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Old 11-28-11, 10:55 PM
MichaelBluth MichaelBluth is offline

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Re: Bupropion HCl and Amphetamine combination produces a neutral affect?

Originally Posted by Helloworld! View Post
I (think I) am following everyone's assessment of the theoretical complementary action of Wellbutin and stims combined. However, I have read a few posts on this forum from people saying that the wellbutrin actually killed the effects of their stims. Any thoughts on this? Anyone else have personal experiences?
The anecdotal evidence going either way is equivocal and I think depends on a number of factors typically unstated. There are scant studies about the combination -- pretty much the only that exist are those looking at bupropion + methamphetamine in meth abusers. Those studies pretty much all report that bupropion reduces the stimulant effects. On the other hand, many on this forum have reported that the two drugs are synergistic. Both are no doubt true.

I want to challenge the apparent theoretical consensus here about the psychopharmacological interaction of the two drugs. Bupropion inhibits the re-uptake of dopamine (DA) by binding to the dopamine transport molecule (DAT). At all doses, amphetamine also binds to DAT, resulting in a similar inhibition in DA reuptake. At sufficiently high doses, amphetamine induces the release of DA. It does this through two steps: first, it diffuses into DA vesicles and disrupts the proton gradient established across the vesicle wall, in effect making the wall leak DA into the cytoplasm; second, it reverses the mechanism of DAT such that it carries DA out from the cytoplasm into the synapse. DA is normally carried out by a protein called VMAT2, to which amphetamine binds (by itself this would decrease the transmission of DA, were it not for the other effects, because the amphetamine is occupying the transport molecule that usually facilitates the secretion of DA). How does amphetamine reverse the mechanism of DAT?

There are two hypotheses (perhaps both correct): according to the first, the mere presence of DA in the cytoplasm induces the change in the DAT; according to the second, amphetamine directly interacts with DAT to carry DA from inside the vesicle (not just the cytoplasm) itself into the synapse. Why do I bring this up? Because bupropion should disrupt the mechanism of amphetamine described in the first hypothesis by occupying the DAT molecules, while it should probably have less of an effect on the mechanism described in the second hypothesis since in that case, the DAT has been phosphorylated and is less susceptible to bupropion binding. In any event, the mechanism by which amphetamine releases DA relies on the DAT, which means that by occupying the DAT, bupropion will both inhibit the re-uptake and inhibit the release of DA. If amphetamine is still bound to VMAT2 at this point, the release of DA will be less than without any drug at all. This suggests that if this combination is used, the bupropion should be taken later, when the amphetamine starts to wear off, but before it has worn off completely.

Of course, this entire preceding line of reasoning depends on the assumption that bupropion and amphetamine work in the exact same locations in the brain. Amphetamine is a very specific drug -- in some regions of the brain (e.g., D2 memory circuits in the hippocampus, where incidentally bupropion is somewhat active), it has no effect whatsoever on dopaminergic transmission. To the extent that they effect different areas of the brain, they should have a synergistic effect independent of the interaction discussed above.

It is probably the case that bupropion is synergistic with some of the effects of amphetamine, while disrupting other effects. The experiences of people in this forum suggest that it can help the amphetamine last longer (though it is unclear to me if this is primarily due to inhibition of DAT, inhibition of CYP2D6, or some other mechanism). Studies have identified cases where bupropion primarily interferes with certain effects of amphetamine -- for example, bupropion completely blocks the ability of amphetamine to reverse the akinetic effects of reserpine, which raises questions that I won't address here but should be apparent to people who know a bit about the psychopharmacology of reserpine (which is also much more complicated than most people understand it to be). Amphetamine and bupropion have exactly opposite effects on the ratio of dopamine metabolites to dopamine in the striatum of persons pre-treated with haloperidol, and the various explanations offered for this phenomenon are complicated, to say the least.

All of the above aside, there are other mechanisms of interaction between the two drugs. Bupropion inhibits the CYP2D6 enzyme, which is involved in the metabolism of amphetamine. This means that by taking bupropion, you will be increasing the amount of time the amphetamine is in your blood. It seems that this effect is much more pronounced with 300 mg of bupropion than with 150 mg. The effect bupropion has on nicotine receptors undoubtedly interacts with the effects of amphetamine, particularly relating to things like feelings of craving. Perhaps through this mechanism, a recent study showed that bupropion blunts any anxiogenic (anxiety causing) effects of amphetamine (at close to the exact rate that it blunts the anxiogenic effects of nicotine...).

My point is simply that it is more complicated than simply "amphetamine induces the release of DA and bupropion inhibits the reuptake of DA, therefore they have a synergistic effect." There are remarkably few studies on the combination, which makes it all the more difficult to understand. I suspect that the efficacy of the combination depends on the dosages of each, the interval of time in between taking the amphetamine and the bupropion, and many very individual factors (relating to things like variations in metabolism, and to particularly troublesome symptoms). If you are interested in this combination, it may take some experimentation to find the correct dosage & time interval. For people who take or have taken this combination, I'd be very interested to hear what dose and time interval was used, and which symptoms were most affected.
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