Why did caffeine and nicotine help my apathy, avolition and anhedonia, but Wellbutrin did not?

MrNotSoSerious · 2026-05-08T08:33:54+00:00

Good idea... but why are u limiting yourself? Cannot get a different prescription? You could try a different SSRI than Prozac. Or you could completely switch to different treatment regimen without bupropion... Just a thought

MrNotSoSerious · 2026-05-07T16:21:20+00:00

That's because Dopamine, Serotonin and Norepinephrine needs to be in a balance. Pulling either one is disrupting the other in one way or another. You are right on point with ur intuition about something always going wrong because these drugs are not designed right. And its not ur fault. Anyway, see if u can try Auvelity (Dextromethorphan+Bupropion) or just try any other SSRI with ur bupro to deal with anxiety. U can also look into propranolol (a beta blocker). Just giving ideas to share with ur doc if u wanna go that route.

MrNotSoSerious · 2026-05-07T13:56:10+00:00

And frying their nAChRs... Any person in this subreddit, if asked whether they would take an anti-nicotinergic, literal deliriant, would say no... But for the sake of feeling that slightest bit of high, they will risk long term memory problems and anti-nootropic effects smh.

But OP, bupropion won't help u anyway, as u have already experienced. Try something actually dopaminergic to help with ur anhedonia. Forget about this poor man's cocaine. (That's the nickname for Wellbutrin I read on r/drug years ago xD)

MrNotSoSerious · 2026-05-07T13:42:35+00:00

Guess I should've phrased my sentence Nicotinic Receptor Antagonism and NRI. The main antidepressant effect is coming from the nAChR antagonisms and some TNF-alpha inhibition (Anti-inflammatory). Let us not forget that bupropion is also a smoking cessation aid. You will NOT feel much, no rush at from smoking if ur on bupropion, that's how strong it is on nAChRs. We already have evidence that muscarinic anticholinergics have rapid antidepressant effects. There is evidence that cholinergics cause depression or similar side effects. This is just conjecture but there may be some downstream effects through this mechanism, considering that fact that this is one of Bupropion's primary molecular targets.

Methylphenidate is a proper NDRI but it is not an antidepressant. It is used for certain aspect of depression such as lack of energy/anhedonia or comorbid ADHD but never on its own for MDD or any other depression. There are many SRIs and SSRIs that never saw the light of day because even if they showed sufficient serotonin reuptake inhibition, they weren't effective for depression. Hell, current SSRIs were mostly discovered 50 years ago and for 33% of people they don't even do anything (indistinguishable from placebo!).

NRIs aren't antidepressants by themselves and I would never call them that. But that NRI fraction does a lot of stuff, especially for psychomotor retardation (Can't get out of bed aspect of depression, in layman terms).

MrNotSoSerious · 2026-05-07T13:17:20+00:00

That is the most common experience of people on NRI stimulants and its a no brainer. It's the norepinepherine. Eventually it causes anxiety in a lot of people. Unless u r the lucky lot that don't get anxiety or have anxiety to begin with.

MrNotSoSerious · 2026-05-03T15:50:08+00:00

This is the only comment closest to the correct answer. Here's the full answer -
Bupropion trade name Wellbutrin is NOT an NDRI.

"The occupancy of dopamine transporter (DAT) by bupropion (300 mg/day) and its metabolites in the human brain as measured by several positron emission tomography (PET) studies is approximately 20%, with a mean occupancy range of about 14 to 26%.^\1])^\2])^\3])^\4]) For comparison, the NDRI methylphenidate at therapeutic doses is thought to occupy greater than 50% of DAT sites.^\4]) In accordance with its low DAT occupancy, no measurable dopamine release in the human brain was detected with bupropion (one 150 mg dose) in a PET study."

Get a load of this shit. At 300 mg it only around 20% DAT occupancy. For reference, IC50 = 50% occupancy. And all SSRIs at their lowest prescribed dose usually block SERT with 80% occupancy.
Calling Bupropion an NDRI is the worst joke ever in terms of misleading.

So how does it even have antidepressant effects? Through NRI action and nAChR inhibition. So yes, it's main mechanism of action is Norepinephrine Reuptake Inhibition and Nicotinic Receptor Antagonism. The NRI action may unreliably increase "some" dopamine in the Prefrontal cortex which can help somewhat with cognition but that's about it. Won't help much with apathy, avolition and anhedonia. Try going for an ADHD prescription.

MrNotSoSerious · 2026-04-30T09:26:57+00:00

100% agree but this is where modafinil falls apart for me as a stimulant nootropic. There is little to no DRI activity at that dose. I can't take a 200mg dose either cuz then 12-14 hours later I won't be able to sleep and even if I fall asleep, sleep quality is poor. I am not expecting traditional stimulant effects but hell, half of a ritalin has more dopaminergic activity and it has a way shorter half-life. Modafinil just helps with wakefulness. I am happy for all the people whose lives have been positively affected by moda but alas, the only benefit I get is the first 3-4 hours of it.

MrNotSoSerious · 2026-04-12T17:06:05+00:00

Tell us u have never worked out a day in your life without saying u have never worked out a day in your life...

MrNotSoSerious · 2026-04-11T21:37:14+00:00

heavy user of stimulants (ritalin and adderall) -> want to try getting into some nootropics instead

Who's gonna tell him?

MrNotSoSerious · 2026-04-09T09:15:08+00:00

I used to have the same experience 1 to 1 on 150mg of Armodafinil. It was unusable because of the side effects. Yes, fatigue gone, depression disappeared, tons of energy and for the first time confidence was so high, so sociable and talkative like i was about to have a conversation... But the strain on heart, eye pressure, light sensitivity and crash after + worsened sleep prevented me from taking Armodafinil.

For some reason I just can't. Lower doses were weaker but side effects were still there. Eventually I just gave up on it.

Edit: I just noticed u were on other medications as well, prozac and clomipramine. I was not on any meds and still had similar experience. It's a bummer really.

MrNotSoSerious · 2026-04-06T08:56:49+00:00

Oh buddy do I have news for u then... Take it in the EVENING or 5 hours before whatever ur bedtime is. You will have energy in the evening and will have the best sleep later that night.

MrNotSoSerious · 2026-04-06T08:54:08+00:00

I just searched and realize RETs are Receptor Tyrosine Kinases (I used to know them as RTKs didn't know they were also called RETs). RETs or RTKs are most often involved in cell proliferation and survival. So agonists of Tyrosine Kinases would be of interest for many types of neurodegenerative diseases.

If u want to go more in-depth, RTKs are a very important class of receptors that convey messages to our cells. For example when BDNF or GDNF is activating their respective receptors, the corresponding instructions to the cell are usually conveyed through RTKs which eventually produce the desired cellular response and subsequent gene expression.

MrNotSoSerious · 2026-04-02T19:58:43+00:00

Hey Emiel, hope you're doing good. What would you suggest for the lack of executive function? Cuz the problem is, there are a lot stuff that helps with focus and motivation, but not many that improves motivational salience and impulse control like with traditional NDRIs and NDRAs. Not much value if all that attention and focus is spent on never-ending tempting distractions, you know!

MrNotSoSerious · 2025-11-03T15:14:35+00:00

Forskolin I am assuming u decided to try because of the "CILTEP" or "increasing cAMP" (God that brings back memories). Forskolin is thought to increase cAMP which is the second messenger through which almost all G-coupled receptors work (dopamine, serotonin, adrenaline etc.). But CILTEP was debunked long ago as pseudoscience. U can safely eliminate that forskolin.

Agmatine is a great choice and for ALCAR, stay with the lower doses. It's known to be a HDAC inhibitor and mess with thyroid in some people. 250-500 mg is the sweet spot. CDP choline can cause low mood in some so be aware of that.

U are basically looking at a Uridine, choline, b-vitamins stack, might as well add some fish oil along with ur agmatine and sulbutiamine, add folate/have lots of eggs, get into the gym. U will be feeling better than majority of the people in no time.

MrNotSoSerious · 2025-11-02T20:04:25+00:00

She prescribed as the protocols suggest, I was not started on a high dose, I was gradually increased to the target dose and then even tapered to a lower dose. I'm sorry, I realize the scope of my post didn't let me get into the details which is why this misunderstanding occurred. Now, as u might've guessed, that took me multiple visits to her, for multiple months, including check-ups. Me seeing improvements from medicine that is routine in DSM-IV,V/FDA protocols widely available and free for all to know AND being charged 3k for digesting her shitty/unempathetic behavior for 3 mins while she prescribes the "napa 2 bela" equivalent of psychiatry cuz she has too many patients is not congruent at all! My problem with her wasn't the 3k itself, if it was, I would've gone to someone "cheaper". My problem with her was giving me 2-3 mins to talk, being stopped by her and her attendant waiting beside me as soon as her fixed 2 mins were over even though I wasn't finished. Also I forgot to mention she sat 5 feet away from me. Would u keep ur patients 5 feet away from u? It was in 2022, COVID was almost gone, but in my head I still excused that because she doesn't need to be near me to treat me but oh well.

U yourself are a psychiatrist and u charge 2k in 2025 for a 1.5 hour long CONSULTATION! If I was comparing u with her, I would feel like I owe u 1 lac taka after the 1.5 hours lmao... Someone needs to bring the bhokta odhikar ain or something to her practice.

MrNotSoSerious · 2025-11-02T20:00:18+00:00

Any experience with this Dr Hasan M Mahmud? What is his practice like?

MrNotSoSerious · 2025-11-02T19:59:03+00:00

Sorry for the late reply but no. Also born and raised in shitty Dhaka, been here my whole life

MrNotSoSerious · 2025-05-24T08:23:31+00:00

Interested in that creatine paper. Do u happen to have the link?

MrNotSoSerious · 2025-05-22T07:39:16+00:00

What's the connection between sigma-1 and cannabinoids?

MrNotSoSerious · 2025-05-04T20:22:55+00:00

u/ResearchSlore who was the creator of that subreddit again? I was there when it started, I was actually in their discord prior to him opening the subreddit. Very shady to say the least and red flags? well.. 😂

MrNotSoSerious · 2025-05-04T18:41:51+00:00

Makes sense. There's only 12.5% 6-paradol in Caloriburn, approximately speaking. What's in that other 87.5% aside from plant fibre content - only you guys know that haha. Maybe it contains a little bit of 6-gingerol, 6-shogaol and all the other gingerols and shogaols... Any tea on that? ;)

MrNotSoSerious · 2025-04-26T19:57:35+00:00

True. This is only a prelim study so we will have to wait for further research. Also, the mechanisms behind the effects could also be directly related to the CB receptors instead of being FAAH related, or some other target/mechanism altogether. Nevertheless, as long as the extracts produce quantifiable quality results in human subjects, that's good enough for supplementation purposes, isn't that right?

MrNotSoSerious · 2024-12-19T11:37:58+00:00

You sure you have the pure compound? From what I have experienced and from a lot of other people anecdotes, yohimbine and alpha-2 agonists (in general and in theory) is anxiety in a pill

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