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The Bad News Isn't In
A Look at the Evidence for Specific Mechanisms of
Dissociative-Induced Brain Damage and Cognitive Impairment
Version 2.2, June 2003
Edited, HTML, Published by Erowid.org
Citation:   Anderson C. "The Bad News Isn't In: A Look at Evidence for Specific Mechanisms of Dissociative-Induced Brain Damage and Cognitive Impairment". Erowid.org, June 2003: http://www.erowid.org/chemicals/dxm/dxm_health2.shtml.
Table of Contents


Introduction #

In November 1998, William E. White published to Usenet and the Web a rather startling paper with the incendiary title This is Your Brain on Dissociatives: The Bad News is Finally In1 (version 0.1). In this paper, he argued that DXM, ketamine, and other dissociatives cause a specific type of brain damage called NMDA Antagonist Neurotoxicity (NAN). As I hope to demonstrate, the state of the evidence in 1998 did not support the conclusion that White reached, nor does the evidence available now necessitate his conclusion. White's case is built on speculation, extrapolates from anecdotal reports of post-use problems, and makes the cliché logical error of assuming correlation indicates causation. Although his article highlighted the important issue of cognitive impairment resulting from heavy use of dissociatives, his determination of brain damage was not methodologically sound or statistically valid. Because his other writings2 were far more careful not to make these errors, his leaps in logic and generally alarmist tone beg the question of why he chose to publish this inflammatory early draft and then completely quit publishing or participating in the discussion about the topic. White's paper has had a substantial impact on many readers because no other article has solidly critiqued his claims. This paper is an attempt to provide some balance to this issue.

White's Argument #

William White's article begins by stating that it "covers a type of brain damage known as NMDA Antagonist Neurotoxicity or Olney's Lesions (after the researcher who discovered it)." He suggests this type of brain damage can be caused by dissociative anaesthetics including "ketamine, PCP, dextromethorphan, and nitrous oxide" and then lists a set of "Summary Findings":
  • Dissociatives definitely cause brain damage if used heavily. One sub-anesthetic "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" 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
--William E. White, 28 November 19983
NMDA Antagonist Neurotoxicity (NAN, or, colloquially, "Olney's Lesions") is a form of neuronal injury that has been observed in rodents (tested species include rats, mice, and guinea pigs). Reversible toxic changes (vacuoles in the posterior cingulate/retrosplenial cortex) appear in the brains of rodents treated with moderate doses of NMDA antagonists, and as the dose rises, these changes become irreversible. Testing with a variety of NMDA antagonists has shown this to be a general property of these agents in rodents.4

The effects of NMDA antagonists (which include several "dissociatives") in rodents thus appear to be quite frightening. Here we have substances that can put literal "holes in the head" of some animal species - an eerie parallel to many common rhetorical themes of the "Just Say No" camp ("Any questions?"). Indeed, in discussing the mechanism by which NAN occurs, William White stated:
"To put it bluntly, taking excessive doses of dissociatives makes certain parts of your brain fry like the proverbial egg-on-the-frying-pan in the 'This is Your Brain on Drugs' commercial." --William E. White, 28 November 19985
White's statement extrapolates from the animal research and assumes that the same thing would happen to humans. His statement raises the issue in question: how do dissociatives affect human brains? It is quite apparent that the brains of rodents are seriously injured by moderate doses of dissociatives. How do the brains of human users fare? In regard to the question of the relevance of NAN to human users, J.W. Olney and his colleague Nuri B. Farber replied to my request to comment on this issue in private correspondence:
"The evidence is that ketamine and many other NMDA antagonists that have been tested in humans, cause an acute disturbance in neural circuitry that leads to psychotic manifestations. These same drugs cause the same disturbance in neural circuitry in rats and when we look at their brains we see evidence for physical neuronal injury. Since no one has looked at the brains of humans immediately after administering these drugs, we do not know whether the physical neuronal injury occurs." --J.W. Olney, 28 January 20026
"The quick and easy answer is that we do not know. The reason is that one cannot study the brain of a human in an adequate fashion after exposure to a NMDA antagonist. Since there are no data on humans, I do not see how anybody can be "certain" one way or another. Based on the totality of the evidence I have concerns that NAN can occur in the human brain." --Nuri B. Farber, 15 April 20027
"The bad news" is not in yet; nor is "the good news". The known facts, as of this writing, are as follows:
  1. NMDA-antagonists can cause severe brain damage in rodents.
  2. This brain damage manifests itself in permanent learning deficits in the treated animals.
  3. Many heavy users of PCP, ketamine, and/or DXM report substantial cognitive difficulties following the cessation of use.
From this evidence, it is possible to develop an indirect case that the cognitive difficulties in question are due to NAN. However, it is important to remember that this case is, at this date, circumstantial. It is difficult to make valid conclusions from these three points, unfortunately, both because different species of animals can react differently to the same chemical and because the reported cognitive problems in heavy users has not been well documented or characterized.

For example, despite the fact that problems related to PCP use are the best documented of this NMDA dissociative class, there are still many open questions about the extent of problems and mechanism(s) which might cause them. PCP8 has a number of complex interactions with brain chemistry beyond NMDA antagonism (including anticholinergic and cholinergic actions)9 and it is not clear that PCP use is responsible for (as opposed to being a symptom of) various emotional and cognitive disorders.

The literature on PCP abuse notes that problems of cognitive organization may persist for up to 12 months following the cessation of use.10 If these cognitive problems were a result of NAN damage, we would expect permanent problems with learning: memory and attention span should show irreversible deficits. The fact that a significant number (if not the vast majority) of users display no consequential functional change in behavior should, at the very least, leave us wary about jumping to conclusions. It should be noted that such a length of time for recovery may reflect the fact that real brain damage has occurred, and that the human brain is able to eventually at least somewhat adjust to such damage. The important point to keep in mind is that while heavy use may be associated with cognitive problems, we have no direct evidence that these cognitive problems are a result of NAN.

A further problem with such an indirect case is that it relies on an elementary logic error, often lamented by the professors of inattentive philosophy classes: the assumption that correlation necessarily demonstrates causation.11 In this case White ups the ante, so to speak, when he argues that such correlation indicates a causation of a specific kind.

A parallel situation is the issue of reports of lasting negative effects from taking LSD. Some heavy LSD users demonstrate a stereotypical "burn out" syndrome12 and some complain of being "perma-fried"13, but there is little evidence that LSD causes permanent alterations in the physical structure of the brain. Even further, if we accepted for the sake of argument that these self-reports indicated organic brain damage, it would still be an even larger leap to believe we could guess the specific mechanism for this damage.

White also fleshed out his case by discussing the manner in which reported impairments corresponded to areas of the brain that we might expect to be affected by NAN. Modern science has little understanding of the manner in which the human brain works, and no understanding of the manner in which the human brain works if affected by NAN. Although White makes it clear that he is largely guessing in this section of his paper, the lack of other commentary on this topic has lead many to take his theories too seriously. Wild (if informed) speculation coupled with circumstantial "evidence" is, perhaps, interesting to think about, but it is certainly not the final word on a subject.

Mr. White himself took a far more balanced tack in the DXM FAQ version 4.02 (an exhaustively referenced work on most relevant issues surrounding DXM use):
On the other hand, Olney's lesions have never been found at human recreational levels, and DXM has received little attention. Ketamine users, some of whom have used ketamine for many years, don't typically show mental impairment. Even the few DXM users who do show impairment typically return to normal after staying off DXM for several months, and at least one paper suggests the mental impairment from dissociatives may be caused by depression, not brain damage…Weighing the two sides I personally believe that moderate use of dissociatives is probably no harder on your brain cells than moderate use of alcohol or amphetamines (I said moderate use, not some five day fry-yer-brain speed freak binge), and that if you use DXM sparingly (e.g., once or twice a month at lower plateaus, maybe once or twice a year at upper plateaus), you'll be just fine. In fact, I've never known anyone to suffer lasting impairment even after going through a few months of weekly DXM use at upper plateaus. But I could be wrong! Mild brain damage has a nasty way of showing up years later when you've forgotten about the stupid things you did when you were young. --William E. White, 199814

The Evidence #

In examining the evidence, one is surprised to find such a dearth of it. Dismissing the remote possibility of deliberate fraud by William White or those who reported symptoms of brain damage to him, there are still reasons to question the reliability of the data he presents. William White was not a doctor nor did he have formal training as a researcher and the majority of the data he presents are highly interpreted and filtered self reports from an undocumented set of users. Is this the extent of the evidence? Unfortunately, we have no information about whether the afflicted people had any symptoms or psychopathology before they tried dissociatives, what their specific histories with dissociatives are, or what their other drug histories are. It is difficult, given the theoretical nature of White's argument, to accept his conclusions without even being presented with the data upon which he has based his findings.

Also, it is notoriously difficult to verify the causal relationship between a set of anecdotal reports of poorly defined problems and their specific, sole cause. As Mr. White noted, at least one study has found that some cognitive difficulties may be related to depression itself. The issue of identifying causation for most psychological problems is extremely complex and it is rare to be able to isolate a single cause with any certainty. Finally, we have no indication of the length of time that these individuals had abstained from their reported use of dissociatives (or, for that matter, other recreational drugs).

One must also note the severely limited nature of the user samples. In the DXM FAQ, Mr. White stated that, "Out of approximately five hundred current and former DXM users I have heard from, three have suffered lasting cognitive impairment." In the NAN document, Mr. White wrote: "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." Extrapolating from that data is difficult since he fails to specify the number beyond "dozens", because he does not specify whether he had a correspondingly large increase in the total number of people he had heard from, and because the statement in the DXM FAQ probably acted as a call for those with problems to write in to him, thus skewing responses in favor of reporting problems.

Although it is important to watch for potential health risks of recreational dissociative use, it is equally important that harm reduction does not become an excuse for exaggerated, unscientific claims of brain damage. As an example of White's sacrificing accuracy for apparent risk-aversion, he lists a set of drugs he says will "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!15
Unfortunately, the third of these, the anticholinergics, are not likely to increase NAN damage. Olney wrote:
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. 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 neurons. 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…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. --J. W. Olney et al. 6 December 199116
This research could lead a reader to conclude, assuming NAN occurs in humans, that Coricidin (DXM + CPM) users would be at less risk of it, rather than more. But, the theory that combining CPM with DXM might reduce the risk of NAN damage says nothing about other much more serious pharmacological interactions that might occur. The available evidence (which is sparse) indicates that Coricidin is more likely to provoke allergic reactions, memory impairment, and delusional behavior than other DXM preparations. There have been several reports of deaths involving the use of this substance, and while many of them involved multiple substance combinations (i.e., alcohol, heroin, and/or any number of other drugs in addition to Coricidin), it is clear that this preparation poses a greater health risk than DXM itself (which by itself has been known to cause death in high doses)17. But these interaction problems very likely have nothing to do with NAN damage and although it is important to warn potential users away from using this combination, it should not be because of incorrect theoretical fears of increasing Olney's Lesions.

White also includes ketamine with DXM in his list of NAN-causing drugs, as it shares some mechanisms and there is research with rats which shows that ketamine can cause lesioning. However, in his book Ketamine: Dreams and Realities, Dr. Karl L.R. Jansen comprehensively documents the beneficial and detrimental effects of ketamine and argues convincingly that NAN's relevance to human use of ketamine has been exaggerated. He wrote:
In 1989, psychiatry professor John Olney reported that ketamine caused reversible changes in two small areas of the rat brain. 40 mg/kg resulted in fluid-filled bags ("vacuoles") appearing inside cells. The bags disappeared after several days, unless high doses of the far more toxic PCP or close relative MK801 were repeatedly given, in which case some cell death was seen. Roland Auer injected monkeys with MK801 and was unable to produce any vacuoles. I asked Auer in 1998 whether persons undergoing anesthesia with Ketalar were at risk of these changes. His reply was that he doubted that it was even a remote possibility because of fundamental differences in metabolism between the rat and human brain. As discussed in chapter 4, ketamine can block excito-toxicity (brain damage due to low oxygen, low sugar, epilepsy, trauma etc.) but it can also excite the brain at low doses by switching off the inhibitory system. Why isn't this damaging in monkeys and humans? The answer probably lies in the fact that ketamine binds to an increasingly wide range of different receptors as the dose level rises, and some of these receptors act to shut down the excitement. In humans, by the time a potentially toxic dose is reached, the "excitement window" has been passed and the drug is starting to activate other systems that switch cells off again, a result of ketamine's promiscuity that improves its safety relative to MK801. MK801 binds very specifically to N-P receptors. The other part of the explanation is that rats have rates of brain metabolism that are almost twice as high as those in humans to start with. It is because of this higher base rate of metabolism that ketamine causes over-excitement in rats at doses below those at which it activates shutdown systems.

Frank Sharp also works in this area. I discussed with Sharp how this issue stood in 1998. His view was that reversible toxic changes in the rat started to appear at 40 mg/kg and reached a level at which no further changes occurred (a plateau) at 100 mg/kg, when a little cell death could be seen - but matters would not progress beyond this point. Extensive attempts to produce toxic changes in monkeys had been a total failure at doses up to 10 mg/kg i.m. These monkey studies are unpublished.

I sought the view of Olney's colleague, Nuri Farber. The work of his team indicated that N-P receptors must be blocked for at least 2 hours to cause reversible changes, and at least 24 hours to produce some cell death, in rats. Ketamine has a short half- life (the time required for the blood level to fall to half its original level): only 20 minutes in the rat. His team thus had no ethical qualms about using Ketalar in humans. However, he thought that the methods used in monkey studies so far were unsatisfactory, because the animals were probably too young. Only adult rats show the toxic changes. He was not prepared to accept a clean bill of health for the drug in primates until this work with older monkeys had been done, and until the drug companies published their monkey studies to support their claims of harmlessness.

There is thus no published evidence at this time (January 2000) that ketamine can produce toxic cell changes in monkeys. The unpublished monkey data that we know about, that of Frank Sharp, actually shows that there is no damage at doses up to 10 mg/kg. The failure to produce toxic changes in monkeys is probably one reason why the FDA did not remove Ketalar from the market. Some people see 40 mg/kg as so far above the human dose level as to be irrelevant in any case. This is not the most useful way to look at this issue. When given by intramuscular injection, humans are at least 10 times more sensitive to the anesthetic effects than rats. When rats are given 30 mg/kg, the experimenters describe this as a 'subanesthetic dose,' versus a 'high anesthetic dose' of about 150 mg/kg. In humans, an equivalent subanesthetic dose is about 1 mg/kg and the topc anesthetic dose would be about 13 mg/kg. However, humans are much less sensitive to the neurotoxic effects.

These two matters are directly related: humans are protected from the toxic changes by the rising anesthesia, which cuts in above a certain dose and calms cells down. This also happens in rats, hence the 100 mg/kg plateau, but it happens too late to completely avoid some toxic changes as rats are already running hot because of their twice-as-fast metabolic rate."

These brain cell changes do not appear if rats are pretreated with certain drugs. The list of drugs which can block the toxic changes is long and diverse. Most of these drugs block toxic changes in rats by switching on a range of different "calming" systems, depending on the drug used. Ketamine is highly promiscuous and eventually binds to the same receptors as some of the protective agents listed above, which shutdown the over-excitement. So the toxic effects happen via one neurochemical system (glutamate) and this is switched off by other systems activated at higher ketamine levels (e.g. the opioid system). In humans, the opioid system (amongst others) cuts in before activation of the glutamate systems reaches the point where cell damage occurs, but in rats this is not the case.18
To those who wonder if this model applies to DXM, Doctor Jansen has stated:
I am certain that DXM does not cause Olney's lesions in humans or monkeys. The reasoning is the same as that set out for ketamine in my book Ketamine: Dreams and Realities, and I would refer persons who are interested in the exact details of the argument, and a substantial number of references, to this book. --Karl L.R. Jansen, 20 January 200219
However, both Olney and Farber have criticized Dr. Jansen's position on this matter. In Dr. Olney's words:
On the basis of no relevant evidence Jansen is willing to speculate regarding whether humans are susceptible to this kind of injury. I am not interested in speculation, nor am I inclined to allow my brain to be exposed to NMDA antagonist drugs. --J.W. Olney, 28 January 200220
Farber voiced concerns that repeated use of dissociatives might pose significant risks to human users, and reiterated Olney's sentiments that this issue has not been studied adequately to form any firm conclusions. He also repeated the point he made to Doctor Jansen (which is contained in the above extract from Doctor Jansen's book) that he does not consider the primate studies to be methodologically sound21. Both Farber and Olney appear to feel that it is preferable to err on the side of caution, and to avoid risks to the normal functioning of one's perceptual/cognitive structure. Neither made an extensive critique of Jansen's model, which has a number of strengths. I do feel that Dr. Jansen's model makes a good deal of sense, and that some of the data he offers is at least as relevant for consideration as the original rodent data, but that, pending further investigation, these drugs must still be presumed to be somewhat high risk, and their indiscriminate use is discouraged. Dr. Jansen has added that he doesn't want to be read as saying that ketamine is non-toxic; he simply does not believe that ketamine produces "these particular kind of lesions"22.


"I Broke My Brain!": Other Possible Mechanisms for Lasting Cognitive Problems #

So, if NAN is not occurring, or is probably only occurring in a very small number of users, why do a substantial number (but unknown percentage) of regular dissociative users report cognitive changes? There are a number of possibilities, all of which are real concerns and none of which should be treated lightly simply because they don't cause NAN-related "holes in the brain". Some of the other proposed mechanisms for medium to long term cognitive impairments include: neurotransmitter depletion, receptor re-regulation, interference with long-term potentiation, hypoxic brain damage, or possibly general psychological changes.

Neurotransmitter depletion is a self-explanatory term -- important neurotransmitters, such as glutamate and dopamine, may become depleted with repeated use of dissociatives. Neurotransmitter depletion can lead to difficulties in concentration, inability to feel pleasure ("anhedonia"), memory difficulties, and an array of other problems. This is a rather serious matter, and is indicative that one has been using far too much of one's substance(s) of choice within too short a period of time. Generally, when use of the substance is discontinued, neurotransmitter levels slowly return to normal. Receptor reregulation refers to temporary alterations in the chemical functioning of receptor sites. Psychoactive drugs cause changes in the amounts of neurotransmitters that neurons (brain cells) interact with. Over time or sometimes with a single large dose, the neurons will alter their sensitivity in response to the change in available neurotransmitters. In some instances, this change in regulation can last days, weeks, or possibly months. This shift in receptor regulation can also be a rather serious matter and can cause a wide range of experiential and behavior changes, including symptoms of schizophrenia, depression, and other serious mental disorders. Receptor regulation changes are often treatable with psychoactive pharmaceuticals and often return to normal over time.

Another possible mechanism is called "Long Term Potentiation" or LTP. Dr. Farber writes:
First you might want to consider the possibility that NMDA antagonists produce two broad types of cognitive changes. One is temporary and resolves once the NMDA antagonist leaves the system. The second is a long term change that persists and is a consequence of permanent changes in the brain (be it secondary to neurotoxicity or something else). With respects to the non-permanent changes I have two additional suggestions for potential mechanisms. The first is that activation of NMDA receptors is integral to the induction of Long Term Potentiation (LTP). LTP is currently the best candidate we have for on-line short term memory. Disruption of LTP might underlie the inability of people to store information while on ketamine. A second possibility is that there are data that suggest that doses of NMDA antagonists that are sub-toxic still activate the same systems that toxic doses activate. Since we are at sub-toxic doses the cognitive effects would resolve once the NMDA antagonist left the body. In this scenario since the mechanism is the same, agents found to reverse the neurotoxicity would also reverse the cognitive effects. -Nuri B. Farber, 13 August, 200224
Long Term Potentiation "is a long-lasting increase in synaptic strength (i.e., posynaptic response relative to presynaptic stimulus) which may be induced in vitro in a number of hippocampal regions by a brief high-frequency…stimulation of afferent fibres."25 This means that certain brain cells increase how strongly they react to stimuli after a given 'primer' stimulus. This "potentiation" effect lasts hours or days and has been implicated in short term memory and other learning, although the issues are too complex to cover here. NMDA blockade has been shown to disrupt LTP, though it has also been shown that rats can eventually learn even in the presence of NMDA blockade. Additionally, LTP has also been shown to occur in the CA3 region of the hippocampus in spite of prior NMDA blockade26. Thus, while "[d]isruption of LTP may underlie the inability of people to store information while on ketamine…" further research is needed before we understand the precise underlying mechanisms.

The hypoxic brain damage model, originally developed by the Internet personality "Kid," is best explained by him:
Dextromethorphan Induced Hypoxia of the Brain: A Hypothesis
By: "Kid" (a frequent poster on The Third Plateau and The Dextroverse)
E-mail: Kiddex@hotmail.com
June 25, 2002

Introduction: There has been a lot of speculation about the meaning of self-reported cases of cognitive impairment by hypermedical users of Dextromethorphan (hydrobromide). One well theoretical mechanism of brain damage is NAN; NMDA-Antagonist-Neurotoxicity (often referred to as "Olney's Lesions"). I propose an alternative hypothesis involving hypoxia (dangerous lack of oxygen). Data: In a discussion with Robert F. Golaszewski (RFG) about self-reported cases of cognitive impairment in hypermedical DXM users, he reported (if I recall correctly) that he had received a total of 14 such self-reported cases. (Again, if I recall correctly) the average dosage of the users was 13.5 mg/kg.

Problematics: I am working with very restricted data. The most important unknowns here in these self-reported cases are drug use history (especially duration of DXM use), dosing patterns (how often, standard deviation and distribution), and history of mental and physical health. Also, working with data that is self-reported tends to be a problem in itself, because only those who are motivated to report their cases (for whatever reason) will be likely to do so.

Assumptions: Since none of the data indicates otherwise (except for the fact these people take an OTC cough suppressant hypermedically ;-) I will assume that all of these people are average people, meaning that as a group (or "on average") they have no mental or physical anomalies to distinguish them from the rest of the population. I will also assume, based on my extensive contact with numerous users of DXM over the years, that to build up to such a high average dose, they have each used DXM at least 50 times, and their dosage pattern takes the normal distribution curve. Standard deviation will be assumed to be 1/3 of the average dose (4.5 mg/kg).

Possible cause of cognitive impairment: Doses of DXM at or above 20 mg/kg are cited as being dangerous doses. Deaths from DXM HBr only have occurred. The expected cause of death due to DXM HBr overdose would be respiratory depression.

If the assumptions above are correct, that each user has taken DXM HBr at least 50 times, with a standard deviation of 4.5 mg/kg on a normal distribution curve, then 7.49% of total doses are taken above the 20 mg/kg. Thus, if each user has taken 50 trips, they have taken about 4 trips above 20 mg/kg. The statistically highest dose the user has taken (98th percentile) would be 22.7 mg/kg.

Conclusion: It is reasonable to believe that hypermedical Dextromethorphan users may be causing themselves brain damage due to hypoxia of the brain. More data is required to assess the validity of the conclusion.27
This hypoxia model has been critiqued on the grounds that opiates can also cause respiratory depression, but have not been observed to lead to problems with cognitive functionality.

Finally, it is also possible that some of the symptoms may be explainable by more psychological or systemic effects of the experiences themselves. This might be possible in the same way traumatic experiences can lead to post-traumatic stress disorder (PTSD) or other strong experiences can lead to cognitive, perceptual, and behavioral shifts. In this model, the resulting problems cannot be easily reduced to chemical or structural 'damage' and solutions are obviously far murkier.

Its important to note that including alternative mechanisms for possible functional problems resulting from heavy dissociative use is not intended to suggest that NMDA Antagonist Neurotoxicity is not a possible risk. The point of this article is to illustrate the fact that White simply overstated the certainty of evidence in favor of NAN as a risk for dissociative users. He could have interpreted "the evidence" in a considerably broader manner than he did. Frequent use of dissociatives can, based on self reports from users, cause problematic cognitive impairment, and the fact that this impairment may be largely reversible in the majority of cases does not mean that it is negligible, nor dismissable.


In Closing #

Perhaps the most important point of William White's "Bad News" article is that a concerning number of heavy users of DXM report worrisome problems even months after they stop taking the drug. Lasting problems have also been reported by doctors treating very heavy users of PCP and ketamine. Unfortunately, the article's flaws have often drowned this important message in the controversy around whether NAN is the mechanism for these lasting problems. Frequent "recreational" use of these dissociatives can lead to a number of psychological difficulties; in addition to cognitive disruption and annoyances, frequent users may experience delusions of grandeur (i.e., "I'm some sort of messiah"), 'synchronicity' and delusions of reference (i.e., "I was just thinking about my ex-girlfriend, and the sign I just looked at has her name on it, hence the universe must be trying to tell me to go to her house right now"), symptoms similar to manic depression, and a host of other problems.

(Whether one interprets synchronicities and deep insights as "delusions" or "Truth" is, ultimately, a matter of faith not one of logic or evidence, and I'm certainly not going to take a final position on epistemological imponderables. The yardstick for sanity is simply functionality: if you find yourself standing in the middle of the street naked, yelling about the coming apocalypse, the police are not likely to look upon the matter kindly, even [or especially] if you really are a "prophet" of God.)

In addition, regular use of NMDA-dissociatives can complicate academic and professional work and pose serious difficulties for relationships with family, significant others, and friends. Suffice it to say that regular use of these drugs puts a severe strain on one's social interactions. It is hard to be friends with an alien anthropologist, let alone wake up next to one every morning.

NAN is one of several possible explanations for the medium and long term negative consequences of heavy dissociative use. It may be that none of the proposed mechanisms are the cause of the problems reported. The evidence in favor of NAN as the mechanism is equivocal and it is important not to jump to conclusions and foreclose a complete inquiry into the issue.

All of this has been a very long way of saying: the bad news isn't in, we still don't know, and users need to be careful whether or not these chemicals cause Olney's Lesions.

If you are using or considering using DXM or other dissociatives, it's your nervous system that you may or may not be "frying". Evaluate your use carefully, and try to be honest. Frivolous use of these drugs seems far from wise; that their use is wise at all is open to considerable question. Many people report life-changing reorientations in philosophical perspective (myself among them); many others report becoming unexpectedly "whacked out", left wondering how they got that way. Try to take care of yourselves, whether on the path of knowledge or in the pursuit of pleasure.

NOTE: Prior to publication, this paper was submitted to J.W. Olney, Nuri B. Farber, and Karl L.R. Jansen for review. All found it satisfactory.



References #
  1. White WE. "This is Your Brain on Dissociatives: The Bad News is Finally In". Originally published on Frognet, now hosted on Erowid.org. Version 0.1 - 11/28/1998. http://www.erowid.org/chemicals/dxm/dxm_health1.shtml
  2. White WE. "The Dextromethorphan FAQ: Answers to Frequently Asked Questions about Dextromethorphan (DXM)". Originally published on Frognet, now hosted on Erowid.org. Version 4.02 - 1997-2001. http://www.erowid.org/chemicals/dxm/faq/dxm_faq_white_1998.shtml
  3. http://www.erowid.org/chemicals/dxm/dxm_health1.shtml
  4. Olney JW et al. "Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs." Science 244(4910):1360-2, 1989 Jun 16.
  5. http://www.erowid.org/chemicals/dxm/dxm_health1.shtml
  6. Olney JW. Personal Communication. 28 January 2002.
  7. Farber NB. Personal Communication. 15 April 2002.
  8. http://www.nida.nih.gov/Infofax/pcp.html
  9. http://www.emedicine.com/med/byname/toxicity-phencyclidine.htm
  10. http://www.nida.nih.gov/Infofax/pcp.html
  11. http://stat.tamu.edu/stat30x/notes/node42.html
  12. See http://iscr.webspace.fish.co.uk/eskimo/archives/burnout.htm for an amusing discussion of this stereotype in relation to the case of Syd Barrett.
  13. http://www.erowid.org/experiences/exp.php?ID=10101
  14. http://www.erowid.org/chemicals/dxm/faq/dxm_faq.shtml
  15. http://www.erowid.org/chemicals/dxm/dxm_health1.shtml
  16. Olney JW et al. "NMDA antagonist neurotoxicity: mechanism and prevention." Science 254(5037):1515-8, 1991 Dec 6.
  17. http://www.dextromethorphan.ws/dxmdeaths.htm
  18. Text extracted by author from Ketamine: Dreams and Realities; this book can be ordered from www.maps.org
  19. Jansen KLR. Personal Communication. 20 January 2002.
  20. Olney JW. Personal Communication. 28 January 2002.
  21. Farber NB. Personal Communication. 15 April, 2002.
  22. Jansen KLR. Personal Communication. 13 April, 2002.
  23. Neisewander JL, Baker DA, Fuchs RA, Tran-Nguyen LTL, Palmer A, Marshall JF. "Fos Protein Expression and Cocaine-Seeking Behavior in Rats after Exposure to a Cocaine Self-Administration Environment." J Neuroscience 20(2):798-805, 2000. http://www.ucsf.edu/cnba/courses/Neisewander.pdf
  24. Farber NB. Personal Communication. 13 August, 2002.
  25. Nicholls DG. Proteins, Transmitters, and Synapses p. 239 .1995, Blackwell Science. There are a number of interesting articles online about LTP as well as some good definitions to help give a better sense of what this system involves and why NMDA antagonists may disrupt this system. http://instruct.uwo.ca/physiology/468b-001/Cohen.html
  26. Nicholls DG. ibid.
  27. "Kid". Personal communication; also published in DXM Zine and several discussion groups.



Appendix A: So Why'd He Say That? #

There has been widespread speculation about why William White chose to drop this bomb on the community he used to frequent and then become incommunicado for years. One can only speculate as to why White's position on NAN shifted from the rather conservative (and quite defensible) position advocated in the final version of the "DXM FAQ" to the frankly alarmist tone of his NAN article. On Usenet and web boards, it has been suggested that White wished to distance himself from the image of "that DXM guy". I do not think this position is consistent with the pride and care with which he wrote the DXM FAQ. If he had wanted to be forgotten, he could have simply stopped posting on the topic. Instead, the "Bad News" article further put his name into the online discussions and libraries as "that DXM guy".

Others have suggested that White wished to fend off charges that he 'promoted drug use' (a common enough charge for anyone willing to publicly discuss factual information about recreational drug use). This possibility seems to hold more promise, but doesn't adequately explain why he would publish a very early draft of a technical paper and then stop responding to discussions and not update the paper in five years. He could have issued a revision of the DXM FAQ with substantially increased warnings and been more likely to have that message get across. Viewed in light of this model, the NAN document is quite a bit of "overkill" if he was simply trying to make it clear he felt that DXM use was dangerous.

Another option that has been proposed is that Mr. White believed that he had suffered NAN himself and he ignored some of the obvious problems with his paper because he was trying to find a 'scientific' explanation for his own perceived lasting problems. This explanation could offer insight into why he was willing to go so far out on a limb and break his tradition of careful thinking. White confessed in Usenet posts to extensive use of DXM, including "Plateau Sigma" usage. In White's classification scheme for DXM dosing, "Plateau Sigma" is a high dose regimen, referring to taking two low second plateau and one high second/low third plateau dose of DXM within six hours of each other, resulting in a "psychotic" experience. If this is correct, I can sympathize with Mr. White's position, but must maintain that self-diagnosis of tiny holes in the head is impossible, and that the tone of his document is, in general, overly alarmist.

The possibility that White, himself quite familiar with the pharmacology of this substance and a firm advocate of its responsible use, could develop serious cognitive disorders in relationship to his DXM use is quite sobering, even if only a guessed possibility. If he wrote this in response to his own perceived mental decline, it would suggest that Mr. White was perhaps suffering from a touch of "intern's syndrome", and was perhaps motivated by the desire to prevent others from developing his condition.




Appendix B: What to do if you think you may suffer from cognitive impairments resulting from dissociative use #

For those who fear that they have suffered cognitive impairment due to the use of DXM and/or other dissociatives, the first and most obvious step is to stop using. Many users seem to use these substances compulsively, in efforts to self-medicate and/or satisfy recreational or "spiritual" curiosities. I cannot presume to judge the validity of "spiritual" experiences, but I will note that one is taking considerable risks in using them as medication for depression. If you feel that you suffer from depression, consulting a psychotherapist, taking up the practices of meditation and/or hatha yoga, and any number of other disciplines would probably be a wiser and more effective form of self-medication (I will note that I also consider these options to be preferable, in many cases, to the use of prescription antidepressants).

In my opinion, the most promising treatment of dissociative related cognitive dysfunction may be piracetam (Nootropil). This substance has been used by millions of people worldwide, has demonstrated extremely low toxicity, and appears to positively affect both acetylcholine and NMDA receptors, both of which may be adversely affected by (over)use of dissociatives. Both ketamine and DXM users have reported that piracetam alleviates cognitive dysfunction associated with overuse of dissociatives. Interestingly, there are also anecdotal reports that regular use of piracetam greatly attenuates or even abolishes the psychoactive effects of dissociatives. This could be of aid in treatment programs dedicated to dissociative abusers, and I consider it a promising avenue of further research. Piracetam is widely available by mail order and currently not controlled in the United States.

Both DMAE (dimethylaminoethanol) and centrophenoxine (Lucidril) have been anecdotally reported to alleviate problems with concentration and memory associated with abuse of dissociatives. Interestingly enough, both have also been reported to synergize quite well with piracetam. Among other of their beneficial effects upon the body/brain, both DMAE and centrophenoxine (which metabolizes, in part, into DMAE) function as precursors for the neurotransmitter acetylcholine. They appear to function as mild stimulants/"cognitive enhancers".

Some individuals may find that DMAE or centrophenoxine make them overly "jittery" and persons with high blood pressure are advised to consult a doctor before using any of these substances. There have been conflicting results with different animal species as to whether DMAE extends lifespan or shortens it, but this is probably not of concern if it used on a limited basis for a few months.

Some heavy users of dissociatives have reported experiencing anhedonia similar to that experienced by cocaine or methamphetamine users upon the cessation of use. This may indicate a severely taxed dopamine system, and deprenyl supplementation may prove useful in enhancing dopamine production. Deprenyl has also been anecdotally reported to be useful in treating persistent visual abnormalities that sometimes arise as a result of abuse of dissociatives. Deprenyl has been extensively researched since the 1960s, is of relatively low toxicity unless absurd overdoses are taken, and is approved in the treatment of Parkinsonism.

A considerable amount of information on these substances can be obtained by visiting www.ceri.com and www.piracetam.com (a vendor). As I have stated above, these substances are of relatively low toxicity (particularly piracetam), but anyone suffering serious cognitive difficulties should be under a doctor's supervision, and these suggestions should be taken precisely as what they are: suggestions. Read this again: any individual intending to use any of these substances should seek a doctor's advice.

A few more suggestions for those fearing that they may suffer cognitive impairment: begin exercising intellect and memory again. Rather than compulsively ingesting drugs and expecting tremendous personal insights and the ability to function as you would when not on drugs, make a conscious effort to learn. Play logic/memory games, learn new skills, hobbies, etc. There is far more to the world than simply spending all of one's time "out of body" in "the Void" (which is not to imply that such experiences may not prove valuable, or at least entertaining, for some). Take care of yourself -- eat regularly, and take a good multivitamin/multimineral. I cannot emphasize strongly enough that those suffering from cognitive impairments should avoid the use of any "recreational" drugs, including alcohol and marijuana.