I posted this recently in another forum, but I didn't realize how dead the place was and it didn't get any attention because of it. So, I thought I'd see what you all think.


I feel that many people are enticed by this compound who have not previously been interested in NMDA antagonists. Many of them also have the same question I do: does occasional moderate use threaten significant toxicity? A reasonable dose for someone without a tolerance would seem to be around 10mg, based on reports I've read. We aren't talking about holing, as this substance's effects and duration don't really make that too intriguing in the first place.

Anyway, there's a fair amount of information about ketamine's toxicity out there, but I feel like most of it is conflicting and less-than-comprehensive. It also seems that MXE's duration may further complicate any inferences that are made with shorter-acting compounds like ketamine.

Yet another complicating factor is the study that discussed ketamine's effectiveness as a treatment for depression. Not only did it mention that ketamine effectively improves mood, but it also discussed the fact that it strengthened the neural connections that were weakened by depression. This seems like something that an NMDA agonist would do, not an antagonist. Apparently, it's caused by mTOR activation. I can't tell if this is a downstream effect of NMDA antagonists or something unique to ketamine. People have subjectively reported MXE having similar antidepressant effects, though. I'll post the abstract to this article below.

Anyway, I'll quote some studies that have been done on ketamine to add a little substance to this post and spark the conversation.

http://www.ncbi.nlm.nih.gov/pubmed/22045596
Ketamine induces motor neuron toxicity and alters neurogenic and proneural gene expression in zebrafish.

Ketamine, a noncompetitive antagonist of N-methyl-d-aspartate-type glutamate receptors, is a pediatric anesthetic that has been shown to be neurotoxic in rodents and nonhuman primates when administered during the brain growth spurt. Recently, the zebrafish has become an attractive model for toxicity assays, in part because the predictive capability of the zebrafish model, with respect to chemical effects, compares well with that from mammalian models. In the transgenic (hb9:GFP) embryos used in this study, green fluorescent protein (GFP) is expressed in the motor neurons, facilitating the visualization and analysis of motor neuron development in vivo. In order to determine whether ketamine induces motor neuron toxicity in zebrafish, embryos of these transgenic fish were treated with different concentrations of ketamine (0.5 and 2.0?mm). For ketamine exposures lasting up to 20?h, larvae showed no gross morphological abnormalities. Analysis of GFP-expressing motor neurons in the live embryos, however, revealed that 2.0?mm ketamine adversely affected motor neuron axon length and decreased cranial and motor neuron populations. Quantitative reverse transcriptase-polymerase chain reaction analysis demonstrated that ketamine down-regulated the motor neuron-inducing zinc finger transcription factor Gli2b and the proneural gene NeuroD even at 0.5?mm concentration, while up-regulating the expression of the proneural gene Neurogenin1 (Ngn1). Expression of the neurogenic gene, Notch1a, was suppressed, indicating that neuronal precursor generation from uncommitted cells was favored. These results suggest that ketamine is neurotoxic to motor neurons in zebrafish and possibly affects the differentiating/differentiatedneurons rather than neuronal progenitors.

http://www.ncbi.nlm.nih.gov/pubmed/21886601
Ketamine-induced neurotoxicity and changes in gene expression in the developing rat brain.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used for analgesia and anesthesia in obstetric and pediatric practice. Recent reports indicate that ketamine causes neuronal cell death in developing rodents and nonhuman primates. The present study assessed the potential dose- and time-dependent neurotoxic effects and associated changes in gene expression after ketamine administration to postnatal day 7 (PND-7) rat pups. Pups were exposed to ketamine subcutaneously at doses of 5, 10, or 20 mg/kg, in one, three or six injections respectively. Control animals received the same volume of saline at the same time points. The animals were sacrificed 6 h after the last ketamine or saline administration and brain tissues were collected for RNA isolation and histochemical examination. Six injections of 20 mg/kg ketamine significantly increased neuronal cell death in frontal cortex, while lower doses and fewer injections did not show significant effects. The ketamine induced cell death seemed to be apoptotic in nature. In situ hybridization demonstrated that NMDA receptor NR1 subunit expression was dramatically increased in the frontal cortex of ketamine treated rats. Microarray analysis revealed altered expression of apoptotic relevant genes and increased NMDA receptor gene expression in brains from ketamine treated animals. Quantitative RT-PCR confirmed the microarray results. These data suggest that repeated exposures to high doses of ketamine can cause compensatory up-regulation of NMDA receptors and subsequently trigger apoptosis in developing neurons.

http://www.ncbi.nlm.nih.gov/pubmed/19580862
Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain.

Ketamine, a widely used pediatric anesthetic, has been associated with enhanced neuronal toxicity in the developing brain, but mechanisms and neuronal susceptibility to neurotoxic insult leading to neuronal cell death remain poorly defined. One of the main goals of this study was to determine whether there is a duration of ketamine-induced anesthesia below which no significant ketamine-induced neurodegeneration can be detected. Newborn rhesus monkeys (postnatal day 5 or 6) were administered ketamine intravenously for 3, 9 or 24h to maintain a steady anesthetic plane, followed by a 6-h withdrawal period. The 9- and 24-h durations were selected as relatively long and extremely long exposures, respectively, while the 3-h treatment more closely approximates a typical duration of pediatric general anesthesia. Animals were subsequently perfused under anesthesia and brain tissue was processed for analyses using silver and Fluoro-Jade C stains and caspase-3 immunostain. The results indicated that no significant neurotoxic effects occurred if the anesthesia duration was 3h. However, ketamine infusions for either 9 or 24h significantly increased neuronal cell death in layers II and III of the frontal cortex. Although a few caspase-3- and Fluoro-Jade C-positive neuronal profiles were observed in some additional brain areas including the hippocampus, thalamus, striatum and amygdala, no significant differences were detected between ketamine-treated and control monkeys in these areas after 3, 9 or 24h of exposure. These data show that treatment with ketamine up to 3h is without adverse effects as determined by nerve cell death. However, anesthetic durations of 9h or greater are associated with significant brain cell death in the frontal cortex. Thus, the threshold duration below which no neurotoxicity would be expected is somewhere between 3 and 9h.

http://www.ncbi.nlm.nih.gov/pubmed/19133891
Ketamine use, cognition and psychological wellbeing: a comparison of frequent, infrequent and ex-users with polydrug and non-using controls.

INTRODUCTION:
Preliminary research has indicated that recreational ketamine use may be associated with marked cognitive impairments and elevated psychopathological symptoms, although no study to date has determined how these are affected by differing frequencies of use or whether they are reversible on cessation of use. In this study we aimed to determine how variations in ketamine use and abstention from prior use affect neurocognitive function and psychological wellbeing.
METHOD:
We assessed a total of 150 individuals: 30 frequent ketamine users, 30 infrequent ketamine users, 30 ex-ketamine users, 30 polydrug users and 30 controls who did not use illicit drugs. Cognitive tasks included spatial working memory, pattern recognition memory, the Stockings of Cambridge (a variant of the Tower of London task), simple vigilance and verbal and category fluency. Standardized questionnaires were used to assess psychological wellbeing. Hair analysis was used to verify group membership.
RESULTS:
Frequent ketamine users were impaired on spatial working memory, pattern recognition memory, Stockings of Cambridge and category fluency but exhibited preserved verbal fluency and prose recall. There were no differences in the performance of the infrequent ketamine users or ex-users compared to the other groups. Frequent users showed increased delusional, dissociative and schizotypal symptoms which were also evident to a lesser extent in infrequent and ex-users. Delusional symptoms correlated positively with the amount of ketamine used currently by the frequent users.
CONCLUSIONS:
Frequent ketamine use is associated with impairments in working memory, episodic memory and aspects of executive function as well as reduced psychological wellbeing. 'Recreational' ketamine use does not appear to be associated with distinct cognitive impairments although increased levels of delusional and dissociative symptoms were observed. As no performance decrements were observed in the ex-ketamine users, it is possible that the cognitive impairments observed in the frequent ketamine group are reversible upon cessation of ketamine use, although delusional symptoms persist.

http://www.sciencemag.org/content/329/5994/959.abstract
mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.

Thus, the threshold duration below which no neurotoxicity would be expected is somewhere between 3 and 9h.

interesting...I wonder how many other compounds tested have only shown toxicity after some prolonged exposure like this, as there would have to be repeated/constant dosing to keep someone sedated for 3+hours on ketamine

what does "threshold duration" mean exactly in relation to the drugs effect and metabolism?

Hey Toady how do you feel when you stop the MXE? Does it just help you get past the worst of the WD's or actually stop them?

Quote

Thus, the threshold duration below which no neurotoxicity would be expected is somewhere between 3 and 9h.

interesting...I wonder how many other compounds tested have only shown toxicity after some prolonged exposure like this, as there would have to be repeated/constant dosing to keep someone sedated for 3+hours on ketamine

what does "threshold duration" mean exactly in relation to the drugs effect and metabolism?

This is really the main complicating question, considering that MXE's duration is between three and nine hours. The fact that less MXE is generally used (people don't usually hole with it) may also play a factor, although it would be hard to estimate the level at which it becomes toxic.

*sigh* I really wish there were more thorough and timely studies on the toxicity of psychoactives. The uncertainty is really unsettling and makes it more or less not worth the risk.

Oh...I love holing on MXE. Nothing quite like a nice big shot of IV MXE, with maybe 10-20mg of oxycodone added

lol thats the way toady me mate I'm on your side

One problem with drug studies, when they get known enough to be studied, thats when governments make excuses to ban the drug in question

sigh...yeah and they've banned virtually every substance which can be made that might have recreational potential...so FUCK THEM and hone your art