Bupropion (Wellbutrin) Pharmacology In-Depth: Attenuates Psychostimulant Response?

[Geaux Tigers!]

Hey, everybody!

I've been contemplating bupropion lately as it is extremely relevant to me— I take Aplenzin (bupropion hydrobromide) 522mg.

((Aplenzin is bioequivalent to Wellbutrin XL 450mg. because Aplenzin is manufactured as the hydrobromide salt of bupropion; therefore, it has a different molecular weight (requiring 522mg. and not 450mg. like the hydrochloride salt). There is evidence that the hydrobromide salt may be more appropriate for some patients.))

Additionally, I therapeutically consume Adderall IR 40mg. QAM 20mg. QPM. I take 40mg. in the morning and a booster dose of 20mg. in the afternoon.

Also relevant, I swallow a Nuvigil (armodafinil) 250mg. tablet every morning.

Essentially, I am wondering about the interactions of these medications in terms of psychostimulant response because my earlier thread on this forum had this post by fellow poster, atara (thank you for such an intriguing response!)

Bupropion and modafinil can inhibit the dopamine releasing effect of amphetamine. I'm not sure why you would combine these, though I would love to hear sekio's opinion. It's possible that by removing these two, amphetamine will be able to work at full effectiveness and you'll see an improvement! The short version is that bupropion blocks the function of DAT whereas amphetamine reverses it, but you can't reverse something that isn't running. Modafinil is also a DRI, with additional action as a D2R partial agonist (the highest efficacy at the schizophrenia receptor that medicine is willing to fuck with).

NOOB SPECULATION ALERT WITH NO SOURCES PURELY FROM MY HEAD:

It is my understanding that bupropion will basically increase dopamine by inhibiting DAT and have some DA uptake via VMAT2 come into play and transport some dopamine into basically like a swimming pool in the synapse not really released yet. So you get all of that DA into those cells and get more transmission out of them like release of DA because the other DA can't get into the swimming pool so that DA fires; therefore, you're getting your psychostimulatory action via this mechanism.

Basically amphetamines come over there and try to do a reversal and reduce or kinda release all of that VMAT2 activity and try to work on the same DA receptors to release DA along with the DA that was released because it was inhibited by bupropion.

I've read that bupropion will at maximum occupy only 30% of the dopamine transporter-- is this how amphetamine is able to get away with stimulatory effects while a patient takes it with bupropion? Does it augment even? How does modafinil come into play?

What are the effects of these psychostimulants in the body and do they really work together?

Thanks for your time!

 

[endotropic]

Hey, everybody!

I've been contemplating bupropion lately as it is extremely relevant to me professionally— and personally, as I take Aplenzin (bupropion hydrobromide) 522mg.

((Aplenzin is bioequivalent to Wellbutrin XL 450mg. because Aplenzin is manufactured as the hydrobromide salt of bupropion; therefore, it has a different molecular weight (requiring 522mg. and not 450mg. like the hydrochloride salt). There is evidence that the hydrobromide salt may be more appropriate for some patients.))

Additionally, I therapeutically consume Adderall IR 40mg. QAM 20mg. QPM. I take 40mg. in the morning and a booster dose of 20mg. in the afternoon.

Also relevant, I swallow a Nuvigil (armodafinil) 250mg. tablet every morning.

Essentially, I am wondering about the interactions of these medications in terms of psychostimulant response because my earlier thread on this forum had this post by fellow poster, atara (thank you for such an intriguing response!)



NOOB SPECULATION ALERT WITH NO SOURCES PURELY FROM MY HEAD:

OK, so it is my understanding that bupropion will basically increase dopamine by inhibiting DAT and have some DA uptake via VMAT2 come into play and transport some dopamine into basically like a swimming pool in the synapse not really released yet, sorta works like that right? So you get all of that DA into those cells and get more transmission out of them like release of DA because the other DA can't get into the swimming pool so that DA fires? So, you're getting your psychostimulatory action via this mechanism, correct?

So basically amphetamines come over there and try to do a reversal and reduce or kinda release all of that VMAT2 activity and try to work on the same DA receptors to release DA along with the DA that was released because it was inhibited by bupropion?

I've read that bupropion will at maximum occupy only 30% of the dopamine transporter-- is this how amphetamine is able to get away with stimulatory effects while a patient takes it with bupropion? Does it augment even? How does modafinil come into play?

What are the effects of these psychostimulants in the body and do they really work together?

Thanks for your time!

I think atara was referring to a scenario where a transporter blocker like bupropion was occupying 100% of the available dopamine transporters. Since amphetamine acts as a substrate for DAT (meaning it has to pass through the transporter much like dopamine), with 100% of the transporters blocked amphetamine can no longer enter the cell, and its effectiveness would be reduced.

I think you're correct though that bupropion usually doesn't occupy nearly that many of the available transporters, so by combining the two you actually get the additive effect of the DAT reversal by amphetamine at some transporters, and the reuptake inhibition of modafinil at others.

That's usually the case when we're talking about the dopamine transporter (no one ever talks about their cocaine blocking their amphetamine effects, quite the opposite usually). As a side note - with serotonin reuptake inhibitors it's quite a different story, as those drugs tend to occupy nearly all of the available serotonin transporters, so those drugs tend to blunt the effects of releasing agents like MDMA.

 

[Geaux Tigers!]

I think atara was referring to a scenario where a transporter blocker like bupropion was occupying 100% of the available dopamine transporters. Since amphetamine acts as a substrate for DAT (meaning it has to pass through the transporter much like dopamine), with 100% of the transporters blocked amphetamine can no longer enter the cell, and its effectiveness would be reduced.

I think you're correct though that bupropion usually doesn't occupy nearly that many of the available transporters, so by combining the two you actually get the additive effect of the DAT reversal by amphetamine at some transporters, and the reuptake inhibition of modafinil at others.

That's usually the case when we're talking about the dopamine transporter (no one ever talks about their cocaine blocking their amphetamine effects, quite the opposite usually). As a side note - with serotonin reuptake inhibitors it's quite a different story, as those drugs tend to occupy nearly all of the available serotonin transporters, so those drugs tend to blunt the effects of releasing agents like MDMA.

Thank you for clearing this up for me! I understand where atara is coming from now that I put a 100% scenario in mind; however, it seems contrary to suggest to remove bupropion or modafinil to make amphetamine more efficacious due to its occupancy at DAT.

Very interesting about the cocaine and amphetamine! I figured they had to work together some kind of way lol. So how does Ritalin work with Adderall, for example? I think bupropion's actions at DAT are too insignificant to really have an effect on amphetamine's MOA.

 

[ebola?]

One can achieve drastically higher proportionate transporter occupancy with methylphenidate, so we should expect attenuation of effects, depending on the timing of the combination: taking ritalin at the tail of an amphetamine experience should lead to additive stimulant effects (possibly synergy, due to prior dopaminergic release). However, anecdotally, people tend to find the combination to feel just ugly and side-effect ridden.

ebola

 

[Privateer]

After hearing it discussed in some journal articles and textbooks, I find myself coming around to the idea that dopamine release has little contribution to the activity of amphetamine in therapeutic doses, and only becomes relevant (in terms of the overall effects profile) in higher doses and routes of administration that cause large concentration spikes. From what I can find a 20mg XR dose produces a peak plasma concentration that's about a tenth of the dopamine release EC50. So assuming a linear dose-concentration (and a lot of other things) you'd need a 200mg XR dose to have half-maximal dopamine release. So we can see that there might be some dopamine release happening in low therapeutic doses but it wouldn't really be relevant in relation to a recreational effect. A small additional trickle of dopamine may have a therapeutic implication, but that's really just speculation.

 

[ebola?]

Why are we using 50 percent of maximal DA release as our criterion for behavioral and experiential relevance?

I'll agree that all of these monoamine releasing stimulants exert far greater of an effect on NE, but most of our discussion of the interaction between DA releasers and DARIs applies to that between NE releasers and NRIs.

ebola

 

[h3lp]

From my experience both welbutrin and amphetamines have powerful effects on the personality.

As for the topic in terms of harm reduction I would err on the side of caution.

 

[Geaux Tigers!]

After hearing it discussed in some journal articles and textbooks, I find myself coming around to the idea that dopamine release has little contribution to the activity of amphetamine in therapeutic doses, and only becomes relevant (in terms of the overall effects profile) in higher doses and routes of administration that cause large concentration spikes. From what I can find a 20mg XR dose produces a peak plasma concentration that's about a tenth of the dopamine release EC50. So assuming a linear dose-concentration (and a lot of other things) you'd need a 200mg XR dose to have half-maximal dopamine release. So we can see that there might be some dopamine release happening in low therapeutic doses but it wouldn't really be relevant in relation to a recreational effect. A small additional trickle of dopamine may have a therapeutic implication, but that's really just speculation.

Hey, Privateer!

Thanks for sharing your idea, but I believe it's wrong. Dopamine release is an essential factor of amphetamine's therapeutic efficiency.

I looked up the KI values of amphetamine:

The order of
amphetamine potencies was NET (KI = 0.07–0.1 µM), DAT (KI ≈ 0.6 µM), and SERT (KI between
20 to 40 µM).

BMC Pharmacology 2006

Can you provide a citation for your EC50 values? And as ebola? pointed out, why 50% occupancy rate as a behavioral indicator given the potency of amphetamine at the occupancy rate it does have based on these values?

Dopamine release is the necessary factor of recreational and therapeutic usage. For example, why do you think D2 antagonists attenuate the therapeutic effectiveness of amphetamines for people with ADHD?

It is not speculation.

 

[h3lp]

I think the matter of speculation in terms of welbutrin usage would be minimal if any.

The thereaputic effectiveness of welbutrin as an antidepresent can safely be considered as positive when considering how often it is prescribed.

I haven't bothered to dig up any links to verify my argument though.

 

[TriputoryHeadicine]

I know this is off topic, sorry.

A guy in town recently had an aneuryism and died. He was taking wellbutrin and cymbalta. I didn't realize the number of people that have reported anereurisms or other cerbebrovascular incidents. How often does this happen with your pts.s doc?

 

[Hammilton]

While talk about blocking transporters is fine, you have to consider the affinities these drugs have to the transporters. Amphetamine is surely much stronger than bupropion and would surely displace it from the transporter.

 

[Coolwhip]

While talk about blocking transporters is fine, you have to consider the affinities these drugs have to the transporters. Amphetamine is surely much stronger than bupropion and would surely displace it from the transporter.

Even when considering that serum levels of buproprion and its active metabolites will be much, much higher than amphetamine at therapeutic doses of each?

 

[h3lp]

Welbutrin is a very often perscribed medication especially for those concerned with mental health.

I'm sure the unfortunate death you heard of is unrelated to the medication he was taking.

 

[yaesutom]

A long time ago I tried taking buproprion (in the form of a Zyban tablet) while I was taking Adderall (and had been for years around 40mg/day) and it seemed to almost totally block the amphetamine effects..

 

[atara]

The other more important point about bupropion's nicotinic antagonism was the main reason i had suggested to discontinue bupropion. This is a *far* more obvious antistimulant effect than decreasing amphetamine transporter occupancy, which would only be a side effect. Bupropion is nonaddictive precisely because of nAChR antagonism, so the story goes.

 

[endotropic]

The other more important point about bupropion's nicotinic antagonism was the main reason i had suggested to discontinue bupropion. This is a *far* more obvious antistimulant effect than decreasing amphetamine transporter occupancy, which would only be a side effect. Bupropion is nonaddictive precisely because of nAChR antagonism, so the story goes.

Well that makes a lot more sense, I'm glad you came by to clear that up.

 

[h3lp]

Well that makes a lot more sense, I'm glad you came by to clear that up.

Going along with that I found this:

Hypertension (sometimes severe) has occurred with bupropion therapy either alone or in combination with transdermal nicotine in patients with and without pre-existing hypertension.¹ Safety in patients with recent history of MI or unstable heart disease not established.

Seeing how the substance is perscribed for sessation of smoking I think this makes it more evident that safety and precaution is advised.

I think that this may also help the OP understand the relevance of drug interactions with bupropion.

"Interactions for Bupropion Hydrochloride

Metabolized principally by CYP2B6; may also inhibit CYP2D6 and induce other hepatic microsomal enzymes"

The is also a handy chart in the link with commonly perscribed drugs and their interactions with bupropion.

Source: http://www.drugs.com/monograph/bupropion-hydrochloride.html

 

[Geaux Tigers!]

I regularly dip tobacco and will even smoke someone's cigarette rarely "for the fuck of it". I have not noticed any difference in my nicotine intake. I can still catch a buzz off a dip in the morning, and I still get stimulated by nicotine. I started a thread about it one time: Bupropion's effect on nicotinic pleasure which is now apart of a Bupropion megathread here: http://www.bluelight.org/vb/threads/472006-The-Big-and-Dandy-Buproprion-(Wellbutrin)-Megathread?p=10354968&viewfull=1#post10354968 if you're interested.

 

[Geaux Tigers!]

Thank you for your input, h3lp. The chart is interesting. And, I'm aware of its hypertensive properties, well worth evaluating indeed.

 

[Geaux Tigers!]

Even when considering that serum levels of buproprion and its active metabolites will be much, much higher than amphetamine at therapeutic doses of each?

I, too, would like the know the science of this.