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[Qowpel]

Hello everyone. I am on Wellbutrin 150 mg. My concern is that Wellbutrin lowers levels of glutathione which is associated with premature aging.... 

 

Is this entirely true and has it ever been proven right or wrong, and if so to what degree?

 

Is there anything I can do about this IF it does decrease glutathione

[Duchykins]

Hi there.

 

I'm on bupropion too and have looked up the same stuff.  I found next to nothing in the scientific literature about bupropion and glutathione specifically after searching PubMed and EBSCOhost.  I found one paper in the database that contained information about bupropion and NAC though:

 

http://www.sciencedi...278584613000420

 

 

The key finding of this study is that a dose of NAC devoid of antidepressant-like effects in the mice TST, a model with established predictive value (Willner et al., 2003), reduces the minimum effective doses of imipramine and escitalopram, but not those of desipramine and bupropion in the same model. Moreover, the same subeffective dose of NAC increases the minimum effective dose of fluoxetine. Considering the advantages consequent to lowering antidepressant effective doses the results of this study suggest a potentially clinical useful interaction of NAC with imipramine and escitalopram.

 

...

 

It has been suggested that, despite differences in primary mechanisms of action, ADs might work by stabilizing glutamate neurotransmission in key brain areas, such as the hippocampus (Bonanno et al., 2005, Hashimoto, 2011 and Sanacora et al., 2012). Our data show that NAC interacts selectively with different ADs, indicating that specificities in how different agents affect glutamate function are of relevance. Barbon et al. (2006)concluded that desipramine exerts moderate but selective effects on glutamate receptor expression and editing. FST-induced increase in glutamate levels (mouse dorsolateral prefrontal cortex) was reversed by acute desipramine administration (Kim et al., 2010). Relevant to this discussion, Bouron and Chatton (1999) showed that in cultured hippocampal neurons desipramine rapidly enhanced the spontaneous vesicular release of glutamate. The effects of bupropion in glutamate transmission are less clear. While it has been shown that bupropion inhibits glutamate release in rat cerebral cortex nerve terminals (Lin et al., 2011), acute and chronic exposure of rats to bupropion results in enhanced striatal overflow of glutamate (Santamaría and Arias, 2010). The increase in glutamate release induced by these two ADs may be the basis for their lack of interaction with NAC, which decreases glutamate release.

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Now this failure to enhance the efficacy of bupropion with NAC (which you might expect see if bupropion really was depleting glutathione) might have nothing to do with glutathione due to buproprion's effect on glutamate.  But it is something to think about.  

 

Then there is this to consider, I found this a while back when researching about migraine (because from my reading there is a clear relationship between glutamate, histamine, glutathione, these guys seem to like to rise and fall together):

 

http://ajpcell.physi...81/6/C1964.long

 

 

 

Cysteine is the limiting precursor for glutathione synthesis. Because of its low bioavailability, cysteine is generally produced from cystine, which may be taken up through two different transporters. The cystine/glutamate antiporter (x −C system) transports extracellular cystine in exchange for intracellular glutamate. The XAG transport system takes up extracellular cystine, glutamate, and aspartate. Both are sensitive to competition between cystine and glutamate, and excess extracellular glutamate thus inhibits glutathione synthesis, a nonexcitotoxic mechanism for glutamate toxicity. We demonstrated previously that human macrophages express the glutamate transporters excitatory amino acid transporter (EAAT)1 and EAAT2 (which do not transport cystine, X −AG system) and overcome competition for the use of cystine transporters. We now show that macrophages take up cystine through the x −C and not the XAG system. We also found that glutamate, although competing with cystine uptake, dose-dependently increases glutathione synthesis. We used inhibitors to demonstrate that this increase is mediated by EAATs. EAAT expression in macrophages thus leads to glutamate-dependent enhancement of glutathione synthesis by providing intracellular glutamate for direct insertion in glutathione and also for fueling the intracellular pool of glutamate andtrans-stimulating the cystine/glutamate antiporter.

...

 

Previous reports have demonstrated, with different cell types, that extracellular glutamate decreases intracellular levels of GSH by competing with cystine for use of the cystine/glutamate antiporter, reducing intracellular cystine availability (11, 16, 20). Because MDMs may take up glutamate by the cystine/glutamate antiporter as well as by EAATs, we investigated the effects of glutamate on GSH synthesis. The incubation of MDMs for 4.5 h in the presence of a 50-fold excess of glutamate over cystine did not inhibit GSH synthesis and even increased it (Fig. 4). During this 4.5-h culture period, competition between cystine and glutamate for x −C transport was likely to occur. Indeed, we had already shown (19) that MDMs clear <20% of 1 mM added glutamate over a 6-h culture period. Moreover, as shown in Fig. 2, excess extracellular glutamate does compete with cystine uptake in a 5-min assay under our conditions. We therefore cannot explain GSH synthesis enhancement by glutamate clearance from the medium. Nevertheless, enhancement of GSH intracellular level by excess extracellular glutamate shows that cystine entry over a 4.5-h culture period was sufficient to support increased GSH synthesis. This strongly suggests that in the presence of extracellular glutamate EAATs efficiently fuel the intracellular glutamate pool, permitting an increase in x −C transport velocity that leads to enhanced cystine uptake, albeit under competition conditions (trans-stimulation). Indeed, in human fibroblasts that transport glutamate through the x −C system, Bannai and Ishii (3) showed that the intracellular pool of glutamate is a limiting factor for cystine uptake and is rapidly depleted in cystine-containing medium. To assess whether our observation was dependent on EAAT activity, we used L- andD-Asp instead of glutamate and measured GSH levels (Fig.5). These amino acids are two other substrates for EAATs that efficiently compete with glutamate uptake. As expected,L-Asp increased GSH synthesis, because it can be converted to L-Glu by aspartate aminotransferase and subsequently contribute to the glutamate pool. In contrast, D-Asp is not a substrate for aspartate aminotransferase and did not modify GSH levels. Moreover, excess D-Asp over glutamate abrogated the effect of glutamate on GSH synthesis, showing that EAAT-mediated uptake of glutamate is necessary for GSH synthesis enhancement (Fig. 6).

...

 

Our data strongly suggest that intracellular GSH level is controlled by the activity of transporters for cystine, glutamate, and glutamine. To maintain their intracellular pool of glutamate MDMs may thus use either glutamine, as fibroblasts do (3), or glutamate itself, as previously described in astrocytes (13). Indeed, Kranich et al. (13) reported that astrocytes, unlike neurons and fibroblasts, preferentially use extracellular glutamate rather than glutamine for GSH synthesis, probably because of their high level of EAAT activity. In contrast, extracellular glutamate inhibits GSH synthesis in C6 glioma cells (11). However, these authors also demonstrated that extracellular cystine inhibits glutamate uptake in these cells, suggesting that C6 cells mainly use the cystine/glutamate antiporter rather than EAATs (11). Moreover, glioma cell lines derived from human tumors exhibit a lower level of Na+-dependent glutamate uptake and a higher level of cystine/glutamate antiporter activity than astrocytes (26). As a consequence of the reduction of EAAT activity in these cells, competition occurs between cystine and glutamate, leading to an increase in extracellular glutamate concentration if an excess of extracellular cystine is present. The presence of the XAG transport system, which transports glutamate, cystine, and aspartate, on cultured astrocytes derived from neonatal rats also suggests that competition between these amino acids may occur and may have profound effects on the redox status and structural and functional integrity of the central nervous system (5). Consistent with our observations, Reichelt et al. (18) reported that extracellular glutamate increases intracellular GSH level in retinal Müller glial cells dependent on EAATs. This was confirmed by Igo and Ash (9), who demonstrated, using somatic cell mutants (CHO-K1 Xag-null), that X −AG provides a significant proportion of the glutamate used in the uptake of cystine for GSH synthesis. From these numerous observations in different cell types, it appears that cells that express the cystine/glutamate antiporter are sensitive to GSH depletion and subsequent oxidative stress induced by glutamate unless they also express another glutamate transporter that fuels their intracellular pool of glutamate, then increasing their antioxidant potential. The presence of both the cystine/glutamate transporter and EAATs on macrophages, and the absence of the XAG transport system, may accordingly increase the antioxidant activity of macrophages by increasing intracellular GSH concentration when extracellular glutamate concentration increases (see Fig. 7).

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Every mention, that I personally read, of a relationship between bupropion and glutathione resulting in a lowering or depletion of glutathione  was found in nutrition- or supplement-related sites, alternative medicine sites, anti-aging sites, "prescription drugs are bad" sites, blog articles, testimonials, message boards like these, or other nonscientific sources.  No explanations are offered, no citations, it's usually presented as "bupropion can lower or deplete glutathione" or "I took NAC (or milk thistle) to replenish my glutathione after bupropion depleted it and now I feel awesome"  and that's it.  Literally.   

 

I find this very suspicious.  But that's as far as I can go with it right now since I don't know anything else about it.

 

 

After I learned all this, I tried NAC on myself anyway.  I do not tolerate NAC at all, even breaking open a capsule to get smaller doses would make miserable.  I believe this is primarily caused by NAC's relationship with histamine (indirectly via glutathione), and I have a problem with that despite my daily antihistamine.  I did later add small doses of milk thistle to my stack because I take a bunch of shit every day, and have some herbal teas, but I didn't notice any change.

 

So... yeah, I'm pretty tired now and I don't have much more to say about it.

Edited by Duchykins, 11 July 2015 - 01:30 AM.