Plants - Drugs Mind - Spirit Freedom - Law Arts - Culture Library  
Erowid References Database
Carvalho M, Hawksworth G, Milhazes N, Borges F, Monks TJ, Fernandes E, Carvalho F, Bastos ML. 
“Role of metabolites in MDMA (ecstasy)-induced nephrotoxicity: an in vitro study using rat and human renal proximal tubular cells”. 
Arch Toxicol. 2002 Oct 09;76(10):581-8.
The metabolism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has recently been implicated in the mechanisms underlying ecstasy-induced neurotoxicity and hepatotoxicity. However, its potential role in ecstasy-induced kidney toxicity has yet to be investigated. Thus, primary cultures of rat and human renal proximal tubular cells (PTCs) were used to investigate the cytotoxicity induced by MDMA and its metabolites methylenedioxyamphetamine (MDA), alpha-methyldopamine (alpha-MeDA), and the glutathione (GSH) conjugates 5-(glutathion- S-yl)-alpha-MeDA and 2,5- bis(glutathion- S-yl)-alpha-MeDA. Cell viability was evaluated using the mitochondrial MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. MDMA and MDA were not found to be toxic to either rat or human PTCs at any concentration tested (100-800 micro M). In contrast, 800 micro M alpha-MeDA caused 60% and 40% cell death in rat and human PTCs, respectively. Conjugation of alpha-MeDA with GSH resulted in the formation of even more potent nephrotoxicants. Thus, exposure of rat and human PTC monolayers to 400 micro M 5-(glutathion- S-yl)-alpha-MeDA caused approximately 80% and 70% cell death, respectively. 5-(Glutathion- S-yl)-alpha-MeDA (400 micro M) was more toxic than 2,5- bis(glutathion- S-yl)-alpha-MeDA to rat renal PTCs but equally potent in human renal PTCs. Pre-incubation of rat PTCs with either acivicin, an inhibitor of gamma-glutamyl transpeptidase (gamma-GT), or bestatin, an inhibitor of aminopeptidase M, resulted in increased toxicity of 5-(glutathion- S-yl)-alpha-MeDA but had no effect on 2,5- bis(glutathion- S-yl)-alpha-MeDA-mediated cytotoxicity. The present data provide evidence that metabolism is required for the expression of MDMA-induced renal toxicity in vitro. In addition, metabolism of 5-(glutathion- S-yl)-alpha-MeDA by gamma-GT and aminopeptidase M to the corresponding cystein- S-yl-glycine and/or cystein- S-yl conjugates is likely to be associated with detoxication of this compound. Thus, it appears that toxicity induced by thioether metabolites of ecstasy at the apical membrane of renal proximal tubular cells is the result of extracellular events, presumably redox cycling.
Comments and Responses to this Article
Status: display
Apr 17, 2011 1:59
Conclusions Weaker than News Suggests #

June 18, 2001:

This has come up before, when the authors did a press release a year before it was published. But now we have a paper we can really look at.

The same study was discussed in the news in March 2000.

The study also mentions that smokers were more likely to be obese, but have lower history of angina and hypertension.

Of 3758 patients who'd had heart attacks, only 120 reported smoking cannabis in the last year. Of these 9 reported using it within an hour of their heart attack. 3 of these reported engaging in other heart-strenuous activities (1 used cocaine, 1 had coke with sex, and another just had sex).

37 had a heart attack within 24 hours of smoking pot, but if you look at the frequency table (table 2), 22 of those in the study smoked daily and 30 used cannabis between once and 6 times per week and another 32 used between once a week and once a month. So to my guestimation, that 37 number looks a pretty good, since that means that 15 (37 total - 22 daily smokers) of the 1-6 weekly or 1-3 monthly smokers had heart attacks within 24 hours.

If we assume average numbers, thats 3.5 times per week for the weekly people and 2 times a month for the monthlies. That means that of the 30 people who smoked it 3.5 times per week, if that were distributed evenly through the week, we'd expect about half of those to hit on a heart attack, at random. That makes 15. Adding in the other smokers, we'd expect a little over 1/10 of them to hit (heart attack within 24 hours of smoking), so thats another 3 or so. Given that rough guestimation, I'd say there's no evidence that the pharmacological effects increase the chances of heart attack in the day afterwards.

The primary finding of interest in this paper is that people are more likely to have a heart attack within the first hour after smoking cannabis, but we only have 6 people who smoked pot, didn't engage in other risky behaviour of 3,750 people who had heart attacks, and had a heart attack within an hour of smoking. That's a pretty small number to work with.

The other finding is that the smokers were more likely to have a heart attack closer to the time they smoked the cannabis, doing a statistical analysis. While this is interesting, it certainly seems to be grossly exaggerated in the news story about the paper.

It wouldn't surprise me very much that smoking cannabis would increase heart risks, because it does cause an elevated heart rate and bp in many people who smoke it. But I would say this paper is just the very first look at how great this risk really is.

As the cannabis-smoking population ages further, we will probably learn more about this. I look forward to more research into this.
Submit Comment
[ Cite HTML ]