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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 information.
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, high-dose use.
� 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.

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 there!
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 powder
� Dextromethorphan (DXM), in capsules or as powder
� PCP (Angel Dust, Embalming Fluid, etc.), powder, liquid, or on smoking material
� 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" 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.

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
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 scenario.
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 nitrous oxide.

II.1. Limbic Seizures and "Temporal Lobe Lability"
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 didn't.
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.