Prevent NMDA Antagonist Neurotoxicity

Rats were injected with the dissociative MK-801, either alone or along wiuth DOI, DOM, DOB or LSD. It was found that the rats given the psychedelics had less brain damage than the rats given the dissociative alone. DOB was the most effective.

Interesting, eh?

Reputation Comments on this post:

Awesome! Thanks for the post. This information is VERY valuable to the community! :)

[enquirewithin]

Very curious! I can't help noticing that the effects of dissocatives are described in terms of ''schizophrenia-like psychosis and cognitive impairments in normal humans,'' which is one way of looking at it, and "drugs such as LSD and its analogs, ... are notorious hallucinogens..."

The rats who were "sacraficed" must have been very high in their last hours!

Are we to conclude that, if you want to take, MK-801, you protect your self with a dose of DOI?

[Aaron]

Imagine that, curing the negative side of drugs with more drugs! Sounds great, but I would still be hesitant to take some dissasociatives and then wash it down with hallucinogens. The mental issues involved with this could be just as damaging as the physical aspects it prevents, if not more so.

[bewilderment]

I've had some experiences mixing an rc (either 2c-i or 5-meo-amt) with dxm...I already know and have been criticized in another thread for this potentially very harmful combination...anyway, what I found curious about the experiences was that it felt less toxic than using either of the substances by themselves. As far as I know both 2c-i and 5-meo-amt are lumped into the category of 5HT2 agonists (at least I've read that all tryptamines and phenethylamines are in this category, if not then correct me) and I believe that dextromethorphan is also a NMDA antagonist like MK-801...so, would it be reasonable or unreasonable to speculate that these hallucinogens counteracted some of the more negative effects I feel sometimes on DXM? I do know that I felt much calmer and relaxed with the combination although I don't doubt that the combination was probably more harmful than using either of the two substances alone...I mean, I assume that it was although perhaps the physical manifestations of the toxicity were lacking for some reason. Am I completely off-base? Any thoughts?

[Kcaj]

This is great news, I'm an avid user of "LSDXM", and the synergy between LSD and DXM is pretty amazing. The negative effects that soemtimes accompany a DXM trip in the > 1.5gram range and the negative aprt of an acid trip (like the come down and anxiety) are not present...

Instead you are kind of ushered in to this crazy dream-like reality where what you considered "living" is... well I can't even get in to it, its some crazy shit though.

Interesting to know that any possible damage caused by DXM is counteracted by other psychedelics. How strange is that? Maybe in the great chemical scheme of the universe the two substances were destined to be taken together? lol

[Richard_smoker]

I discuss this in my Ibogaine replacements for US opiate addiction interuption in the addction/recovery thread. Members, check it out if you're interested in some of the many benefits of NMDA antagonists like Ibogaine, DXM, Ketamine, PCP (yeah--even PCP! lol), in helping to restore normal brain chemistry after onslaught from several different types of drugs.

I read this journal entry from Nature, and there are others similar to it. Quite amazing results, actually. I hope this research continues on. Thanks for the post! Excellent information--food for thought!
-Dick

[Kcaj]

Any way you could link the thread? I'm searching for it not but things are a bit hectic over here.

[Richard_smoker]

SURE! I should have thought of that myself! Life must be kinda hectic over here at the Smoker Mansion!

Here's the thread. I encourage everyone who is even the SLIGHTEST bit interested in DXM's potential, or in treatments for opiate addiction to please give this research an honest look-over. I actually researched and WROTE these posts (with blood, sweat, and tears!)!

Seriously, the only parts that I copied-and-pasted is the last half of the DXM information. It was copied from the DXM user's guide, but the similarities between DXM and Ibogaine were all things that sort-of came to me 'in a dream'!! (SWEAR TO GOD!!!)

Please Enjoy! I haven't really heard much from anyone after posting these findings. For some reason, I thought I was going to get some kind of huge fanfare... like I'd discovered the cure for cancer or something!
But... alas,... no one seems to be that impressed...

Oh well... It apparently takes a LOT to impress people around here!
-RS

p.s. let me know if anyone has any questions or suggestions. i would LOVE to discuss this with ANYONE! This is a subject that I've developed a new-found passion for, and I would love to discuss and/or clarify any claims that I've made to anyone who will listen!

[Kcaj]

Seeing as how DXM revolves around me sometimes, you can rest assured I'm going to read this in very good detail Getting right on it right now

[Forthesevenlakes]

the weird thing is that dissociatives are supposed to prevent neurotoxicity as well, and yet in this article are being used to induce it? wonder what the difference is in psychedelic and dissociative mediated neurotoxicity...like if different regions of the brain are affected, or what. of course, i'm just basing my dxm neuroprotective hypothesis from the dxm faq, what i can recall of it. but i'll back richard, go check out that other thread and add to the thought process going on there!

Reputation Comments on this post:

NICE! That's the way to throw in your fucking 2 cents! Bravo. I didn't even notice that our conversations were saying...

[Richard_smoker]

Wait--huh? yeah, Sevenlakes is right. The dissociatives do protect and also assist with re-wiring of the neural circuits involved in events downstream from the NMDA's. I'll have to check that article out again, I'm afraid they might be discussing the neurotoxicity from super-high-dose DXM and/or chronic use. Because chronic use leads to alteration inthe expression of the NMDA receptors (and sigma receptors, I think)... and there are also reports of acute neurotoxicity from an outrageous amount of shitloads of DXM.

I will find out the answer to this question and post it here... RS

[Kcaj]

Being a chronic user of DXM and someone who often takes DXM by the gram (and redoses often without sleep), I hope most of the negative things people say about DXM are not true... haha, or I'm in for some serious brain damage.

Reputation Comments on this post:

i'd like to see some further post on SWIM's opinions on this matter!

[Richard_smoker]

um... Kcaj, please don't tell us what YOU do. Tell us what your friends do. SWIM="Someone Who Isn't Me"

Look around and you'll see that everyone is doing it. This keeps people from incriminating themselves. I know that DXM is OTC, but I still wouldn't come to a site called "drugsforum" and announce to the entire world of law enforcement that you are a chronic user of dxm and that you often take it by the gram... although i'm not even sure if that's illegal. but either way, it's in the rules. read the rules before you post again. people are really touchy around here about others who don't follow the rules. -Dick

Reputation Comments on this post:

fantastic, and easy to understand

[bewilderment]

Originally Posted by Kcaj

Being a chronic user of DXM and someone who often takes DXM by the gram (and redoses often without sleep), I hope most of the negative things people say about DXM are not true... haha, or I'm in for some serious brain damage.

Hmm...be kind of careful with the redosing thing. From what I understand, the lesions from dissociative use are caused because neurons in specific areas of the brain enter a state of excitation and when they receive too much stimulation they can die, and of course when a bunch in a certain area die off then you get those nice tiny holes they've found in the lab rats. Thus, it's certainly a good idea to let your brain have some time to breathe or else they may not be very resourceful.

However, swim understands because she used to take dxm almost every day which included the redosing deal. Looking back at it, swim thinks it was self-medication because the nice serotonin boost (especially directly afterwards) was what she mostly looked forward to because it made her feel like she could conquer the world. Swim also says that after being off the dex for some months (it's hard to recall because it was tapered off and she doesn't remember when it actually ended, but no heavy use, or much use at all, for maybe ~7 months) that she can't really detect any sort of damage, but it's difficult to tell because while her memory's not as sharp as it once was this may be due to the other drugs she still uses. But, she says that her concentration and mental dexterity (ha) are improving quite a bit since she stopped the use. Swim also didn't read all that much about the negative effects while she was using...she read some, but it's such a downer, ya know? After she began to get really in depth while her brain was still recuperating she became kind of paranoid about potential damage. Swim recalls (or doesn't) her dxm dayze with much fondness and wouldn't change a thing except maybe taking just a bit more precaution. Happy trails!

[Richard_smoker]

Originally Posted by forthesevenlakes

the weird thing is that dissociatives are supposed to prevent neurotoxicity as well, and yet in this article are being used to induce it? wonder what the difference is in psychedelic and dissociative mediated neurotoxicity...like if different regions of the brain are affected, or what. of course, i'm just basing my dxm neuroprotective hypothesis from the dxm faq, what i can recall of it. but i'll back richard, go check out that other thread and add to the thought process going on there!

OK... Forthesevenlakes, I found the definitive answer to your question. It is not exactly what I had hoped to find, but I certainly wouldn't panic at this information... instead, take it in-stride, as I am doing. I will be updating my thread on DXM for Addiction Interruption soon.

In a way, it seems that I've been barking up a tree that is changing shapes on me... It is, in fact, the dissociatives (DXM) that are responsible for creating the so-called "Olsney Lesions" that I've seen thrown around this board and elsewhere with absolutely no idea to what they were referring. Now, this is NOT to say that a small amount of DXM *or* a limited small number of 'trips' will hurt you, but there is definitely such thing as an NMDA Antagonist-Induced Neurotoxicity: from here.

I. Onley's Lesions (NMDA Antagonist Neurotoxicity)

(this is excerpted largely from the DXM FAQ's "Side Effects" section)

When NMDA antagonists were first studied they seemed like a dream come
true: here were drugs which could block from part to all of the damage
from strokes, head injury, hypoxia, polio, and a variety of other
conditions. However, it seems that nature never gives something for
nothing, and here too there was another side to the coin.

The dream ended when Olney et al. demonstrated that animals given high
doses of dizocilpine (MK-801), a new dissociative used in research,
showed curious vacuoles (essentially, tiny holes) in their brains.
Specifically, the vacuoles showed up in the posterior cingulate cortex
and retrosplenial cortex (see I.1 for an explanation of what these
parts of the brain do). Further research showed that other indicators
of damage were present, such as proliferation of microglia, secretion
of a protein called HSP70 (Heat-Shock Protein 70), and expression of
certain genes.

Since then, Onley's lesions, also known as NMDA Antagonist
Neurotoxicity or NAN, have been discovered with ketamine, PCP, and
dextrorphan (the metabolite of DXM), as well as a bunch of
dissociative drugs you won't find outside of a research lab. PCP
causes additional damage to the cerebellum and other areas, by the
way.

For a long time, nobody knew whether Olney's lesions applied to human
beings or not, or at what dosage they applied. The amount of ketamine
used to knock out a rat, for example, is obviously different than the
amount used for humans; it's also not the same dosage in mg/kg
(milligrams per kilogram) either. And different effects of drugs
"scale" differently too.

However, several things have happened recently which have led me to
conclude that Olney's lesions apply to humans at recreational doses.
First, I've received reports from many hundreds of users of DXM, some
of whom have used it heavily and been clearly harmed. Second, more
recent studies have shown that damage occurs to lab animals' brains
even at lower doses (including ordinary anaesthetic doses of ketamine
and dizocilpine!). Third, reports of ketamine-related brain damage
have started to show up. Finally, the type of impairment people are
reporting coincides exactly with the areas of the brain damaged in lab
animals.

If you think you might be suffering from Olney's lesions, DON'T PANIC.
You may just have depleted neurotransmitters, or induced long-term
(but reversible) changes to neuroreceptor function. If you feel you
are impaired, STOP USING NOW, and stay clean for several months before
you get worried. Many people have told me that their "brain damage"
cleared up after a few months.

IMPORTANT NOTE: Olney's lesions are WORSE in female animals than
males, probably because females have different limbic connections.
This may apply to humans.
__________________________________________________ _______________

I.1. Areas of the Brain Involved

Nobody's totally sure exactly what most parts of the brain do, but
there is some evidence which may indicate possible functions for the
posterior cingulate and retrosplenial cortex. Although modern
science's understanding is far from complete, and mine is considerably
worse than that, I'll try to put together the published results into a
coherent whole.

The posterior cingulate cortex is the posterior (rear) part of the
cingulate cortex, a section of the cerebral cortex interconnected with
the limbic areas. The front part of the cingulate cortex is called,
appropriately enough, the anterior cingulate cortex (you expected
"fore" and "aft" maybe?). Like most areas of the brain, the boundaries
of the cingulate cortex are somewhat indistinct. There are differences
between the posterior and anterior cingulate cortex (beyond the
obvious one of location); notably, the anterior cingulate cortex has
fewer pyramidal neurons than the posterior cingulate, and in the
anterior cingulate these neurons have more complex connections. This
entire area may relay information between the hippocampus (and other
limbic systems) and other areas of the brain.

There is a lot of disconnected research that points towards possible
purposes for the posterior cingulate cortex. It may be one of the
components of verbal and auditory memory, multisensory perception,
visuospatial cognition and/or evaluation of emotional behaviour. The
right hemisphere posterior cingulate is activated in comprehension of
metaphors, and the left in associative learning. Story comprehension
seems to use the posterior cingulate. In late Alzheimer's disease the
posterior cingulate may be subject to atrophy. It is activated during
anxiety and in OCD (Obsessive-Compulsive Disorder), and may be
overactive in bipolar disorder; it is deactivated during phobic fear.

It has been suggested that the cingulate cortex in general may be
involved in evaluating (posterior) and acting on (anterior) one's own
behaviour and spatial orientation. This is, in my opinion, the most
comprehensive view of the existing research. To put it simply, the job
of the posterior cingulate cortex might be to evaluate and consider
where you are and what you're doing. Since dissociatives tend to
interfere with the ability to evaluate one's own behaviour, it may be
that the posterior cingulate is a part of a self-evaluation system.

An interesting aside here, many people who really like dissociatives
have told me they find them so attractive because they help to take
away a near-constant self-consciousness, an almost self-absorbing
embarassment or "inner critic". While I don't think any one part of
the brain can be the "home" of anything so complex, I am willing to
accept that the posterior cingulate may be a major contributor to
self-evaluation gone haywire. The good news is, there are healthier
ways of getting beyond this problem; see III.4 below.

Another paper analyzed the network properties of the posterior
cingulate, and suggested that neural output from the hippocampus that
was in sync with the theta rhythm would pass through the posterior
cingulate cortex in preference to other routes. What makes this so
interesting is that the flanging or strobing effects of DXM and other
dissociatives seem to occur at theta rhythm, which may be a
consequence of their effects on the posterior cingulate.

There was considerably less information published on the retrosplenial
cortex. One paper found that it was activated during the encoding of
novel situations. Another suggests that the circuitry between the
retrosplenial cortex and hippocampus is an important path by which the
hippocampus affects learning, memory, and emotional behaviour.
Numerous papers suggest it has a role in visual processing
(interestingly, some dissociative users report problems getting their
eyes to track right after heavy binges). My totally unfounded hunch is
that the retrosplenial cortex may be involved in converting the
two-dimensional data that appears on the retina into a
three-dimensional space, and the "third person perspective" some get
on dissociatives may be related to retrosplenial cortex disruption.

To sum up: these are the skills which damage to these areas might
impair:
* Memory, especially language-related (e.g., finding words)
* Understanding metaphors
* Evaluating, and possibly controlling, your own behaviour
* Multi-sensory thinking
* Learning in new situations
* Certain aspects of visual perception

With increasing doses, damage spreads beyond the posterior cingulate
and retrosplenial cortex into other areas of the brain including the
hippocampus and olfactory areas. Damage to the olfactory tubercule
would, obviously, impair one's sense of smell. Damage to the limbic
system itself could have wide-ranging consequences including:
* Autobiographical memory
* Declarative memory (as opposed to remembering skills)
* Place-memory (learning and remembering your way around)
* Coupling of emotions to experience
__________________________________________________ _______________

I.2. How and Why Olney's Lesions Happen (probably)

The mechanism for Olney's damage is still being sorted out, and is
somewhat perplexing, since NMDA antagonists generally protect neural
tissue from damage rather than causing it. Trying to tie everything
together is a little like trying to solve a crime with only
circumstantial evidence; there are clues, but nobody's been able to
watch the criminal in action. Here is what current research seems to
indicate, pieced together into a coherent whole. A simplified
explanation is given below.

1. Dissociatives activate neurons in the posterior cingulate cortex
(PC) and retrosplenial cortex (RC). These overactive neurons pass
along their excitation to "downstream" areas such as the
hippocampus and olfactory areas.
There are two theories on why the PC and RC neurons get
overexcited in the first place; either one, both, or neither could
be true. One theory is that NMDA receptors are found on inhibitory
GABA interneurons, and that when these receptors are blocked,
these interneurons secrete less GABA, and thus excitatory
pyramidal neurons that normally receive a lot of GABA inhibition
are overexcited.
The other theory is that the PC and RC are less affected by NMDA
blockade than the hippocampus (and related areas), and that these
formations serve as feedback to the hippocampus and surrounding
networks. As these limbic networks are inhibited, the PC and RC
increase their output to compensate, resulting in overactivity.
2. The overactive cells begin to heat up, use up their energy supply
generate toxic waste products, and/or let in too many calcium
ions.
3. Regardless of the mechanism, or whether the mechanism is none of
the above, the overactivity seems to cause intracellular
organelles (notably mitochondria and endoplasmic reticulum) to
malfunction.
4. The mitochondria probably lose their proton gradient and allow
their innards to spill into the surrounding cell material, where
they cause all sorts of trouble, possibly including forming free
radicals which cause further damage to the cell. Another
possibility is that the free radicals come first, and they cause
damage to the mitochondria and other organelles. Mitochondrial
damage can occur within 15 minutes of the drug dose, the
endoplasmic reticulum is damaged 30 minutes, and in both cases
gets worse as time progresses. The free radicals, basically,
destroy everything in the cell like a rampant two-year-old on a
spending spree through Toys-R-Us.
5. The cell responds to this damage with a protein called HSP70. This
"heat shock" protein is made and activated when something (such as
overheating, thus the name "heat shock protein" or HSP) is causing
a cell to malfunction so badly as to be in danger of
self-destructing, and its job is to turn the cell off until
repairs can be made. Hopefully, the cell will get a lot of rest
(about 24 hours) until it goes back to normal. At this point the
problem is still reversible and the brain cells have not been
permanently damaged.
6. If the cell continues to be overexcited, it eventually burns out
completely as the increased temperature, disrupted ion gradient,
hypoxia, calcium ions, free radicals, and/or buildup of waste
products kill it. At this point, surrounding support cells called
microglia are activated and come in and eat the cell (probably
under the theory that if an infectious organism caused the cell
death, it'd better be destroyed before the infection can spread).

To put it bluntly, taking excessive doses of dissociatives make
certain parts of your brain fry like the proverbial
egg-on-the-frying-pan in the "This is Your Brain on Drugs" commercial.

I hope this information is taken into careful consideration by those attempting to utilize DXM's effects on NMDA receptors... like, for example, if trying to induce changes in habits like addiction.

[.rar]

Originally Posted by Richard_smoker

there is definitely such thing as an NMDA Antagonist-Induced Neurotoxicity: from here.

Cliff Anderson's Rebutton to this document: 'The Bad News Isn't In', June 2003

William White's retraction of 'This is your brain on dissociatives', Dec 2004

Reputation Comments on this post:

GREAT POST! Thanks for the rebuttal!! I was SO UPSET to find DXM-->OLSNEY'S LESIONS!!! :) Thanks for a sigh of rel...

[Forthesevenlakes]

ahh yes, the Olney's Lesions information. that information had swim pretty worried when he was a regular user (2x month, but this was occuring invariantly for years), although the doses required to cause the lesions are probably much larger. IF they exist, i have yet to read the rebuttals...and i should take the time to do that. if it turns out that even chronic use won't induce the lesions, so much the better for the NMDA-mediated interruption of addiction theory that is being pieced together. in some way i feel like we're making scientific history on these boards, ha ha.

[Richard_smoker]

Shhh!! we ARE making history, dammit! We've actually unearthed some serious shit here regarding what could be THE cutting edge pharm science in motivation/reward interruption... NMDA antagonism was a BIG part, but found some newer research... (think hunger and satiety!) we were right about the intracellular cascade idea (i think it was YOUR idea, right?)

I'm growing concerned about what we post here for all the world to read... check your pms. For some reason, i'm pretty sure that not very many people around here are even paying attention to these talks (EXCEPT FOR YOU .RAR!! -really, though thanks for the rebuttals!). I'm onto something *else* but similar; err--WE're onto something--and well, just check your damn messages already.