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OK, here's the recently-mentioned and awaited results in full detail. This is
an "alpha pre-release", references not included and I hadn't planned
on posting this at all except it's kinda started to spread on its own.
Bottom line: all dissociatives carry a real risk of permanent brain damage.
Dissociatives include ketamine, DXM, PCP, dizocilpine, and nitrous oxide (tho
it may not be nearly so dangerous due to very short duration of action).
Individual susceptibility varies *greatly*, so if you've snorted enough K to
tranq an entire pet shelter and downed A. H. Robins' entire year's production
of Robo and are still OK, this *doesn't* mean that everyone else can do the
same thing. I've spoken with numerous people who *have* suffered permanent
impairment from heavy dissociative use. This document explains the process by
which it occurs, and how to minimize or prevent it. I take NO RESPONSIBILITY
for any errors; if you're old enough to do drugs, you're old enough to take
responsibility for your own fuckups.
I don't get on Usenet much, so don't expect rapid response. If you have a
question, ask RFG or email me; I have a real job that takes up almost all of
my time these days. Most general questions about DXM are answered in the FAQ;
ketamine probably has an FAQ somewhere too. (Note that ketamine is probably
*slightly* better for you than DXM *in theory*, but the hydrobromide in DXM
HBr may make it about even. It's still too early to know).
This is Your Brain on Dissociatives:
The Bad News is Finally In
Version 0.1 (pre-release)
William E. White
(hint: for the down-and-dirty, see section ii.)
i. Introduction To This Document
ii. Summary of Findings
iii. Why am I Telling You This (My Background)
iv. The Dissociative Drugs
I. Onley's Lesions (NMDA Antagonist Neurotoxicity)
I.1. Areas of the Brain Involved
I.2. How and Why Olney's Lesions Happen (probably)
I.3. Lab Critters vs Humans (or, Yes, it can happen to you!)
I.4. Best and Worst Case Scenarios
II. Other Complications of Dissociative Use
II.1. Limbic Seizures and "Temporal Lobe Lability
II.2. Psychosis and Schizophrenia
II.3. Other Problems
III. How to Minimize the Risks
III.1. Abstinance and Limiting Use
III.2. GABAergic Sedatives and Other Drugs
III.3. Health Issues
III.4. Safer Alternatives to Dissociatives
III.5. What to Avoid Like the Plague
i. Introduction To This Document
This is a fairly detailed file which covers a type of brain damage known as
NMDA Antagonist Neurotoxicity or Olney's Lesions (after the researcher who
discovered it). It also covers other risks of using dissociatives, and how to
minimize them. If you currently use, have used, or plan to use, any
dissociative (drug which blocks NMDA receptors or which is a dissociative
anaesthetic), then you should read this document. This includes ketamine, PCP,
dextromethorphan, and nitrous oxide; see Section iv. below for more
This document is copyright (C) 1998 by William E. White. You may copy this
document provided it is kept intact, with this notice in place. I encourage
everyone to show this to anyone they know who might benefit from it.
ii. Summary of Findings
Several years ago, JW Olney discovered that dizocilpine (MK-801), a chemical
being tested to prevent brain damage from strokes, actually caused damage to
specific areas of the brain in rats. Since this time, numerous other drugs in
the same class (the dissociatives) have been tested, and they all share this
problem. As some of you might know, I have spent a great deal of time trying
to make sure that the Internet community, and the larger world, has detailed
information about this complex, difficult-to-use, and often dangerous class of
drugs. I first learned of Olney's lesions a few years ago, but it has taken me
much time to review all the evidence, compare drug dosage within and across
species, speak to heavy dissociative users, and so on. I am now ready to state
my conclusions and make some recommendations, which are as follows (explained
in detail in the full document).
- Dissociatives definitely cause brain damage if used heavily. One
sub-anaesthetic "line dose" of ketamine, an equivalent dose of
PCP, or a third plateau DXM dose, is probably at least as damaging to your
brain as a few day "bender" on hard liquor, and possibly more so
because it affects specific areas of the brain.
- The risk of brain damage is worse the longer you stay high at any given
time; constant moderate-dose use is probably just as damaging as a brief,
- Reaching the anaesthetic level is exceedingly hard on your brain.
- Ketamine is probably the least harmful, PCP the most, and DXM somewhere
in the middle, but this is a rough guesstimate. Nitrous oxide is brief
acting, but it too may be dangerous; it is also known to damage both
central and peripheral nerves by depleting vitamin B12.
Some people may be more susceptible to Olney's lesions than others. There is,
to my knowledge, NO way of knowing how susceptible you are.
In addition to brain damage, these drugs can also trigger psychosis, limbic
seizures, temporal lability, depression, and other neurological and
psychological diseases much more frequently than other types of drugs. The
dissociatives can be highly addictive to a minority of users. In comparison,
the marijuana and the serotonergic psychedelics (LSD, psilocybin mushrooms,
peyote, DMT) are many times safer.
People who have used dissociatives heavily have shown clear evidence of brain
damage. This is not necessarily conclusive, since the people who become
addicted to them might have underlying conditions (specifically, temporal lobe
complex partial seizures) which could be responsible for some of the damage.
Nonetheless, I can't ignore the fact that most everyone who uses dissociatives
both frequently and heavily ends up with some sort of neurological or
psychological problem, ranging from impaired memory to a schizophrenia-like
syndrome. Many of the impairments correspond exactly to the areas of the brain
damaged in lab animals.
If you will not abstain from using dissociatives, there are several steps you
can take to protect your brain, ranging from limiting frequency and dosage to
taking nutrients and neuroprotective drugs. You can also use alternative
methods (ranging from safer drugs to meditation) to reach the same places that
dissociatives take you.
iii. Why am I Telling You This: My Background
If you know me, you probably know me from the Dextromethorphan FAQ
which covers the dissociative drug
dextromethorphan (DXM) in considerable detail. I've been studying the brain
for several years now, concentrating specifically on memory and congition, the
limbic areas, and neuropharmacological agents that affect NDMA receptors. I've
tried to keep everything I write down-to-earth while still supporting it with
medical fact, and I've also tried to be as honest as possible. Sometimes this
means speaking the truth, even when the truth happens to conflict with the
"official version" given by those who participate in the War on
I'm in favor of drug reform, and I don't try to hide that fact. I think the
current policy is wrong-headed, and I think that psychedelic drugs in
particular should be available to people who want to use them with respect and
who can take responsibility for their actions. With some psychedelics, there
is extensive evidence showing that careful use is less harmful than many
currently legal drugs, and many societies have successfully integrated
psychedelic use into their culture.
However, I also have to admit when there's a danger out there that people
should be made aware of. Even now that the dangers of DXM are better known, I
still stand by my decision to publish the FAQ, because I still think that
people make better decisions about risks when they have information than when
information is kept from them (and they learn about drugs by hearsay). Telling
the truth means telling the whole truth, the good along with the bad.
Sometimes there's bad news. This is one of those times. Please read and think
carefully, and take good care of your body and brain.
iv. The Dissociative Drugs
The term "dissociative" derives from "dissociative
anaesthetic", a class of anaesthetics which produce unresponsiveness to
stimuli by dissociating various elements of the mind (in simple terms, they
knock you out by putting you 'out of your body'). Consciousness, memory,
perception, and motor activity are all dissociatied from each other. The
dissociative anaesthetics all block the N-methyl-D-aspartate (NMDA)
neuroreceptor, though many act on other receptors like sigma. I prefer
"dissociative" to "dissociative anaesthetic" when
discussing these drugs, for two reasons: first, most recreational use occurs
below the anaesthetic level; second, some drugs in this category are not, and
probably never will be, marketed as anaesthetics.
Dissociatives are not frequently used as anaesthetics in humans because of
what are known as "emergence effects", various odd effects that can
happen when people come out of anaesthesia. All anaesthetics can produce these
effects, but with the dissociatives it is much more common and much more
severe. Dissociative anaesthetics (ketamine and tiletamine) are used in
veterinary practice, since animals don't often complain about out-of-body
experiences. Ketamine is also used in burn trauma and in children (who don't
get the psychedelic effects of the dissociatives, and are not susceptible to
dissociative brain damage).
The psychedelic effects of the dissociatives are difficult to explain. They
are nothing whatsoever like LSD or related drugs (mescaline, DMT, mushrooms,
etc.) but they are clearly psychedelic. For years I've struggled to understand
the dissociatives, and the best way I can explain the difference between
dissociatives and traditional serotonergic psychedelics is this:
Serotonergic psychedelics are Eros, and dissociatives are Thanatos. The
serotonergics are Birth, they are sensory overload, focus on the details,
awareness of the external universe. The dissociatives are Death, sensory
shutdown, focus on the archetypes, awareness of the internal universe.
Serotonergics are the "Ana" side of Chaos, dissociatives the
"Kata" side of Chaos (Chaos being the essential driving energy
behind reality, if you will).
Ultimately, they can both take you to the same place -- mystical union,
ego-loss, or just plain "trippin' balls" depending on your point of
view -- but they take you by different routes. I like to think of both routes
as complementary ... but only if they don't hurt you in the process of getting
A recent study confirms that nitrous oxide is a dissociative anaesthetic. YOU
HAVE BEEN WARNED! Nitrous oxide also depletes vitamin B-12, incidentally.
These are some dissociative drugs you might encounter:
- Street Drugs:
- Ketamine (K, Special-K, Vitamin-K), in injection bottles or as
- Dextromethorphan (DXM), in capsules or as powder
- PCP (Angel Dust, Embalming Fluid, etc.), powder, liquid, or on
- Over-The-Counter and Quasi-Legal Drugs:
- Dextromethorphan (DXM), available in cough syrups and pills
- Nitrous Oxide ("Whippets" and iSi whipped cream chargers)
- Prescription Drugs:
- Ketamine (veterinary and human anaesthetic)
- Tiletamine (veterinary anaesthetic)
- Memantine and amantadine
- Research Drugs:
- Dizocilpine maleate (MK-801)
I. Onley's Lesions (NMDA Antagonist Neurotoxicity)
(this is excerpted largely from the DXM FAQ's "Side Effects"
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
IMPORTANT NOTE: Olney's lesions are WORSE in female animals than males,
probably because females have different limbic connections. This may apply to
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
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.
- 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.
- The overactive cells begin to heat up, use up their energy supply
generate toxic waste products, and/or let in too many calcium ions.
- 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.
- 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
- 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.
- 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.3. Lab Critters vs Humans (or, Yes, it can happen to
As I stated above, there are several reasons why I now believe that Olney's
lesions can, and do, happen to humans.
First, the animal data. Ketamine is normally used as an anaesthetic in a
mixture with another drug called xylaxine, an alpha-2 adrenergic agonist
sedative. When used alone, it takes about 40mg/kg to knock out a rat. The same
dosage will also induce HSP70, the protein that shuts down damaged neurons;
twice this dosage will actually kill cells. Note that this is from just one
dose; if you give a rat multiple doses, or extend the dosage too long, the
damage will be much worse. A prolonged, lower dose of dissociatives may be
just as dangerous as a single higher dose!
If humans respond like rats do, this means that taking a single anaesthetic
dose of ketamine will put an enormous amount of stress on the neurons in your
posterior cingulate and retrosplenial cortices. (Recreational doses are, of
course, less than anaesthetic doses, but not by enough; it may take a dose
five times lower before the danger is gone). This stress will cause the
neurons to shut down in order to make repairs; if they can't make repairs, or
if they are damaged again too quickly (i.e., from too-frequent use of
ketamine), they will die. Ketamine is used as an example; any dissociative
will cause the same sort of damage.
Then there's also the issue of people's experiences. Since publishing the DXM
FAQ, I've heard from dozens of people who have used dissociatives (mostly DXM,
but also ketamine and PCP) and had lasting impairment. Most of these people
were very heavy users (daily use of PCP, ketamine, or high-plateau DXM), but a
few weren't. One person I heard from recently used DXM for less than a year,
taking it twice a week at most, in doses of 600mg to 1500mg (once at 2000mg).
This particular individual complained of impaired memory and difficulty
understanding metaphors which has lasted over a year.
Many of the peculiar effects of dissociatives seem to correspond with their
effects in animals (including damage). DXM users often report that their
upper-plateau trips rapidly lose the interesting effects, perhaps because the
cells that are going haywire (and making the whole temporal lobes function
unusually, thus the effects) are burning out. After frequent use, a lot of DXM
users and some ketamine users have reported strange "jolts" or
"shocks" when moving their eyes, and sharply impaired visual
tracking is characteristic of high dose use; this may be related to the
retrosplenial cortex, which encodes eye position (among other things).
Impaired recognition of metaphor, impaired language skills, and memory
problems are all frequent consequences of excessive dissociative use (in most
people these problems fade with time).
There seems to be a lot of unpredictability here. Some people can use
dissociatives heavily and not suffer; others suffer after using more
moderately. Unfortunately, you don't know how susceptible you are until it's
too late. Sure, the chance may be one in a hundred, but if you're that one,
it's not terribly comforting to know that the other ninety-nine percent are
I.4. Best and Worst Case Scenarios
There's still a lot of unknowns here. Nobody has ever seen Olney's lesions in
a human brain. It could be that this damage only occurs very rarely, to people
with underlying neurological disorders, and that most people who experience
impairment are simply suffering from neurotransmitter depletion, receptor
reregulation, or some sort of learned phenomenon (similar perhaps to the
flashbacks a small percentage of LSD users get). That's the best case
The worst case? Everyone using dissociatives may be doing permanent damage to
their temporal and perhaps frontal lobes. This damage would be cumulative,
adding up over each experience, with heavy or extended doses doing especially
heavy damage. Unfortunately, you may not know there's anything wrong at first.
Neural networks are a lot like holograms, in that you can remove or damage
part of them and the built-in redundancy will keep things working more or less
properly (perhaps with a bit less flexibility). Once you get to a certain
threshold, however, it gets rapidly worse. Think about it like a curve ball;
from the batter's perspective, the ball goes in a straight line and then
suddenly darts away, even though it's really making a steady arc.
The damage you do now may not even show up until you are much older. There are
many causes of neuron loss; mild head injuries, high blood pressure, unnoticed
infections, maybe even the passage of time. The neurons that were overstressed
may be forever weakened. You may find, thirty or forty years from now, that
you've developed severe memory problems. I realize that sounds like a long
time off, but believe me, the years pass a lot faster than you'd think.
The reality probably lies somewhere in the middle. After all, there are a lot
of potential causes of brain damage. If activities were regulated on their
potential to damage the brain, marijuana would be legal and alcohol would be
banned, and boxers would get life in prison. And there are a lot of steps you
can take to minimize the damage and improve your chances. I can't make
decisions for you, and I wouldn't try to either; all I can do is point out all
the risks. Climbing mountains is risky too, but I wouldn't suggest that nobody
should do it.
II. Other Complications of Dissociative Use>
Just in case you didn't already know, there are a lot of other problems you
can run into from using dissociatives. I don't intend to try and
"preach" here, but a lot of people know very little about the drugs
they take. There are some drugs, like marijuana, mushrooms, and LSD, which are
very forgiving of ignorance. The dissociatives are not forgiving. I don't
necessarily agree with the distinction between "hard" and
"soft" drugs, but dissociatives probably lie on the borderline
between the two. Not nearly as addictive as cocaine or heroin (or nicotine for
that matter), but far more dangerous and difficult to use safely than the
serotonergic psychedelics and marijuana.
Here are some of the major dangers of dissociative use. At the end of this
section are the dangers of specific dissociatives -- DXM, ketamine, PCP, and
II.1. Limbic Seizures and "Temporal Lobe
Simply put, if you are epileptic (diagnosed or not) or are susceptible to
seizures, you should absolutely avoid dissociatives. They can induce
seizure-like brain activity even in normal individuals, and there are several
documented cases of people with underlying seizure disorders who suffered
severe brain damage from using dissociatives.
There's also the possibility that dissociative use may induce seizures even in
normal individuals. EEG activity suggests this, and many of the more
extraordinary effects of dissociatives -- religious visions, for example --
are reminiscent of temporal lobe seizures. But I have yet to hear any solid
evidence, and I'm skeptical.
A more reasonable phenomenon sometimes goes by the name "temporal lobe
lability", and refers to a cluster of symptoms which are similar to those
experienced by temporal lobe epileptics, without the involvement of actual
epilepsy. Some of the more common symptoms include hearing voices (especially
in white noise or static), visual disturbances, frequent deja vu or jamais vu,
intense and fluid emotions, somatic hallucinations (electric shocks,
"crawling skin"), delusions of reference (events seem to have
unusual meaning), sensed presences, and spiritual experiences (within the
current mythology this can appear as alien encounters). By the way, this
refers to symptoms experienced while sober, not while intoxicated.
It's not clear (to me) whether this represents a real phenomenon or whether
it's a product of cultural factors, but I'm inclined to believe the former.
The phenomenon is more frequent and intense in women and left-handers, which
implicates the temporal lobe or limbic areas (thus the name). Michael
Persinger has published papers on the subject, suggesting it may be an
undiagnosed seizure disorder, but I think Persinger sees limbic seizures
hiding behind every tree.
Whatever the nature of temporal lobe lability, quite a few long-term
dissociative users have told me these specific symptoms tend to become more
frequent over time. Most seem to view it as an annoyance more than anything
else. I have a personal hypothesis on this subject, but it's rather complex
and detailed; essentially, I think its a learned phenomenon, not a
neurological one. The counterpoint view is that it is neurological, and may
represent a gradual loss of inhibitory GABAergic neurons or glial cells (this
would be bad).
II.2. Psychosis and Schizophrenia
There is always a risk of psychotic breaks whenever you use psychedelics;
intense experiences have a way of doing that. I don't believe that the
serotonergic psychedelics (LSD, mescaline, DMT, psilocybin, etc.) can turn
normal individuals psychotic; instead, I suspect that people with an
underlying mental condition may find the drug experience triggers an outbreak
of the disease. This isn't good, of course, but keep in mind that any intense
experience can do this; if we want to protect such people from outbreaks of
mental illness, we'd be best off by outlawing divorce, marriage, and having
children. A followup study of people who used LSD in the 1960's showed no
evidence of more frequent mental illness, and among native Ayahuasca-using
cultures, those who used the drug were just as stable and sane as those who
The dissociatives may be a different story, however. I don't yet have complete
statistical data here, but it seems thus far that psychotic breaks and
schizophrenia-like symptoms (both positive and negative, unlike LSD-induced
breaks) are far more frequent with heavy or regular dissociative use than any
other type of psychedelic. I base this opinion on having communicated with
hundreds of current and former users of DXM and a smaller number of ketamine
and PCP users; it seems that the duration of intoxication is the crucial
element here (and that DXM is the worst offender, possibly because of greater
activity at sigma receptors and longer duration). About 5% of regular users of
DXM in my sample have experienced some form of psychotic reaction that lasts
well beyond the drug effects (usually a few weeks, rarely requiring
hospitalization). It's worth noting that PCP's negative stereotypes come from
these (rare) reactions.
II.3. Other Problems
All dissociatives are extremely toxic to developing fetuses and they should
never be used during pregnancy (this probably includes cough-suppressant doses
of DXM, by the way). Severe brain damage and mental retardation may result.
Dissociatives are addictive. Regular use depletes neurotransmitters, and heavy
use (or addiction) will usually leave you depressed, anxious, and mentally
impaired. Alcoholics are at higher risk of dissociative addiction, as are
people with anxiety problems, social phobias, and mood disorders. My opinion
is that the addiction is psychological and may be largely a response to the
Many dissociatives have a heavy "body load". DXM is the worst
offender here, for details see The DXM FAQ (briefly, there's potential for
hypertension or hypotension, and rarely, cardiovascular and liver damage).
Some sources claim that breathing may be suppressed or slowed down too much at
high doses; others say this doesn't happen. My personal feeling is that
near-anaesthetic doses are risky if you are already at risk for hypoxia (e.g.,
you smoke a lot of cigarettes).
Dissociatives impair judgement and coordination so driving is a definite
no-no. You are also prone to self-injury, and won't feel it until the drug
wears off, so avoid overexertion. For unknown reasons some people seem to be
attracted to water, and drownings have happened on ketamine and DXM; remember,
you can't breathe water no matter how much you may think you can. Generally
speaking, always keep in mind that you're somewhat "out of your
body", and that no matter what you think you can do, you still have to
consider whether your body can do it.
There's literally dozens of problems that people have reported from
dissociative use, some of the uglier ones include bad allergic reactions,
peripheral neuropathy, impotence, tinnitus (persistent ringing in your ears),
and "acting like a narcissistic, self-absorbed wacko" (to quote one
former ketamine user).
III. How to Minimize the Risks
Okay, that's the bad news. The good news is, there are ways to protect
yourself and alternatives to dissociatives that may work for you. I'm going to
go over some of the more general ones, as well as some especially risky things
you should avoid.
III.1. Abstainance and Limiting Use
Obviously the best thing to do is not use dissociatives. Duh. And the best way
to avoid hitting the ground at terminal velocity is to avoid skydiving, the
best way not to get pregnant is to avoid sex, and so on. A lot of people in
this country (USA) have problems taking responsibility for the risks they
take, so I'd better mention it.
If you won't quit, at least make sure you don't overdo it. The things to
consider are frequency, duration, and dose. An analogy would be driving a car
with a broken radiator. The longer or harder (heavier dose) you drive it, the
more the engine heats up, and the longer you have to wait to let it cool off.
If you drive it too long, too hard, or too frequently, you'll ruin your
engine. I don't have any definite recommendations here, just try to keep use
to a minimum (once a week at most).
After each dose you should wait at least two days before taking another dose;
that is the minimum time it takes for neural activity in lab animals to return
to normal. Dosing again within this time may be especially hard on your brain
cells. If you do decide to take an extended dose, it's probably a good idea to
wait a long time before dosing again. With DXM, for maximum safety I recommend
one week per plateau between uses (and at least a month if not two between the
extremely-dangerous "plateau sigma" trips). With ketamine, two weeks
between uses would be the approximate equivalent. I'm not going to speculate
on PCP because of its additional toxicity to other areas of the brain. Because
nitrous oxide is so short-acting, I have no recommendations other than
"use as little as possible" (not usually a problem, since it tends
to deplete one's wallet of cash before depleting one's brain of neurons).
III.2. GABAergic Sedatives and Other Drugs
If you aren't going to abstain, the best thing you can do to protect your
brain when you take a dissociative may be to take another drug which will keep
the susceptible brain cells from becoming overactive, or help them resist the
stress. There are several possible options, however keep in mind that I am
only going to report what has helped in animal tests, and what some have
suggested may help in humans. I do not recommend that you take these drugs, of
course; that decision is up to you and your doctor. I'm only offering you the
knowledge that's available from medical science.
Sedative drugs which act upon the GABA receptor are proven to prevent Olney's
lesions in lab animals. They almost certainly work in humans too, and their
use in conjunction with nitrous oxide may be what keeps the anaesthetic from
being more dangerous to brain cells. Of the various types of GABAergic
sedatives -- benzodiazepines and barbiturates, chiefly -- the benzodiazepines
are by far the safest; barbiturates are extremely dangerous. Unfortunately,
benzodiazpines are also prescription drugs in the USA and some other
countries, so if you live in such a country, you must see your doctor to
obtain benzodiazepines legally. Benzodiazepines are the minor tranquilizers,
including Valium, Librium, Klonopin, etc. (chemically they go by names ending
in -pam, e.g., diazepam, clonazepam, etc.). A very low dose is all that is
needed to protect lab animals, so a single dose may be enough for humans (but
this is unknown).
Note that the major tranquilizers (antipsychotics) are an entirely different
class of drugs, and you do not want to take them with dissociatives. They
protect some brain cells, but make the damage far worse for others. They also
lower the seizure threshold, making it more likely you may experience seizures
GHB, gamma-hydroxybutyrate, is a sedative drug but its interaction with
dissociatives is unknown. Some research suggests it may also lower the seizure
threshold. There is another class of sedatives which activate the alpha-2
adrenergic receptor (xylaxine is one), but research is inconclusive and you
should probably avoid them.
Alcohol is partially a GABA blocker, and may be effective, but this is
unproven. Alcohol also blocks the NMDA receptor and has some qualities of
dissociatives; it hasn't been shown to cause Olney's lesions in animals
(though keep in mind that it is toxic to the brain and liver, especially in
higher doses). Most people say that drinking more than one or two drinks can
make them violently ill while on dissociatives. I personally don't think
alcohol is a good choice.
There are some problems with using GABAergics, though. The biggest danger is
respiratory depression. All sedatives will suppress breathing to some degree,
and mixing a sedative and a dissociative could be very dangerous, especially
when you approach the anaesthetic level. Also, some people find that the more
interesting effects of dissociatives are blocked when they take a sedative,
possibly because it is the unusual limbic activity that creates such unusual
effects on consciousness. Finally, keep in mind that all GABAergic sedatives
are addictive, and should never be used for long periods of time because
withdrawal can be very dangerous. Remember, in many areas these are
prescription drugs and you must see your doctor to get an actual
recommendation and a prescription.
You can also try to prevent damage by increasing the resilience of your brain
cells. There are several different vitamins and nutrients which may help, may
do nothing, or may even hurt; I'm going to mention some which physicians and
researchers have mentioned. Coenzyme Q10 may offer some protection by
preventing mitochondria from running out of energy. Antioxidants (vitamin C,
vitamin E, and several natural products) may help to curb the free-radical
reaction thought to be involved. A few people have suggested Ginko biloba
which may increase cerebral metabolism (and help bring nutrients to cells and
clear out waste products); on the other hand, it may also affect brain
activity more directly, and the results are unknown (it could make things
worse). And of course a multivitamin (an ordinary dose, not megadoses!)
probably wouldn't hurt, since many people don't eat as well as they should.
Finally, there may be drugs which specifically protect against Olney's
lesions. Curiously, in animal tests, LSD is one such drug (because of its
affinity for a particular neuroreceptor, incidentally it's probably not the
neuroreceptor involved in its psychedelic effects). However, LSD is also
illegal so of course you shouldn't take it. Furthermore, combining LSD and
dissociatives may produce overpowering effects which many find very
Nitrous oxide specifically depletes vitamin B12, so a supplement may be a good
idea. Vitamin B12 doesn't absorb well, but there are sublingual forms available
which may absorb better
III.3. Health Issues
Always stay healthy! The very best thing you can do to protect yourself, short
of abstinance, may be to keep yourself in good physical health so your brain
can heal itself before permanent damage occurs. This means eat right,
exercise, and don't smoke cigarettes. You want to keep your blood pressure
low, because high blood pressure makes Olney's lesions much worse (but taking
drugs to lower blood pressure probably won't help; high blood pressure may be
more a symptom than a cause). Exercise and not smoking will improve oxygen
flow to the brain, and help limit and clear out free radicals.
III.4. Safer Alternatives to Dissociatives
No matter what altered state you are looking for, there are usually
alternative ways to find it. Sometimes they can be easy, sometimes it may take
more effort, but this effort usually pays off.
If you find yourself using dissociatives to self-medicate -- to make yourself
feel better, to block out anxiety or social phobia, or for other such reasons
-- then you might be best off consulting a psychiatrist. You may have an
underlying problem which is treatable, either by therapy or safer drugs or
both. Many areas have low-cost mental health services available. Barring that,
you may wish to try natural products like St. John's Wort for depression and
Kava Kava for anxiety; they can be surprisingly effective (not to mention
cheaper than commercial drugs). It should be obvious, but if you have social
anxiety problems, cutting down on caffeine can help. For a major problem,
though, natural products may not be strong enough, and you should always see a
professional. Keep in mind that antidepressants alone can trigger manic
reactions if you have bipolar disorder.
If you like the introspective, self-exploratory aspects of these drugs, then
consider meditation. It takes awhile to get good at it, and until you do it
can seem rather silly, but it really does work if you stick with it.
Transcendental Meditation was suggested to me as an alternative for some of
the more interesting altered states induced by dissociatives, and though I
know little about it, there are published papers which seem to support this
If you're just looking to get high, or for a party drug, then there may be far
safer drugs available to you. If you live in an area where marijuana
(cannabis) is legal, that is the best alternative; not only is it non-toxic to
the brain (recent research shows it actually protects brain cells), it's also
impossible to overdose, unlike dissociatives. Unfortunately, marijuana is
illegal in most places so you're out of luck there. Alcohol is a poor
alternative; it is addictive and causes brain damage. Numerous psychedelics
exist in nature which may be legal in your area, though of course most of them
are very different than dissociatives.
There is one natural psychedelic which may be the very best alternative for
those interested in the visionary and self-exploratory aspects of
dissociatives. It is not, however, a party drug. This is Salvia divinorum, the
"Diviner's Sage", a member of the mint family. It can take numerous
tries before the drug has any effect, and set and setting are extremely
important. There is a wealth of information available about Salvia divinorum
at . Be careful with fortified Salvia
products, as large doses of Salvia can be extremely disorienting. If at first
you get no response, keep trying; if you approach this plant with patience and
respect, the quid method (chewing the leaves for sublingual absorption) can be
quite rewarding. Incidentally, it is not known whether Salvia is toxic to the
brain or otherwise dangerous, though indigenous people have used it for many
years without ill effect.
III.5. What to Avoid Like the Plague
There are a number of drugs and conditions which you should absolutely avoid
if taking dissociatives, because they may seriously increase the risk of brain
damage or health problems. Here is a partial list of some of the more common
ones. This doesn't include the various things which can increase the risk of
adverse psychological problems or bad trips; such a list would probably be
- Drugs which may make Olney's Lesions worse:
- Yohimbine and yohimbe (and other alpha-2 antagonists) may
dramatically increase the brain damage! These should be avoided at all
- Major tranquilizers (antipsychotics) may specifically increase
damage to certain areas
- Anticholinergic deliriants (atropine, scopolamine, and anti-nausea
drugs) may increase damage to the hippocampus. This may include
antihistamine-anticholinergics including the DXM-antihistamine
- Drugs which lower the seizure threshold, and may increase the risk of
seizures (this is a very incomplete list):
- Antibiotics of certain classes, notably ofloxacin (which can be
extremely neurotoxic on its own)
- Bupropion, sold as the antidepressant Wellbutrin and as the
"stop smoking" pill Zyban
- Caffeine (in large doses; otherwise probably low risk)
- GHB and 1,4-butanediol (possibly)
- Various unusual drugs, e.g., Absinthe
- Drugs which suppress respiration, when high doses of dissociatives are
- Tranquilizers (benzodiazepine sedative-hypnotics) in high doses
- Barbiturates and methaqualone (Quaaludes)
- Alcohol in moderate to heavy doses
- GHB and 1,4-butanediol (possibly)
- All monoamine oxidase inhibitors (MAOIs) including herbal MAOIs such as
- Concurrent use of too many serotonergic drugs such as selective
serotonin reuptake inhibitors (SSRIs) and tricyclics, MDMA (ecstasy),
tryptophan and 5-hydroxytrypophan (5-HTP), due to risk of serotonin
- Poor physical condition, which can increase risk of hypertension and
Large doses of sugars (like drinking cough syrup) which may increase
free radical damage.
Remember that the risks from dissociatives, though manageable, are also
very real. The everyday drug-ignorant person likely has a belief in
"acid casualties", people who were driven insane by too much
tripping in the 1960's. And there undoubtedly are people who took LSD and
lost touch with reality, just as there are people who have lost touch with
reality subsequent to any number of activities (one study found watching
too many late night movies to be especially significant, probably because
certain mental illnesses cause insomnia). But more than one formal study
of LSD users has shown that the drug hasn't made its users any crazier
than everyone else.
But anyone who has had firsthand contact with enough dissociative users
will eventually run across the casualties, those people who find
themselves addicted to a drug which is driving them deeper and deeper into
the abyss. Like I said, the risks are manageable, but taking risks means
taking responsibility. I've already heard of far too many people who
rolled the dice and lost their sanity, their loved ones, their emotions
and memory, even their lifes. Let's try to keep this sort of thing to a
NMDA Antagonist Neurotoxicity: Mechanism and
J. W. OLNEY, J. LABRUYERE, G. WANG, D. F. WOZNIAK, M. T. PRICE, M.
Antagonists of the N methyl D aspartate (NMDA) subtype of
glutamate receptor, including phencyclidine (PCP) and ketamine,
protect against brain damage in neuro logical disorders such as
stroke. However, these agents have psychotomimetic properties in
humans and morphologically damage neurons in the cerebral cortex of
rats. It is now shown that the morphological damage can be prevented
by certain anticholinergic drugs or by diazepam and barbiturates,
which act at the y aminobutyric acid (GABA) receptor channel complex
and are known to suppress the psychotomimetic symptoms caused by
ketamine. Thus, it may be possible to prevent the unwanted side
effects of NMDA antagonists, thereby enhancing their utility as
Antagonist of the NMDA sub type of glutamate receptor are
potentially useful for preventing neuronal degeneration in
neurological disorders such as stroke (1). However, treatment of
adult rats with noncompetitive (phencycli dine, MK 801, tiletamine,
ketamine) or competitive [D 2 amino 5 phosphonopentanoate (D AP5)]
NMDA antagonists causes neurotoxic side effects consisting of
pathomorphological changes in neurons of the cingulate and
retrosplenial cerebral cortices (2, 3). After low doses these changes
may be reversible, but higher doses can cause irreversible neuronal
necrosis (4). Therefore, it has been questioned whether NMDA
antagonist therapy can be applied without incurring serious side
effects. However, we now report that certain anticholinergic or
GABAergic agents protect cerebrocortical neurons against the adverse
side effects of NMDA antagonists.
The neurotoxic action of MK 801 in the adult rat cingulate cortex
is potentiated by pretreatment with the cholinergic agonist
pilocarpine (5). This potentiating effect was abolished by
coadministration of scopolamine, a cholinergic muscarinic antagonist.
These results suggested that activation of muscarinic receptors might
be involved in the process by which MK 801 causes neurotoxic side
effects. To explore this possibility, we administered scopolamine
intraperitoneally (ip) in various doses (0.01 to 5 mg per kilogram of
body weight) 10 min after a subcutaneous (sc) dose of MK 801 (0.4
mg/kg) that reliably causes neurotoxic side effects in 100% of
treated rats. We examined the brains after 4 hours and found that
scopolamine completely prevented MK 801 neurotoxicity at doses
>0.25 mg/kg. Dose-response studies revealed that the ED50 (dose of
scopolamine that prevented MK-801 neurotoxicity in 50% of treated
animals) was 0.13 mg/kg. Additional anticholinergic compounds were
also effective with an order of potencies correlating with their
binding affinities for M1 muscarinic receptors (6).
To determine whether anticholinergic agents can protect against
the neurotoxic effects of noncompetitive NMDA antagonists other than
MK 801, we treated six rats with a neurotoxic dose (5 mg/kg sc) of
PCP and six rats with this dose of PCP plus scopolamine (0.5 mg/kg
ip) and killed the animals 4 hours later. All of the rats treated
with PCP alone had conspicuous vacuolar changes in cingulate and
retrosplenial cortical neurons, whereas none of the rats treated with
PCP plus scopolamine had such changes.
In order for NMDA antagonists to be optimally useful as
neuroprotective agents in conditions such as stroke, it may be
necessary to use relatively large doses. Therefore, we conducted
experiments to determine whether the dose of anticholinergic agent
required to prevent neurotoxic side effects of a low dose of NMDA
antagonist would also protect against a high dose. It required 0.25
mg/kg ip scopolamine to prevent the neurotoxic side effects in 100%
of treated rats (n = 6) after a relatively low dose of MK 801 (0.4
mg/kg sc); therefore, we treated adult rats with this dose of
scopolamine plus a high dose of MK 801 (5 mg/kg sc) and found that it
prevented the neurotoxic side effect in all animals (n = 6), whereas
all controls (n = 6) that received the high dose of MK 801 by itself
had a severe vacuole reaction in cingulate retrosplenial cortical
Using a chick embryo retina assay, we conducted experiments to
determine whether anticholinergic drugs interfere with the
neuroprotective actions of NMDA antagonists. We have shown that the
neurotoxic action of NMDA (120 mM) in the chick retina is prevented
by adding 200 nM MK 801 to the incubation medium. Therefore, we
incubated the chick retina in medium containing NMDA (120 mM) and MK
801 (200 nM) and added scopolamine in various concentrations from 10
to 50 mM. Scopolamine did not interfere with the ability of MK 801 to
prevent NMDA neurotoxicity. Thus, a tissue concentration of
scopolamine 250 times higher than that of MK 801 does not interfere
with the neuroprotective properties of MK 801, whereas a dose of
scopolamine only 1/20 as high as the MK 801 dose prevented the
neurotoxic side effects of MK 801 in rodent cortex.
The competitive NMDA antagonist D AP5, when injected into the
cingulate cortex, causes a neurotoxic reaction identical to that
caused by systemic MK 801 or PCP (3). In the present study, we
extended these experiments to include systemic administration of 3
[(+) 2 carboxypiperazin 4 yl]-propyl 1 phosphonic acid (CPP), a
competitive NMDA antagonist that is more potent than D AP5.
Intravenous (iv) administration of CPP in a dose of 50 mg/kg caused a
vacuole reaction in six of six rats that was identical to the
reaction in six of six positive controls that received MK 801 (0.4
mg/kg sc) and was not present in six of six controls treated with
normal saline. Administration of scopolamine (0.5 mg/kg ip) 10 min
after CPP (50 mg/kg iv) prevented this reaction in six of six rats.
The psychotomimetic effects of PCP include hallucinogens,
agitation, and disorientation. Ketamine, a PCP receptor ligand, when
used in humans as an anesthetic, causes similar psychotomimetic
effects termed an "emergence" reaction (7). Because diazepam reduces
the severity of the psychotomimetic side effects of ketamine and is
used widely in human anesthesia for this purpose (8), we studied the
effects of diazepam on NMDA antagonist neurotoxicity. Because
barbiturates, such as diazepam, act at GABAA receptors, we also
tested several barbiturates. At a dose of 1 mg/kg ip, diazepam
provided up to 50% protection; this effect could not be exceeded by
increasing the dose sevenfold. However, each of four barbiturates
completely protected against NMDA antagonist neurotoxicity with a
steep dose response curve. The protection conferred by barbiturates
cannot be attributed to general anesthesia properties because the
nonbarbiturate anesthetic halothane did not suppress NMDA antagonist
Although the neurotoxic reaction appears to be confined to
specific neurons within the cingulate and retrosplenial cortices, the
pathological action of NMDA antagonists may not be limited to these
neuronal populations. These agents induce heat shock protein (HSP)
not only in the specific neurons that undergo pathomorphological
changes but also in several other types of forebrain neurons (10,
11). This HSP response is blocked by scopolamine or GABAergic agents.
Thus, the HSP response may be triggered by the same toxic mechanism
that causes vacuolization of cerebrocortical neurons and may serve as
an alternate marker of neuronal susceptibility to the type of injury.
Our evidence that either competitive or noncompetitive NMDA
antagonists cause identical neurotoxic side effects, and either
muscarinic cholinergic antagonists or GABAergic agents block these
side effects, suggests that the effect is triggered by suppression of
NMDA receptor function but also involves muscarinic and GABAergic
The difference in efficacy between diazepam and barbiturates may
relate to their different modes of action at the GABA receptor.
Barbiturates act directly to open the chloride channel, even in the
absence of GABA (12), whereas diazepam acts only to potentiate the
action of GABA (13). Because blockade of the NMDA receptor would
result in cessation of GABA release, there would be very little GABA
in the synaptic cleft for diazepam to potentiate. Therefore,
consistent with our findings, diazepam should have only a partial
effect in contrast to barbiturates which, like anticholinergics,
should provide complete protection against the pathomorphological
effects of the NMDA antagonist.
Typically, diazepam has been found to be partially but not
completely effective in eliminating emergence symptoms associated
with ketamine anesthesia (8). We found no studies pertaining to the
use of anticholinergics for this purpose, and only a single study
(14) pertaining to barbiturates. In this study, a single dose of
thiopental (2 to 3 mg/kg) provided more complete protection against
ketamine emergence reactions than has been reported for diazepam (8,
Because GABAergic agents can prevent both the morphopathological
and psychopathological side effects of NMDA antagonists, a common
mechanism may underlie both effects (15). If so, it is possible that
either GABAergic or anticholinergic drugs may provide a simple and
safe (16) method of preventing both psychotomimetic and neurotoxic
side effects of NMDA antagonists without interfering (17) with the
neuroprotective properties of these compounds.
REFERENCES AND NOTES
1. S. M. Rothman, J. Neurosci. 4,1884 (1984); D. W. Choi, Neuron
1, 623 (1988); J. W. Olney, Biol. Psychiatry 26, 505 (1989).
2. J. W. Olney, J. Labruyere, M. T. Price, Science 24, 1360
3. J. Labruyere, M. T. Price, J. W. Olney, Soc. Neurosci. Abstr.
15, 761 (1989).
4. H. L. Allen and L. L. lversen, Science 247,221 (1990).
5. J. W. Olney and M. T. Price, unpublished data.
6. R. E. Burke, Movement Disorders 1, 135 (1986); S. B. Freedman,
M. S. Beer, E. A. Harley, Eur. J. Pharmacol. 156, 133 (1988).
7. B. E. Marshall and D. E. Longnecker, in Goodman and Gilman's
The Pharmacological Basis of Therapeutics, A. G. Gilman, T. W. Rall,
A. S. Nies, P. Taylor, Eds. (Pergamon, New York, 1990), p. 307.
8. D. L. Rcich and G. Silvay, Can.J. Anaesth. 36,186 (1989), E. N.
Ayim and F. X. Makatia, East Afr. Med J. 53,377 (1976); K. Korttila
and J. Levanen, Acta Anaesthesiol. Scand. 22, 640 (1978); D. L.
Coppel, J. G. Bovill, J. W. Dundee, Anaesthesia 28, 293 (1973).
9. Rats (n = 6) were treated with a standard dose of MK 801 (0.4
mg/kg sc), then anesthetized with halothane, and maintained under
halothane anesthesia for 4 hours. When killed at 4 hours, all rats in
both groups had an abundant display of vacuolated neurons in the
cingulate and retrosplenial cortices.
10. J. W. Sharp, S. M. Sagar, F. R. Sharp, Soc. Neurosci. Abstr.
16, 1122 (1990).
11. M. A. Sesma, M. T. Price, J. W. Olney, ibid., in press. We
localized HSP immunocytochemically using a primary antibody directed
against HSP72 (Amersham RPN 1197) and a modified Vector Elite avidin
biotin peroxidase (ABC) method recommended by F. R. Sharp (9). An
antisera free incubation served as an internal control for each case.
12. R. L. Macdonald and J. L. Barker, Science 200, 775 (1978), E.
S. Levitan, L. A. Blair, V. E. Dionne, E. A Barnard, Neuron 1, 773
(1980); N. Akaike, T. Maruyama, N. Tokutomi, J. Physiol. (London)
394, 85 (1987), C. F. Zorumski and K. E. Isenberg, Am. J. Psychiatry
148, 162 (1991).
13. R. E. Study and J. L. Barker, Proc. Natl. Acad. Sci. U.S.A.
78, 7180 (1981).
14. J. A. O. Magbagbeola and N. A. Thomas, Can. Anaesth. Soc. J.
21, 321 (1974).
15. The proposal that the pathomorphological and psychotomimetic
side effects of NMDA antagonists may be causally linked rests on the
reasonable assumption that reversible injury confined to cingulate
retrosplenial neurons might produce a temporary derangement in
psychological functions mediated by any or all components of an
extensive neural network with which these neurons communicate.
16. Behavioral side effects of competitive and noncompetitive NMDA
antagonists are similar and consist of ataxia and hyperactivity at
low to moderate doses, with a progressive increase in muscle tone at
higher doses that causes the animals to lie on their sides with
partially flexed limbs held in a rigid posture. Anticholinergic drugs
were well tolerated; in fact they tended to relieve these symptoms,
especially the muscular rigidity. Treatment with an NMDA antagonist
plus a barbiturate was also well tolerared. Consistent with the
barbiturate effect alone, the animals appeared heavily sedated, but
there was no apparent potentiation by the barbiturate of the NMDA
antagonisrt's effects or vice versa, and respiratory function was not
17. Certain barbiturates, especially thiamylal, effectively block
both NMDA and non NMDA subtypes of glutamate receptor and can prevent
ischemic neuronal degenerarion [J. Olney et al., Neurosri. Lett.
68,29 (1986); J. Olney, in Excitatory Amino Acids in Health and
Disease, D. Lodge, Ed. (Wiley, London, 1988), pp. 337 352]. Thus,
barbiturates are neuroprotective in a dual sense. They protect
against isehemic neuronal degeneration in many brain regions by
blocking glutamate (induding NMDA) receptors, while preventing NMDA
antagonist neurotoxicity in the cingulate cortex by exerting
GABAmimetic activity that is stronger than their NMDA antagonist
18. G. Paxinos and C. Watson, The Rat Brain in Stereotaxic
Coordinates (Academic Press, New York, 1982).
19. We thank F. R. Sharp for advice on immunohistochemical
methods. Supported in part by a grant from the Huntington's Disease
Foundation, PHS grants DA 53568 and AG 05681, National Institute of
Mental Health Research Scientist Award MH 38894 (J.W.O.), a Weldon
Spring Fund grant, and a Research Leave Award from the University of
Missouri St. Louis (M.A.S.).
Reports of Ketamine Use
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From: email@example.com (William E. White)
Subject: Re: Special K = PCP
Date: Sat, 1 Oct 1994 02:09:09 GMT
In article <firstname.lastname@example.org>, Murple
>Although PCP and Ketamine have virtually identical effects, they
I'd like to point out that most NMDA/sigma agents (of which PCP and
ketamine are two) tend to have fairly individual patterns of affinity and
activity on their targets (which include at least two sigma receptor
types, at least two and probably three NMDA receptor sites, one reuptake
site, and probably a couple of others). Having tried neither PCP nor
ketamine (and not having the desire to try either), I wouldn't know for
sure, but I would bet there would be some difference between the two,
given that they do exhibit subtly different activity and affinity spectra.
Incidentally, MK-801 (dizocilipine? or something like that), which is
another of the same class of NMDA/sigma agents, should have a similar set
of effects. MK-801 is being investigaged for its neuroprotective effects
(against excitotoxicity from endogenous quinolinic acid and other
assaults); PCP and ketamine should have the same abilities, but somehow I
don't see many patients reacting positively to "well, we'd like to
dose you with PCP to cut down on brain damage from that head injury".
>Ketamine is still used in veterinary medicine, but I'm not
>sure if it is used in humans...although it is legal for medical use,
>far as I know.
Several times when this topic has come up, it has been mentioned that
ketamine is used as an anaesthetic in severe burn victims. Why this is, I
From: email@example.com (Yazmar the UnClean)
Subject: Re: Research information
Date: Thu, 9 Jun 1994 06:40:57 GMT
MK-801 is a drug in the PCP/ketamine family. Quite a bit more potent
than both. I've never heard of it being being used as a 'recreational'
psychedelic however. I keep running across references to it while
searching for ketamine articles on medline.
Date: Wed, 17 May 1995 17:32:27 -0700
From: Steven K. Gill
Recently, upon indulging my curiosity on what files hyperreal.com had
under "dissociative anaesthetics", I noticed MK-801 (dizocilpine)
listed along with ketamine, pcp, etc.
The former is not an anaesthetic, and does not induce the entheogenic
states typical of ketamine.
See, for example Physiol. & Behavior, *54*, 547 (1993),
Pharmacology, Biochemistry & Behavior, *48*, 935, (1994), and
Neuropsychopharmacology *11*, 167, (1994). In all three papers, the lack
of pcp-like anaesthesia with MK-801 is mentioned, and it is further
pointed out that blockade of NMDA receptors alone is not the mechanism of
action of dissociative anaesthetics. Of course it is well known that the
latter strongly affect sigma endorphin receptors, and DA receptors as
well. MK-801 is relatively free of these effects, thus listing MK-801 with
ketamine is misleading, to say the least.
If you wish to list other dissociative agents, you should certainly
include tiletamine, the N-ethyl, thienyl analog of ketamine. In admixture
with a benzodiazepine, it is known as Telazol, and is used as an animal
Hopefully this information has been of possible utility...
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