BilZ0r
Bluelight Crew
- Joined
- Dec 15, 2003
- Messages
- 6,675
I often read that the "direct application of MDMA to the brain is not neurotoxic*" or some such things. Examples can be seen on BlueLight in zorn's MDMA/neurotoxicity misconceptions thread, an in Monks et al., The role of Metabolism in MDA and MDMA toxicity.
Now I wanted to look into this a bit more closely, as in the next couple of months, I'm hopefully going to do some in vitro work using primary cell culture, to see if BZP is neurotoxic (crosses fingers and prays for grant money)... Because if as I've read, MDMA isn't neurotoxic if applied directly to the brain, or into the cerebral ventricles, then it would be hard to believe that MDMA is neurotoxic in cultured neurons.
First I did a pubmed search. The two articles I found straight away were Schmidt and Taylor and Paris and Cunningham. These two papers are odd "proofs" that MDMA isn't neurotoxic when applied directly. Schmidt and Taylor in fact DO show MDMA is neurotoxic when MDMA is applied ICV at a cumulative dose of 2 or 1mg/kg for 1 hour in rats, as defined by TPH activity (but not 5-HT at 1mg/kg). Paris and Cunningham on the other hand injected MDMA into the Raphe, which is hurt when MDMA is systemically applied, so that doesn't matter in my opinion.
So I looked what that Monks et al., paper cited as their evidence. Well they cited one paper by O'Shea which I could see had anything to do with anything. The other paper though, was VERY interesting though. I have it here so everyone who is interested can look at it too.
This extremely well executed paper has one major flaw, at least from my calculations. But lets start at the beginning. Firstly, the measure the brain concentrations of MDMA following peripheral administration of a neurotoxic dose (fig 1). Then they make sure that when they directly apply MDMA, it both produces the necessary concentrations, distances (fig 2) and maintained it (fig 3). They made sure the MDMA released serotonin (fig 4) and dopamine (fig 6) like it should. Then they looked at neurotoxicity.
Table 1 and table 2 basically sum it up. On first look everything looks pretty normal, like they say in the results: No differences. But look at little closer here folks. First thing you notice is that there is a big difference between the right and left. The Right is where they injected the MDMA, and left is the control. Okay, so maybe I can believe that serotonin is naturally that asymmetrical (I'm still checking that one out, but initial papers I've read say no, they are normally symmetrical)... I did my own two way ANOVA on the results, and yes, there is a significant difference between the sides, which they don't report, but no difference caused by the treatment (p=0.877).
But table 2! They so no change. Look at it yourself, there is blatantly a difference between the sides. But according to the two way ANOVA I did, there is JUST a significant difference between the normothermic and blanket group (p=0.0407) (Even a two tailed non-paired t-test of right-normothermic vs right-blanket gives a p=0.0012).
Now I don't know what to make of all of this. But it seems to me this is a paper reporting that direct application of MDMA IS neurotoxic, so long as the animal is made hyperthermic. Either way, I've seen papers reporting neurotoxicity to cultured neurons from MDMA, at similar concentrations too.
Basically what I'm getting as is, does anyone know what's going on with that paper, and does anyone know any better evidence on the "toxic metabolite theory"
* When I say neurotoxic, I'm generally talking about lowered 5-HT, 5-HIAA, and SERT. I apologize if you object to this usage.
Now I wanted to look into this a bit more closely, as in the next couple of months, I'm hopefully going to do some in vitro work using primary cell culture, to see if BZP is neurotoxic (crosses fingers and prays for grant money)... Because if as I've read, MDMA isn't neurotoxic if applied directly to the brain, or into the cerebral ventricles, then it would be hard to believe that MDMA is neurotoxic in cultured neurons.
First I did a pubmed search. The two articles I found straight away were Schmidt and Taylor and Paris and Cunningham. These two papers are odd "proofs" that MDMA isn't neurotoxic when applied directly. Schmidt and Taylor in fact DO show MDMA is neurotoxic when MDMA is applied ICV at a cumulative dose of 2 or 1mg/kg for 1 hour in rats, as defined by TPH activity (but not 5-HT at 1mg/kg). Paris and Cunningham on the other hand injected MDMA into the Raphe, which is hurt when MDMA is systemically applied, so that doesn't matter in my opinion.
So I looked what that Monks et al., paper cited as their evidence. Well they cited one paper by O'Shea which I could see had anything to do with anything. The other paper though, was VERY interesting though. I have it here so everyone who is interested can look at it too.
This extremely well executed paper has one major flaw, at least from my calculations. But lets start at the beginning. Firstly, the measure the brain concentrations of MDMA following peripheral administration of a neurotoxic dose (fig 1). Then they make sure that when they directly apply MDMA, it both produces the necessary concentrations, distances (fig 2) and maintained it (fig 3). They made sure the MDMA released serotonin (fig 4) and dopamine (fig 6) like it should. Then they looked at neurotoxicity.
Table 1 and table 2 basically sum it up. On first look everything looks pretty normal, like they say in the results: No differences. But look at little closer here folks. First thing you notice is that there is a big difference between the right and left. The Right is where they injected the MDMA, and left is the control. Okay, so maybe I can believe that serotonin is naturally that asymmetrical (I'm still checking that one out, but initial papers I've read say no, they are normally symmetrical)... I did my own two way ANOVA on the results, and yes, there is a significant difference between the sides, which they don't report, but no difference caused by the treatment (p=0.877).
But table 2! They so no change. Look at it yourself, there is blatantly a difference between the sides. But according to the two way ANOVA I did, there is JUST a significant difference between the normothermic and blanket group (p=0.0407) (Even a two tailed non-paired t-test of right-normothermic vs right-blanket gives a p=0.0012).
Now I don't know what to make of all of this. But it seems to me this is a paper reporting that direct application of MDMA IS neurotoxic, so long as the animal is made hyperthermic. Either way, I've seen papers reporting neurotoxicity to cultured neurons from MDMA, at similar concentrations too.
Basically what I'm getting as is, does anyone know what's going on with that paper, and does anyone know any better evidence on the "toxic metabolite theory"
* When I say neurotoxic, I'm generally talking about lowered 5-HT, 5-HIAA, and SERT. I apologize if you object to this usage.
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