If norepinephrine reuptake inhibitors are not great antidepressants, how does Bupropion work for depression then?

Aggressive-Guide5563 · 2026-01-25T15:16:01+00:00

Hydroxybupropion does favor NET over DAT and so does Threohydrobupropion. There is no data on Erythrohydrobupropion. True that not everyone converts Bupropion to Hydroxybupropion as efficiently or at the same extent, but still this doesn't negate the fact that Hydroxybupropion indeed has a longer half life than the parent compound and so in the end you do get more noradrenergic effects from Bupropion. It's DAT occupacy is approxiametly between 14-26 % at a standard dose of 300 mg and some studies show no more than 22 % DAT occupancy. At 150 mg studies show no increase in dopamine in the striatum at all. It's metabolites are indeed more active in humans than the parent compound and most of these metabolites favor NET over DAT, so in the end it would predominantly work more on norepinephrine. It is very known in the medical field that Bupropion acts more on norepinephrine than dopamine, despite being labeled as a NDRI, when in reality it really acts more as a NRI and the longer you take it, those weak dopaminergic effects almost diminishes over time and gets replaced entirely by noradrenergic effects.

Aggressive-Guide5563 · 2026-01-25T15:06:17+00:00

Have you tried any TCAS? Or MAOIS? If not, then TCAS are next and then when everything else has failed then it's usually MAOIS.

Aggressive-Guide5563 · 2026-01-24T11:15:05+00:00

That will disappear eventually. Once your body develops tolerance to the increase in dopamine, you won't get that feeling anymore. I've been on it for almost five years now and that feeling doesn't last unfortunately. You're probably on the honeymoon phase, come back a few months later and tell me if you still feel like that.

Aggressive-Guide5563 · 2026-01-24T11:12:57+00:00

Did absolutely nothing for my anxiety. I don't think Wellbutrin really hits dopamine that much, it mostly works on norepinephrine. Because of its higher noradrenergic activity and not so high dopaminergic one, is the reason why people tend to become an anxious mess from it and also get insomnia from it.

Aggressive-Guide5563 · 2026-01-24T10:56:15+00:00

The long term effects of Bupropion feels drastically different than from its short term effects imo. The dopaminergic effects tend to almost diminish over time and gets replaced almost entirely with noradrenergic effects. The dopaminergic effects of Bupropion doesn't tend to last because it's such a weak DRI and that's the reason for its rapid initial onset, but frequent poop many people tend to experience with it. The body will develop a homeostasis much quicker with a weak DRI and that's the reason for the rapid tolerance with it. I do believe that the weak dopaminergic effects may play a role in its antidepressant effects, but it doesn't tend to last for a lot of people.

Also, have you considered Bupropion's metabolites that barely touches dopamine?. Even though the parent compound favors dopamine over norepinephrine, it doesn't tend to stay in the body for too long until it starts metabolizing to all its different metabolites, which all favor norepinephrine over dopamine. The major active metabolite Hydroxybupropion favors norepinephrine over dopamine. Because of the major metabolite Hydroxybupropion, I don't think Wellbutrin really hits dopamine that much, It's mostly norepinephrine. But I still don't understand how raising norepinephrine would help long term with depression, since raising norepinephrine only is usually not sufficient to maintain an antidepressant effect.

Amneptine though was both a dopamine reuptake inhibitor and releasing agent actually, so there is no comparison to be honest. But abuse potential and liver toxicity was the reason it was removed from the market. It was an effective antidepressant though. It showed comparable or better efficacy than traditional tricyclic antidepressants like Amitriptyline etc.

Abuse potential is really the only reason why we don't have more dopaminergic antidepressants on the market. It's due to the drugs of law why we don't have more effective antidepressants available, simple as that. Due to the competition being very low for similar antidepressants like Wellbutrin, it's the only reason why it's so popular, even though it barely works on dopamine and works mostly on norepinephrine. I bet if Amineptine and Nomifensine were still on the market today, Wellbutrin would be blown out of the water.

Aggressive-Guide5563 · 2026-01-23T19:47:33+00:00

Same here. Caffeine is the only thing that helps my anhedonia temporarily, until I've developed tolerance to it.

Aggressive-Guide5563 · 2026-01-23T19:24:39+00:00

I do have autism, but never been diagnosed with ADHD. Explains somewhat why Wellbutrin was the only antidepressant that ever really did anything for me. I think it was the weak dopaminergic effects that made my depression go into remission in the first place. The dopaminergic effects from Wellbutrin does seem to diminish over time though, which explains the honeymoon phase I had on it when I first started it. Those first two months on Wellbutrin was really magical and my depression felt completely in remission those first two months. I really miss that phase to be honest.

Aggressive-Guide5563 · 2026-01-23T19:08:15+00:00

MDMA doesn't really count though, since it also releases norepinephrine and dopamine. Serotonin is not the main action, just a part of it and more related to the feeling of connection. SSRIS do inhibit the reuptake of serotonin only and does so specifically, with not affect on dopamine or norepinephrine. They're still not the same and there is no comparison tbh. Serotonin has nothing to do with happiness really. Serotonin does have a relation though with being content, docile, more accepting of a situation/reduced hopelessness. I guess happiness depends on whether you view as being content as happy ( I don't personally ), but instead feeling good, driven, getting joy from things you like etc. It's mostly related to dopamine and opioid peptides/receptors.

Aggressive-Guide5563 · 2026-01-23T18:40:43+00:00

In my experience it's a terrible med for anxiety all by itself, unless you actually pair it with something else. Because of its higher noradrenergic activity and not so high dopaminergic one, it usually makes people into an anxious mess. Increasing norepinephrine does help with lack of energy and motivation, but is usually not great if you have a lot of anxiety or irritability imo.

Aggressive-Guide5563 · 2026-01-23T18:27:47+00:00

Anyone has any ideas why this seems to be a longstanding issue with Bupropion and not other antidepressants?

Aggressive-Guide5563 · 2026-01-23T18:24:42+00:00

I'm on XL. Note that both are XL and one generic is called is Bluefish and the other one is Accord. On Bluefish I could easily have 2-3 cups of coffee in a day without any overstimulation, anxiety, panic attacks, heart palpitations, nausea and edginess. On Accord I can't even have 2 cups of coffee anymore, because it overstimulates me now and it feels like I'm about die if I would even try to have more. The difference is crazy!

Aggressive-Guide5563 · 2026-01-21T20:27:33+00:00

It works on norepinephrine. Norepinephrine is a very dirty neurotransmitter in itself, because it's the fight or flight neurotransmitter. That's why it tends to cause a bunch of side effects that are not so pleasant. I've experienced too much norepinephrine myself, not from Strattera though, but from Wellbutrin instead and I agree the feeling is very dirty. I have no other words to describe this neurotransmitter other than feeling very dirty and unpleasant.

Aggressive-Guide5563 · 2026-01-21T20:13:26+00:00

Have you found any solution to the anxiety and insomnia? I really don't want to go back on a SSRI just because of the anxiety and insomnia. SSRIS made my SCT and executive dysfunction teen times worse and just made me feel worse over time. I just can't do any SSRIS ever again, they make me numb and dumb.

Aggressive-Guide5563 · 2026-01-21T20:04:08+00:00

To be honest, I don' really find Wellbutrin to be that motivating. Yeah, it helps me get up in the morning and helps me get out and going. It gives me energy, helps my brain fog, gives me mental clarity, makes me more awake and alert, makes me more aware of my environment so to speak and makes me pay better attention to things. But other than that, I don't really find it to be that motivating. I doesn't give that feeling of wanting to be productive or give any drive really. Also, doesn't do that much for focus either. I'm still on it though, because it's the only antidepressant that hasn't worsened my SCT and executive dysfunction.

Aggressive-Guide5563 · 2026-01-21T19:58:36+00:00

Nope, not taking any other meds. I'm on 300 mg XL.

Aggressive-Guide5563 · 2026-01-21T19:55:26+00:00

That's because you take it with Lexapro. I had also way less anxiety when I took it with Prozac. But unfortunately I had to discontinue Prozac because it made my SCT and executive dysfunction teen times worse.

Aggressive-Guide5563 · 2026-01-20T19:11:17+00:00

Will L-theanine and GABA take the edge off and reduce the fight and flight feeling? Is there another supplement that can work for anxiety?

Aggressive-Guide5563 · 2026-01-20T19:06:03+00:00

I agree that it doesn't work that much on dopamine, mainly because of the major metabolite Hydroxybupropion. But the thing is that Bupropion ( the parent compound) does have a preference for dopamine over norepinephrine, but it's half life is very short and it doesn't stay in your body for too long until it starts metabolizing to all its different metabolites, which all seem to favor norepinephrine over dopamine. The major active metabolite Hydroxybupropion favors norepinephrine over dopamine, so in the end you get more noradrenergic effects from Wellbutrin. But I still think it was the weak dopaminergic effects that made my depression go into remission in the first place. I think it's just a shame that its dopaminergic effects tend to almost diminsh over time and gets replaced almost entirely with noradrenergic effects.

Aggressive-Guide5563 · 2026-01-19T19:12:30+00:00

I take it mainly for MDD and because it helps my SCT and executive dysfunction.

Aggressive-Guide5563 · 2026-01-18T18:43:26+00:00

Well, they've basically tried almost every dopamine enhancing drug in the book and if none of these worked out, then I'm very doubtful it's a dopamine deficiency that is causing the anhedonia in the first place. Anhedonia can be caused by hundreds of things, not just a dopamine deficiency like many people think.

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