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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.

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

iii. Why am I Telling You This: My Background

iv. The Dissociative Drugs

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)

I.1. Areas of the Brain Involved

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

Autobiographical memory

Declarative memory (as opposed to remembering skills)

Place-memory (learning and remembering your way around)

Coupling of emotions to experience

Dissociatives activate neurons in the posterior cingulate cortex (PC) and retrosplenial cortex (RC). These overactive neurons pass along their excitation to "downstream" areas such as the hippocampus and olfactory areas.

There are two theories on why the PC and RC neurons get overexcited in the first place; either one, both, or neither could be true. One theory is that NMDA receptors are found on inhibitory GABA interneurons, and that when these receptors are blocked, these interneurons secrete less GABA, and thus excitatory pyramidal neurons that normally receive a lot of GABA inhibition are overexcited.

The other theory is that the PC and RC are less affected by NMDA blockade than the hippocampus (and related areas), and that these formations serve as feedback to the hippocampus and surrounding networks. As these limbic networks are inhibited, the PC and RC increase their output to compensate, resulting in overactivity. The overactive cells begin to heat up, use up their energy supply generate toxic waste products, and/or let in too many calcium ions. Regardless of the mechanism, or whether the mechanism is none of the above, the overactivity seems to cause intracellular organelles (notably mitochondria and endoplasmic reticulum) to malfunction. The mitochondria probably lose their proton gradient and allow their innards to spill into the surrounding cell material, where they cause all sorts of trouble, possibly including forming free radicals which cause further damage to the cell. Another possibility is that the free radicals come first, and they cause damage to the mitochondria and other organelles. Mitochondrial damage can occur within 15 minutes of the drug dose, the endoplasmic reticulum is damaged 30 minutes, and in both cases gets worse as time progresses. The free radicals, basically, destroy everything in the cell like a rampant two-year-old on a spending spree through Toys-R-Us. The cell responds to this damage with a protein called HSP70. This "heat shock" protein is made and activated when something (such as overheating, thus the name "heat shock protein" or HSP) is causing a cell to malfunction so badly as to be in danger of self-destructing, and its job is to turn the cell off until repairs can be made. Hopefully, the cell will get a lot of rest (about 24 hours) until it goes back to normal. At this point the problem is still reversible and the brain cells have not been permanently damaged. If the cell continues to be overexcited, it eventually burns out completely as the increased temperature, disrupted ion gradient, hypoxia, calcium ions, free radicals, and/or buildup of waste products kill it. At this point, surrounding support cells called microglia are activated and come in and eat the cell (probably under the theory that if an infectious organism caused the cell death, it'd better be destroyed before the infection can spread).

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.