Subject: Dissociative (DXM,ketamine) brain damage findingS
Date: Mon, 28 Dec 1998 00:48:22 GMT
From: dxm@frognet.net (Max Tussin)
Organization: ISPNews http://ispnews.com

Newsgroups: rec.drugs.psychedelic,alt.drugs,alt.drugs.psychedelics

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

                                 11/28/1998

              (hint: for the down-and-dirty, see section ii.)
     _________________________________________________________________

  Contents:

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. Abstainance 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

IV.    Conclusions
     _________________________________________________________________

  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 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.
     _________________________________________________________________

  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 Drugs.

   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 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.
     _________________________________________________________________

  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.3. Lab Critters vs Humans (or, Yes, it can happen to you!)

   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 doing fine.
     _________________________________________________________________

  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 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.
     _________________________________________________________________

  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 withdrawal
   symptoms.

   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 from dissociatives.

   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 unpleasant.

   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 idea.

   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 rather large.

     * 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 costs.
          + 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 preparation Coricidin!
     * 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)
          + Anticholinergics
          + Antipsychotics
          + 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 taken:
          + 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 Syrian Rue
     * 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 syndrome.
     * Poor physical condition, which can increase risk of hypertension
       and Olney's Lesions
     * Large doses of sugars (like drinking cough syrup) which may
       increase free radical damage.
     _________________________________________________________________

  IV. Conclusions

   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 minimum.