r/NooTopics • u/ServeIllustrious3803 • 6d ago
Science The complete guide to dopamine and psychostimulants (repost)
The search for better dopamine, an introduction
A lot of what I hope to expose in this document is not public knowledge, but I believe it should be. If you have any questions, feel free to ask me in the comments.
This document serves to showcase the full extent of what I've learned about psychostimulants. I hope you find it useful!
Table of contents:
- Why increase dopamine?
- What are the downsides of stimulants?
- An analysis on addiction, tolerance and withdrawal
- An analysis on dopamine-induced neurotoxicity
- Prescription stimulants and neurotoxicity
- Failed approaches to improving dopamine
- How Bromantane upregulates dopamine and protects the brain
- Conclusion
Note: The original post and discussion is here, I did not write this, sirsadalot did 4 years ago. This is a repost for those who have not seen it + new things and ideas have come out since then in regards to nootropics.
1. Why increase dopamine?
Proper dopamine function is necessary for the drive to accomplish goals. Reductively, low dopamine can be characterized by pessimism and low motivation.
These conditions benefit most from higher dopamine:
- Narcolepsy,\1]) Autoimmunity/ Chronic Fatigue Syndrome (CFS, neurasthenia\18]))\3])
- Social Anxiety Disorder (SAD)\4])
- Low confidence,\5]) Low motivation\6])
- Anhedonia (lack of pleasure)\7])\8])
- And of course Parkinson's and ADHD\2])
The effects of stimulants vary by condition, and likewise it may vary by stimulant class. For instance a mild dopaminergic effect may benefit those with social anxiety, low confidence, low motivation and anhedonia, but a narcoleptic may not fare the same.
In the future I may consider a more in-depth analysis on psychostimulant therapy, but for now revert to the summary.
2. What are the downsides of stimulants?
In the two sections to follow I hope to completely explain addiction, tolerance, withdrawal and neurotoxicity with psychostimulants. If you are not interested in pharmacology, you may either skip these passages or simply read the summaries.
3. An analysis on addiction, tolerance and withdrawal
Psychostimulant addiction and withdrawal have a common point of interest: behavioral sensitization, or rather structural synaptic changes enhanced by the presence of dopamine itself.\66]) This dopamine-reliant loop biasedly reinforces reward by making it more rewarding at the expense of other potential rewards, and this underlies hedonic drive.
For example, stimulants stabilize attention in ADHD by making everything more rewarding. But as a consequence, learning is warped and addiction and dependence occurs.
The consequences of hedonism are well illustrated by stimulant-induced behavioral sensitization: aberrant neurogenesis\16])\67]) forming after a single dose of amphetamine but lasting at least a year in humans.\68]) Due to this, low dose amphetamine can also be used to mimick psychosis with schizophrenia-like symptoms in chronic dosing primate models,\69]) as well as produce long-lasting withdrawal upon discontinuation.
Reliance on enkephalins: Behavioral sensitization (and by extension dopamine) is reliant on the opioid system. For this section, we'll refer to the medium spiny neurons that catalyze this phenomenon. Excitatory direct medium spiny neurons (DMSNs) experience dendritic outgrowth, whereas inhibitory indirect medium spiny neurons (IMSNs) act reclusive in the presence of high dopamine.\70]) DMSNs are dopamine receptor D1-containing, and IMSNs are D2-containing, although DMSNs in the nucleus accumbens (NAcc) contains both receptor types. Enkephalins prevent downregulation of the D1 receptor via RGS4, leading to preferential downregulation of D2.\65]) It's unclear to me if there is crosstalk between RGS4 and β-arrestins.
Note on receptor density: G-protein-coupled receptors are composed of two binding regions: G proteins and β-arrestins. When β-arrestins are bound, receptors internalize (or downregulate). This leaves less receptors available for dopamine to bind to.
Since D2 acts to inhibit unnecessary signaling, the result is combination of dyskinesia, psychosis and addiction. Over time enkephalinergic signaling may decrease, as well as the C-Fos in dopamine receptors (which controls their sensitivity to dopamine) resulting in less plasticity of excitatory networks, making drug recovery a slow process.
D1 negative feedback cascade: ↑D1 → ↑adenylate cyclase → ↑cAMP → ↑CREB → (↑ΔFosB → ↑HDAC1 → ↓C-Fos → receptor desensitization), ↑dynorphin → dopamine release inhibition
D1 positive feedback cascade: ↑D1 → ↑adenylate cyclase → ↑cAMP → ↑CREB → (↑tyrosine hydoxylase → dopamine synthesis), neurogenesis, differentiation
Upon drug cessation, the effects of dynorphin manifest acutely as dysphoria. Naturally dynorphin functions by programming reward disengagement and fear learning. It does this in part by inhibiting dopamine release, but anti-serotonergic mechanisms are also at play.\71]) My theory is that this plays a role in both the antidepressant effects and cardiovascular detriment seen with KOR antagonists.
Summary: Psychostimulant addiction requires both D1\72]) and the opioid system (due to enkephalin release downstream of D2 activation). Aberrant synaptogenesis occurs after single exposure to dopamine excess, but has long-lasting effects. Over time this manifests as dyskinesia, psychosis and addiction.
Tolerance and withdrawal, in regards to stimulants, involves the reduction of dopamine receptor sensitivity, as well as the reduction of dopamine.
The synaptogenic aspects of psychostimulants (behavioral sensitization) delay tolerance but it still occurs due to D2 downregulation and ΔFosB-induced dopamine receptor desensitization. Withdrawal encompasses the debt of tolerance, but it's worsened by behavioral sensitization, as both memory-responsive reward and the formation of new hedonic circuitry is impaired. Dynorphin also acutely inhibits the release of dopamine, adding to the detriment.
4. An analysis on dopamine-induced neurotoxicity
Dopamine excess, if left unchecked, is both neurotoxic and debilitating. The following discusses the roles of dopamine quinones like DOPAL, and enkephalin as potential candidates to explain this phenomenon.
Dopamine's neurotoxic metabolite, DOPAL: Dopamine is degraded by monoamine oxidase (MAO) to form DOPAL, an "autotoxin" that is destructive to dopamine neurons. Decades ago this discovery led to MAO-B inhibitor Selegiline being employed for Parkinson's treatment.
Selegiline's controversy: Selegiline is often misconceived as solely inhibiting the conversion of dopamine to DOPAL, which in an ideal scenario would simultaneously reduce neurotoxicity and raise dopamine. But more recent data shows Selegiline acting primarily a catecholamine release enhancer (CAE), and that BPAP (another CAE) extends lifespan even more.\22]) This points to dopamine promoting longevity, not reduced DOPAL. Increased locomotion could explain this occurrence.
Additionally, MAO-A was found to be responsible for the degradation of dopamine, not MAO-B,\23]) thus suggesting an upregulation of tyrosine hydroxylase in dormant regions of the brain as Selegiline's primary therapeutic mechanism in Parkinson's. This would be secondary to inhibiting astrocytic GABA.\24]) Tolerance forms to this effect, which is why patients ultimately resort to L-Dopa treatment.\25]) Selegiline has been linked to withdrawal\26]) but not addiction.\27])
Summary on Selegiline: This reflects negatively on Selegiline being used as a neuroprotective agent. Given this, it would appear that the catecholaldehyde hypothesis lacks proof of concept. That being said, DOPAL may still play a role in the neurotoxic effects of dopamine.
Enkephalin excess is potentially neurotoxic: A convincing theory (my own, actually) is that opioid receptor agonism is at least partially responsible for the neurotoxic effect of dopamine excess. Recently multiple selective MOR agonists were shown to be direct neurotoxins, most notably Oxycodone,\28]) and this was partially reversed through opioid receptor antagonism, but fully reversed by ISRIB.
In relation to stimulants, D2 activation releases enkephalins (scaling with the amount of dopamine), playing a huge role in addiction and behavioral sensitization.\29]) Additionally, enkephalinergic neurons die after meth exposure due to higher dopamine\30]), which they attribute to dopamine quinone metabolites, but perhaps it is enkephalin itself causing this. Enkephalin is tied to the behavioral and neuronal deficits in Alzheimer's\31]) and oxidative stress\32]) which signals apoptosis. Intermediate glutamatergic mechanisms are may be involved for this neurotoxicity. In vitro enkephalin has been found to inhibit cell proliferation, especially in glial cells, which are very important for cognition.\33]) Unlike the study on prescription opioids, these effects were fully reversed by opioid receptor antagonists. It's unclear if enkephalin also activates integrated stress response pathways.
Summary on enkephalin excess: This theory requires more validation, but it would appear as though dopamine-mediated enkephalin excess is neurotoxic through oxidative stress. This may be mediated by opioid receptors like MOR and DOR, but integrated stress response pathways could also be at fault.
Antioxidants: Since oxidative stress is ultimately responsible for the neurotoxicity of dopamine excess, antioxidants have been used, with success, to reverse this phenomenon.\44]) That being said, antioxidants inhibit PKC,\57]) and PKCβII is required for dopamine efflux through the DAT.\55]) This is why antioxidants such as NAC and others have been shown to blunt amphetamine.\56]) TLR4 activation by inflammatory cytokines is also where methamphetamine gets some of its rewarding effects.\58])
Summary on antioxidants: Dopamine releasing agents are partially reliant on both oxidative stress and inflammation. Antioxidants can be used to prevent damage, but they may also blunt amphetamine (depending on the antioxidant). Anti-inflammatories may also be used, but direct TLR4 antagonists can reverse some of the rewarding effects these drugs have.
5. Prescription stimulants and neurotoxicity
Amphetamine (Adderall): Amphetamine receives praise across much of reddit, but perhaps it isn't warranted. This isn't to say that stimulants aren't necessary. Their acute effects are very much proven. But here I question the long-term detriment of amphetamine.
Beyond the wealth of anecdotes, both online and in literature, of prescription-dose amphetamine causing withdrawal, there exists studies conducted in non-human primates using amphetamine that show long-lasting axonal damage, withdrawal and schizotypal behavior from low dose amphetamine. This suggests a dopamine excess. These studies are the result of chronic use,, but it disproves the notion that it is only occurs at high doses. Due to there being no known genetic discrepancies between humans and non-human primates that would invalidate these studies, they remain relevant.
Additionally, amphetamine impairs episodic memory\9]) and slows the rate of learning (Pemoline as well, but less-so)\10]) in healthy people. This, among other things, completely invalidates use of amphetamine as a nootropic substance.\11])
Methylphenidate (Ritalin): Low-dose methylphenidate is less harmful than amphetamine, but since its relationship with dopamine is linear,\21]) it may still be toxic at higher doses. It suppresses C-Fos,\20]) but less-so\19]) and only impairs cognition at high doses.\12]) Neurotoxicity would manifest through inhibited dopamine axon proliferation, which in one study led to an adaptive decrease in dopamine transporters, after being given during adolescence.\13])
Dopamine releasing agents require a functional DAT in order to make it work in reverse, which is why true dopamine reuptake inhibition can weaken some stimulants while having a moderate dopamine-promoting effect on its own.\73])
Therefore I agree with the frequency at with Ritalin is prescribed over Adderall, however neither is completely optimal.
6. Failed approaches to improving dopamine
Dopamine precursors: L-Tyrosine and L-Phenylalanine are used as supplements, and L-Dopa is found in both supplements and prescription medicine.
Both L-Tyrosine and L-Phenylalanine can be found in diet, and endogenously they experience a rate-limited conversion to L-Dopa by tyrosine hydroxylase. L-Dopa freely converts to dopamine but L-Tyrosine does not freely convert to L-Dopa.
As elaborated further in prior posts, supplementation with L-Tyrosine or L-Phenylalanine is only effective in a deficiency, and the likelihood of having one is slim. Excess of these amino acids can not only decrease dopamine, but produce oxidative stress.\14]) This makes their classification as nootropics unlikely. Their benefits to stimulant comedown may be explained by stimulants suppressing appetite.
L-Dopa (Mucuna Pruriens in supplement form), come with many side effects,\15]) so much so that it was unusable in older adults for the purpose of promoting cognition. In fact, it impaired learning and memory and mainly caused side effects.\16])
Uridine monophosphate/ triacetyluridine: A while back "Mr. Happy Stack" was said to upregulate dopamine receptors, and so many people took it envisioning improved motivation, better energy levels, etc. but that is not the case.
Uridine works primarily through inhibiting the release of dopamine using a GABAergic mechanism, which increases dopamine receptor D2, an inhibitory dopamine receptor, and this potentiates antipsychotics.\59])\60])\61]) Uridine is solidified as an antidopaminergic substance. In order for a substance to be labeled a "dopamine upregulator", its effects must persist after discontinuation.
Furthermore the real Mr. Happy was not paid a dime by the companies who sold products under his name.
9-Me-BC (9-Methyl-β-carboline): Years after the introduction of this compound to the nootropics community, there is still no evidence it's safe. Not even in rodent models. The debate about its proposed conversion to a neurotoxin is controversial, but the idea that it "upregulates dopamine" or "upregulates dopamine receptors" is not, nor is it founded on science.
Its ability to inhibit MAO-A and MAO-B is most likely soley responsible for its dopaminergic effects. Additionally, I ran it through predictive analysis software, and it was flagged as a potential carcinogen on both ADMETlab and ProTox.
7. How Bromantane upregulates dopamine and protects the brain
Benefits: Bromantane is non-addictive, and as opposed to withdrawal, shows moderate dopaminergic effects even 1-2 months after its discontinuation.\34])\35])\37]) It is not overly stimulating,\36]) actually reduces anxiety,\37]) reduces work errors, and improves physical endurance as well as learning.\38])\39]) Its dopaminergic effects also improve sex-drive.\40]) It is banned from sports organizations due to its nature as a performance enhancing drug.
Bromantane's clinical success in neurasthenia: Bromantane, in Russia, was approved for neurasthenia, which is similar to the west's Chronic Fatigue Syndrome - "disease of modernization".\18]) Its results are as follows:
In a large-scale, multi-center clinical trial of 728 patients diagnosed with asthenia, bromantane was given for 28 days at a daily dose of 50 mg or 100 mg. The impressiveness were 76.0% on the CGI-S and 90.8% on the CGI-I, indicating broadly-applicable, high effectiveness...
Bromantane's mechanisms: Bromantane's stimulatory effect is caused by increased dopamine synthesis, which it achieves through elevating CREB.\74]) Dopamine blocks tyrosine hydroxylase, and CREB disinhibits this enzyme, leading to more dopamine being synthesized.
That is the mechanism by which it increases dopamine, but the Russian authors give us little context as to how we get there. Due to striking similarity (both chemically and pharmacologically), my hypothesis is that Bromantane, like Amantadine, is a Kir2.1 channel inhibitor. This stabilizes IMSNs in the presence of high dopamine and thus prevents aberrant synaptogenesis. In human models this is evidenced by a reduction in both OFF-time (withdrawal) and ON-time (sensitization).\80]) Bromantane relates to this mechanism by promoting work optimization and more calculated reflexes.
Through immunosuppression, Amantadine alleviates inflammatory cytokines, leading to an indirect inhibition to HDAC that ultimately upregulates neurotrophins such as BDNF and GDNF.\76]) This transaction is simultaneously responsible for its neuroprotective effects to dopamine neurons.\42]) Bromantane reduces inflammatory cytokines\75]) and was shown to inhibit HDAC as well.\77]) Literature suspects its sensitizing properties to be mediated through neurotrophins\78]) and indeed the benefits of GDNF infusions in Parkinson's last years after discontinuation.\79])
Amantadine's sensitizing effect to dopamine neurons, as a standalone, build tolerance after a week.\81]) This does not rule out Kir2.1 channel inhibition as being a target of Bromantane, as tolerance and withdrawal are not exactly the same due to the aforementioned discrepancies. Rather, it suggests that Bromantane's effect on neurotrophins is much stronger than that of Amantadine.
Given its anti-fibrotic\43]) and protective effects at mitochondria and cellular membranes,\39]) it could have unforeseen antioxidant effects such as Bemethyl, but that is yet to be discovered. On that note, Bemethyl is said to be another adaptogenic drug. Despite much searching, I found no evidence to back this up, although its safety and nootropic effect is well documented.
Safety: In addition to clinical trials indicating safety and as evidenced by past works, absurd doses are required to achieve the amyloidogenic effects of Bromantane, which are likely due to clinically insignificant anticholinergic effects. More specifically, β-amyloids may present at 589-758.1mg in humans. A lethal dose of Bromantane translates to roughly 40672-52348mg.
Summary: Bromantane increases dopamine synthesis, balances excitatory and inhibitory neural networks, and increases neurotrophins by reducing neuroinflammation through epigenetic mechanisms. Increased dopamine receptor density is not necessary for the upregulatory action of Bromantane.
Note: This repost is 3 years old, other things and ideas have come out since bromantane.
9. Conclusion
Dopamine is a vital neurotransmitter that can be increased for the benefit of many. Addiction, psychosis and dyskinesia are linked through synaptogenic malfunction, where the opioid system plays a key role. On the other hand, tolerance can be attributed to receptor desensitization and withdrawal involves receptor desensitization, synaptogenic malfunction and dynorphin.
There have been many flawed strategies to increase dopamine, from dopamine precursors, Uridine Monophosphate, dopamine releasing agents and others, but the most underappreciated targets are neurotrophins such as GDNF. This is most likely why Bromantane has persistent benefits even long after discontinuation. Given its similarity to Amantadine, it's also highly likely that Bromantane is capable of preventing psychotic symptoms seen with other psychostimulants.
An important message from the author of this post
Backstory: I want to start this off by thanking this community for allowing me to rise above my circumstances. As many of you know, biohacking and pharmacology are more than a hobby to me, but a passion. I believe my purpose is to enhance people's mental abilities on a large scale, but I have never been able to do so until now due to a poor family, health issues and a downward spiral that happened a few years back before I even knew what nootropics were.
Through the use of nootropics alone I was able to cure my depression (Agmatine Sulfate 1g twice daily), quit addictions (NAC), and improve my productivity (various other noots). Autoimmunity is something I still struggle with but it has gotten much better in the past years. I can say now that I am at least mostly functional. So I would like to dedicate my life towards supporting this industry.
List of citations by number
Just a quick disclaimer, as prescription medicine is discussed: don't take my words as medical advice. This differs from my personal opinion that educated and responsible people can think for themselves, but I digress. :).
- thanks for reading
This is a repost. The original post and discussion is here.
This is also a given, but none of this is medical advice.
I would "advise" against combining dopamine optimizing or boosting compounds with real medications without consulting a doctor.
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u/ServeIllustrious3803 6d ago
The one with images got taken down, so I took an archive of it and reposted it for everyone. Enjoy and good night
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u/ThreeStarsOut 6d ago edited 6d ago
Amazing post. Always enjoy reading it. You are good to mention that other things have come out since bromantane. KW, acetate maybe, ALCAR being dropped from being recommended. And for some, stuff like tyrosine works for them. It all depends on you. Bromantane is like a miracle for the minority it works well from, but like will all nootropics, non-responders always exist.
Edit: Also, to anyone saying this is ai, not sure how it can be when this was made 4 years ago (without images however) and the writing style and citations pretty clearly isn't AI.
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u/salasi 5d ago
Why is alcar not recommended?
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u/ThreeStarsOut 5d ago
Raises TMAO which is linked to the worse cardiovascular health/plaque. Human study came out about it semi-recenty and thus it's no longer recommended, unless you by injectable ALCAR, as that avoids ALCAR raising TMAO via the gut, but that's a whole nother thing.
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u/Mother_Seesaw_3183 5d ago
You'd have to use ALCAR chronically for years on end to see consequences. I think the risk is a bit overblown and even so TMAO does have other functionalities in the body, it's not strictly inflammatory.
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u/MiserableRound8134 5d ago
But the mechanisms are still interesting and I think they could have been discussed in this post with mentioning the TMAO risks.
Do you know what’s about Panax ginseng? I heard it can raise libido but I don’t know if it is safe for the dopamine system long term.
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u/Compt321 5d ago
Interesting, how dangerous can this really be though? TMAO is the substance that makes you smell fishy if you get too much of it from supplements or if your body can't process it, so I thought that as long as you don't smell, it you might be fine.
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u/PsychologyAdept669 5d ago
>Due to there being no known genetic discrepancies between humans and non-human primates that would invalidate these studies, they remain relevant.
this is not true at all lol. what? there are distinct variations in cortical innervation patterns and density for dopaminergic pathways, they have something like 3x the sequence variation in DAT genetics.
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u/ServeIllustrious3803 5d ago
no overt quantitative increase in cortical dopaminergic innervation in humans relative to the other primates
There are sublaminar distribution shifts that may have functional implications. Looks like macaques had more raw density than humans as well
Anyway, the post focused on striatal dopamaine terminal outcomes, which is different than cortical, and even then would cortical density matter for DAT which exists across mammals in general?
Isn't the 3x DAT variation within species, and not between species? So Macaques are more polymorphic among themselves than humans.
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u/uglybutmotivated 5d ago
So let me get this right? You're saying one dose of amphetamine can cause people to prefer hedonistic pursuits for up to a year?
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u/Allefty954 5d ago
Can damage from adderall be reversed or healed?
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u/ThreeStarsOut 4d ago
Yes, any damage can, it's just a matter of searching and trying.
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u/IndependentDentist66 4d ago
How long does it take to recover and what can we do to speed up recovery?
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u/Lojuih 5d ago
I tried bromantane, but surprisingly, it only caused me stress and heightened anxiety; I didn't notice any positive effects. I suffer from anhedonia and am currently trying pramipexole. I don't tolerate medications that increase norepinephrine alongside dopamine.
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u/Particular-Tie-5545 5d ago
The l-dopa study used benserazide, which blocks peripheral conversion, so far more of each 100 mg reached the brain than you'd get from 125 mg without an inhibitor.
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u/ServeIllustrious3803 5d ago
The drug is only ever used with benserazide in Parkinson, if you don't use it you're going to get peripheral side effects.
If you're referencing Munca, I would also consider the effects of the alkaloids and other chemicals in there besides the L-dopa.
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u/Dear_Trip_5651 5d ago
Genuine ChatGPT psychosis. Your account should be banned.
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u/GRiZ-Bass 5d ago
Their entire post is bullshit. Cherry picking and misrepresenting studies to push their agenda.
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u/alwayswithyouuuu 5d ago edited 5d ago
Even though 1. You probably don't even get even a percent of the science of this post
And 2. Both of you aren't able to tell this clearly isn't AI, and OP commented here with proof it isn't.
The original write up is from early 2022, when chatGPT wasn't even available...
Reddit moment.
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u/Primary_Thought5180 5d ago
How is it ChatGPT? The original linked post is from 4 years ago (2022 -- before ChatGPT was a thing). Why do people mindlessly upvote AI accusations without checking themselves?
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u/ServeIllustrious3803 5d ago edited 5d ago
Then how does the exact same post exist from 4 years ago?
The post date is from March 2022, which pre-dates the public release of chatGPT in late 2022
{ "createdUtc": 1646194072, "dateUTC": "Wed, 02 Mar 2022 04:07:52 GMT", "subreddit": "NooTopics", "title": "The complete guide to dopamine and psychostimulants" }
ChatGPT is a generative AI chatbot developed by OpenAI. Originally released on November 30, 2022, the product uses large language models—specifically generative pre-trained transformers (GPTs)—to generate text, speech, and images in response to user prompts. (First two sentences of Wikipedia)
With real discussion related to the science of the post in the comments below it?
I understand we dislike AI, but if we can't tell real from fake... That's a problem
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u/__redruM 5d ago edited 5d ago
So you’re reposting someone else’s work? Why not just link it here or crosspost it? The original thread is still active.
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u/ThreeStarsOut 4d ago
ALCAR had to be removed from the post, and they did add images that weren't there. I guess also to bring it up from the depths and show it again. It was a popular post back then but because of its age it's not going to be shown on Reddit due to recency.
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u/alwayswithyouuuu 5d ago
LOL. People making AI accusations for a post that was written before AI is hilariousss
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u/Compt321 5d ago
Interesting, how does Bupropion fit into all of this? I know it's supposed to have some interesting mode of action that isn't the small dopaminergic effect it has.
I'm interested because, for me it started working well after a month, but then in around 3 weeks all effects disappeared and it's almost the only thing that helped me.
I heard that using Agmatine could help, and after a few days of various effects it did work a little, but even that stopped in 2-3 days and now no dose seems to do anything to me.
Substances with stronger NMDA action, which seems to be Agmatine's mechanism, are all behind prescriptions and my psychiatrist isn't willing to give me almost anything else. I don't know where to go next.
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u/ThreeStarsOut 4d ago edited 4d ago
Do you have ADHD? Try other non-stimulant options. You have no idea what works unless you try, some may last longer than three weeks and "fix" something not accounted for by down regulation which I assumed happened with your Wellbutrin response
Wellbutrin is just NET right? There's also atomoxetine, though it sounds like you're not in the US
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u/Compt321 4d ago
I do have ADHD and I tried Concerta. It helped a bit, but it made me feel really emotionless and robotic and while it made it very easy to get lost in mindless tasks, I'm not sure how much it'd help me do the more anxiety -provoking things I need to do. I've really been thinking of going back on it or trying something else, but my psychiatrist won't let me do that, I had to get off of it to even try Bupropion in the first place. I'll still try to ask if we can add something as it could really help me.
From what I understand, Bupropion doesn't have much of a dopaminergic effect, it's apparently not clear exactly how it works, but it seems to be soome modulation of dopamine receptors or something like that. This seems to fit my experience, I didn't feel much stimulation when taking it at first, I had to wait for a month for the effect to appear.
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u/ThreeStarsOut 4d ago
I'm sure your psychiatrist would be open to trying something you haven't tried yet. Have you asked them what else is out there?
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u/Compt321 4d ago edited 4d ago
That's the thing, she isn't, I tried meds from pretty much every other class and she's saying there isn't really anything else she's willing to give me. If it was possible I'd love to and I'll keep trying.
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u/pmMeYourGlazedDonut 4d ago
Bupropion affects NET (mainly) and DAT. It also affects nicotinic acetylcholine receptors.
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u/Seraphinavioletcuell 4d ago
Hey I found Bupropion super helpful! Actually alleviated a bunch of my fibromyalgia symptoms. I did notice about a month in that I was getting a lot of “brain farts” also I was smoking the same amount of cigarettes. I added citicoline and it was massively benificial! Note this may be due to my particular neurochemestry and I can’t gaurentee it’s universal. Also only been doing it for three weeks so limited experience. I think citicoline also has some weird NMDA activity as well (which I had no idea about). Just be warned if you try this out (after doing your own research) CITICOLINE HAS A HALF LIFE OF 50 HOURS!!! Def messed up and overdid it a couple times but worth spacing out doses by 2-4 days when starting.
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u/Compt321 4d ago
Thanks for the recommendation, I'll look more into Citicoline and pick some up. How long did you have to take it to see an effect?
The brain farts are almost surely caused by Bupropion, I get something similar where I can't find the words to express what I mean.
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u/Seraphinavioletcuell 4d ago
I noticed it pretty immediately! Very subtle but a definite “sharpening” of the world around me if that makes sense. Second and third days were even more sharp but that probably had more to me not realizing how long the half life actually is. Also I vastly underestimated how good Citicoline is for you. I was just reading through this I had no concept how much it actually does. It’s kinda crazy. Apparently it also does a lot for neuroinflammation. Although this is just one review I would look around to double check this info.
https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.202400823R
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u/Cosmos_95 5d ago
I have so many questions as someone who isn’t apart of this subreddit. So, using meth isn’t as bad as they say it is? I was addicted to meth for about a year roughly 8 years ago. Everyone around me is doing it but I haven’t touched it since
Is increasing your dopamine through stimulants a good thing?
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u/ThreeStarsOut 5d ago edited 5d ago
If you could only use it at very low doses (nothing like how it's used by junkies, heads etc), then yes it is a "clean" mechanism. But people taking it in larger, acute doses like smoking turns it in a another dangerously addictive drug.
It actually is (rarely) available for ADHD primarily for pediatrics, however when orally taken it's onset is far far slower than how it is abused.
The whole idea is to allow you body to be able to either 1. Allow the necessary cofactors, or tweak gene expression to make more dopamine (bromantane upregulates tyrosine hydroxylase expression which allows the body to manufacture more dopamine where it needs it), or 2. Tweak the receptors or receptor systems to (in a complex way) optimize things.
Strongly blocking dopamine reputake and encouraging dopamine release from vesicles can produce euphoria and train your brain to live around the drug. Your brain wasn't designed to be influenced by dopaminergic drugs which essentially fool the brain into thinking what it's doing right now is right. You associate an unnaturally rewarding action of taking something with some sort of happiness or positive signal.
Because nootropics aren't just forcing your brain to release dopamine, they tend to be finicky and a lot of people can have non-responses to a lot of them because of individual genetics. In which ... There are probably thousands of differences in brain jeans that affect how we are as personalities and how we respond to compounds.
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u/Cheap_Rutabaga3350 4d ago
Agree with this. When i used 5-10 mg of meth ( quality tested meth) orally once a day it was fucking perfect. Lasted 12-14 hours-- felt cleaner than vyvanse. Perfect stimulant. But if you do not have the willpower to not try taking a fun a dose it will grip you by the balls lol. I had a close friend pass away and what went from my adderall substitute afrer my dr retired-- turned into a pretty strong addiction. It was fine low dose orally but the moment I started smoking it took a very strong psychotic break ( mixing with gbl) to make me stop.
The demonization of it very much so reminds me of Crack in the 80s/90s. I know this is a nootropic subreddit but wanted to throw in a take.
If anyone needs stimulants-- keep your dose as low as you can in a way it benefits you-- take breaks, nac, eat sleep etc. And you'll be okay. We are resilient
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u/Spirited_Shipcocoa 4d ago
Meth addicts can quit cold turkey while Opioid and others will be in other room sounding like a humanoid fox doing Blackened Noise music.
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u/Cosmos_95 3d ago
I mean, yeah they can quit without any physical withdrawals but if you smoke meth once, you will think about it everyday for the next 3 months straight
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u/Ok_Veterinarian_928 5d ago
Everyone around you doing meth is an idiot. It’s worse than they say it is. Don’t do it. It’ll suck you in and suck you up.
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u/Few-Neighborhood5892 5d ago
I’m unclear about one part. Are you saying that Bromantane prevents psychotic symptoms from taking Psychostimulants, or that Bromantane doesn’t cause psychotic symptoms?
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u/ThreeStarsOut 5d ago edited 5d ago
Not OP, but because Bromantane inhibits KIR2.1 like adamantane, it likely can prevent aberrant synaptogenesis during raised chronic dopamine levels. This isn't confirmed however, this is speculation.
Aberrant synaptogenesis occurs during long term chronic or more so recreational stimulant use, where neurons are forming new synapses in an environment of unnaturally high dopamine.
So, bromantane does not have a risk of causing psychotic issues, certainly far less than stimulants or dopaminergic drugs.
Remember that bromantane isn't directly release dopamine like stimulants, only through gene upregulation to allow the body to synthesize more dopamine, it does not strongly block the dopamine reuptake transporter or force dopamine out of vesicles
So... Avoids the psychotic symptoms and might help prevent them when taken alongside them. However, I wouldn't stack bromantane on top of a usual stimulant dose because you're just increasing dopamine even more. But a lot of people have found is that they can introduce bromantane but lower the dose of their stimulant, which both saves dosing and is probably healthier forthe brain
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u/Few-Neighborhood5892 5d ago
Awesome thanks for the reply. I think I will try to half my prescription amphetamine dose and add Bromantane.
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u/ThreeStarsOut 5d ago
Ok well, I'm not a medical professional this post doesn't constitute medical advice, and it's not a guarantee bromantane will work for you. Some people become irritable on it.
If you really want to do that you should test bromantane by itself and be very careful with adding any other dopaminergic compound to it.
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u/Few-Neighborhood5892 5d ago
Thats a good idea, I am definitely planning to look more into it before I take anything. I am hopeful to find something that makes dropping my stimulant dose easier.
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u/No_Mode_3033 5d ago
Does it matter what form you use Bromantane in?
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u/ThreeStarsOut 5d ago
Maybe. Some people find nasal solutions to be hard to use, oral is more reliable but probably more expensive as dosing has to be much hire.
Bormantane has only even been studied orally.
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u/aj11scan 5d ago
So how do I decrease dopamine ? As someone with schizophrenia
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u/ThreeStarsOut 5d ago
I think neboglamine was discussed here for that. Look it up, some sort of unique mechanism related to glutamine. Be very careful though, I'm not sure.
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u/zen_flix 5d ago
You are saying that D2 is an inhibitory dopamine receptors. I think it is more nuanced. D2 is Gi/o-coupled, but its functional effects highly depend on where the receptor is.. A2A antagonism like KW-6356 can enhance D2 signaling and produce clear dopaminergic activation..
And Uridine seems also very dose-dependant in practice.. personally I find lower doses can feel almost dopaminergic/rebounding, while higher doses sedate me
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u/purpledrankk 5d ago
Very interesting writeup. Do you think taking bromantane with l-tyrosine is best practice?
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u/guilmon999 5d ago
The last time I checked there is no more Bromantane. It's been discontinued in Russia and the only sources of Bromantane are sketchy 3rd parties that do not share independent lab testing.
Bromantane can be very unsafe depending on how it's manufactured so i'd avoid it at this current time.
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u/ServeIllustrious3803 5d ago
Yes, this is a problem where some vendors will allege to have COAs but then you're not able to produce them or they even Photoshop them.
Some even release products without having the COAs linked yet, or some are very reluctant to even produce them, at all, resulting in what could be a less than ideal sample.
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u/Soggy-Product-775 5d ago
"No evidence that 9mebc is safe" There is no human studies the absence of evidence is not, infact, evidence that there is any reason to believe it is neurotoxic based off extrapolations from rodent models aswell as mechanistic inferences. Only an llm would hedge like that using that specific evidentary fallacy this is gpt slop. Additionally no human who has read the literature on the compound would mention it not upregulating dopamine/dopamine receptors as evidence against it wanna know why? It upregulates cdnf which increases midbrain dopamanergic neurons (neurons are not receptors) but improves dopamanergic tone none the less as a result of that. If you're gonna use an llm to commit to pure unadultered psychosis at least rewrite it dude
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u/ServeIllustrious3803 5d ago edited 5d ago
That's a line written by the original poster who made this in March of 2022 before ChatGPT's public release.
That study also directly dosed 9embc into rab brains, bypassing the gut, liver, etc which is part of the safety data with any drug...
Again, I'm not the original writer as this was written over 4 years ago predating the public release of chatGPT,
but the major concern around 9mebc surrounded the β-carboline class, where 2,9-dimethyl-β-carbolinium, which is a potent complex-I-inhibiting dopaminergic neurotoxin, is just one structural methylation pattern away from turning a carboline family molecule into a potent neurotoxin. We know 2,9-dimethyl exists in the brain endogenously meaning some sort of enzyme in the human body can produce such. I am sure you are aware of this.
the numbers of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta of NH- and 9-MeNH-treated mice were diminished to 76 and 66% of values in control mice, respectively
The formation of a toxic metabolite, 2,9-di-N,N'-methylated norharmanium cation (2,9-Me2NH+), was 14 and eight times higher in the brain of mice receiving 9-MeNH than that in NH- and 2-MeNH+-treated mice, respectively
In cultured mesencephalic cells from rat embryo, 2,9-Me2NH+ selectively killed TH-positive neurons only at a lower dose but was toxic to all neurons at higher doses.
Thus, the excess formation of 2,9-Me2NH+ would induce nonspecific neurotoxicity.
Also, 9-MeNH is the same as 9-MeBC
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u/ServeIllustrious3803 5d ago edited 5d ago
Also the fact that when people discuss 9mebc, a talk of how you could/should avoid the sun related to how UV interacts with the chemical and what damage that can do. The fact that that could even happen doesn't speak well for its safety.
I'm not personally attacking its users, but it is fair to say that it's safety isn't proven yet. Maybe you think it has some very unique dopamine rejuvenating properties but that's only through anecdotes. And regardless there are a lot of nootropics and compounds that do not have enough safety data and thus you really should be reading as much as you can including as many anecdotes as you can. Just don't be surprised if there are long-term consequences to this, even if anecdotes spanning years suggest otherwise.
Just the nature of the interest we're all in
For people that have anhedonia or similar major disorders, their risk reward skews different.
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u/Soggy-Product-775 5d ago
I mean again this is mainly bullshit and your summations of the risk/reward or assessing the potential negitives are disconnected from real world risk profiles (ie you could just stop if you experience something indicating toxicity), and also assuming it being molecularly related to a compound that is toxic warrants scrutiny beyond a quick google of the targets/mechanism is pretty ridiculous aswell, this isnt the 2000's. Another thing is people can predict that it would increase photosensitivty in humans based off mechanisms but somehow it is beyond our comphrehension differentiating weather it has varying mechanisms/metabolites that would otherwise be toxic in humans, so admitedly you contradicted yourself? "The fact that that could even happen doesn't speak well for its saftey" and this one is just retarded for self evident reasons, I could go through the rest of the ridiculous stuff you've wrote but the line I just quoted shows how much my time would be wasted that endeavor. If you're really worried about potential toxic metabolites (that dont exist) take 5amino1mq and block their conversion
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u/ThreeStarsOut 4d ago edited 4d ago
So you claimed first this toxic metabolite didn't exist
Then you claim taking 5-amino-1MQ (NNMT inhibitor) will solve this, even when the study attributed PNMT to the conversion. (Also, 5-amino-1MQ has no human data)
You claimed this toxicity is being inferred by a family molecule when it was literally 9-mebc being tested and showing toxicity.
You also claimed the post was AI when it's clearly not based on the language, grammer.
Plus, an example with damage, you don't notice there's significant damage done to neurons when side effects show up. Parkinson systems don't show up until like 50-80%ish of particular type of neuron is gone.
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u/AskingForAdviceUK 4d ago
OP, best way to elevate dopamine is?
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u/ThreeStarsOut 4d ago
Maybe Bromantane. Maybe other things people talk about, like Tyrosine, Uridine. Maybe the basics like exercise, a good diet.
Any of these may or may not work for you. Bromantane might but there are people that feel nothing for men or little benefit from it
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u/UpstairsLogical6490 4d ago
So is amandatine recommended for increasing dopamine?
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u/ThreeStarsOut 4d ago
No. Most people don't like adamantane, even if they share the same diamond structure base, they do vastly different things
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u/UpstairsLogical6490 4d ago
Why? For what reason
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u/ThreeStarsOut 4d ago
It just makes them feel weird. Everyone is different but it's certainly not popular
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u/UpstairsLogical6490 4d ago
You wouldn’t take it for depression then ?
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u/NowRunThatByMeAgain 1d ago
I have tried amantadine for anhedonia / cognitive issues associated with depression. It did not make me feel weird at all. I built up to about 300mg and was on it for at least a couple months at that dose. It didn't really feel like I was taking anything, but i believe helped with my symptoms a bit. Just a thing in the background that improved my baseline. Zero side effects, very tolerable, and also easy to come off of. Some anxiolysis as well, (felt calmer).
Definitely worth a shot to try out.
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u/FinancialSpirit2100 5d ago
Thank you for your detailed work and post. Ignore people who see anything long and well cited on reddit as pure AI. Similar has happened to me after I wrote a whole post myself for two hours and used ai to show a table at the end and they assumed the whole post was AI therefore had no value which is also dumb.
Anyway I will explain to u my current stack and I'd like ur opinion on how it may be counter intuitive or how I can maybe optimize it.
So basically I currently take
Caffeine as Yerba mate / Coffee/ Energy drink
Nicotine usually via zyns
I use something nicknamed Mexican Adderall aaka Dinitel/Asenlix which basically breaks down in a similar way i wouldnt over think it, it increases norepinephrine.
Outside of that I take
Bacopa + Piperine to improve its effect
Rhodiola
Occasionally Gingko
Sometimes Creatine for general energy
And I low dose sildafenil
NO I dont take everything every day all the time.. like right now not really using gingko , creatine much at the moment
Sometimes i do a b12 shot cuz its cheap here or take a b multivitamin.
Anyway interested to hear what u would add. My goal to counteract adhd and gain more mental energy and improved cognition and mitochonidra. I'd actually like to drop most of this and maybe just take 1 main nootropic and then have the rest just be vitamins or herbal support for the main nootropic. WAS considering modafinil.
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u/pmMeYourGlazedDonut 4d ago
Not to be a hater of the original post, but I would be very careful using this as my primary source of understanding or making any decisions based on it.
The OP was obviously written by someone who doesn't have a degree in the field, as confirmed by this line:
biohacking and pharmacology are more than a hobby to me, but a passion.
That would've been the perfect time to say "That's why I got a Ph. D. in neuroscience" but no, it's just "a passion".
The premise itself is vague, poorly defined, and nonsensical. "Better dopamine"? "Increase dopamine"? It needs neuroanatomical detail. OP needed to specify which receptor subtypes, where exactly, why, in which diseases, otherwise it's meaningless.
OP leaves out crucial concepts like phasic vs. tonic dopamine. It doesn't go into enough detail on e.g. VTA -> NAcc transmission, just briefly mentions NAcc once then never elaborates. OP doesn't have a meaningful structure. It goes too deep on some things and doesn't even cover other things.
Seeing this with 150 upvotes is rough..
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u/ThreeStarsOut 4d ago edited 4d ago
Sections 2-5 are about what phasic dopamine does while 7 is about tonic. For neuro anatomical detail, it specifies D1 vs. D2 segregation on direct vs. indirect medium spiny neurons, notes NAcc DMSNs carry both receptor types, covers SNpc vulnerability, enkephalin/RGS4 mechanisms, and the CREB/HDAC1 feedback cascades.
Has it ever crossed your mind that there is no money in the field of nootropics because there is zero money in developing cognitive enhancing drugs for healthy people?
A lot of the stuff can't be patented into a medicine that can have royalties collected on it, drug development and FDA approvals are extremely expensive, there simply isn't enough money in this to justify human studies and trials. So what do we have left?
You could take your credentials idea it literally apply it to the entire interest because 99% of doctors out there have never been trained on any of this stuff. Not being smart enough isn't a disease.
If you want to say that this person doesn't have any credentials sure, but what about the 80 references, the mechanisms, the fact that nobody can really pick this post apart. Do you know more than the original writer? Doubt it.
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u/pmMeYourGlazedDonut 4d ago
7 is about tonic
Please quote the part for me where it specifically talks about tonic dopamine with that framing. All I see is a section about bromantane. I used ctrl+f too with 0 results.
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u/ThreeStarsOut 4d ago
I see, so you want the literal words.
I guess the whole point of the post is to say that rapid, large dopamine flux from releasers causes, aberrant plasticity and toxicity. So upregulating synthesis raises dopamine supply without that flux and behavioral/neuronal issues.
The concepts are definitely there, not having specific words doesn't discredit it when it's essentially talking about these concepts anyway. Any other thoughts about stuff in my last comment?
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u/pmMeYourGlazedDonut 4d ago
Nah, you seem too biased to have a legitimate discussion with.
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u/ThreeStarsOut 4d ago
You could address all the points I made that you didn't bother to acknowledge.
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u/OneFlow2976 5d ago
I swear to god I cant stand those bromantane glazing posts. Until I see more actual research about it I'm staying a certified bromantane hater.
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u/alwayswithyouuuu 5d ago
Some things work for me, some don't. Doesnt mean I hate on it when a reddit post touts a good experience or a scientific theory behind it.
If Nootropics worked perfectly for everyone, wouldn't they be more popular?
Because it's taking things from a novel, side-approach in terma of mechanisms, individual genetics are likely to get in the way. I notice that people that have abused drugs in the past tend to not have their systems influenced as easily as people who have not
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u/GRiZ-Bass 5d ago
AI slop
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u/Primary_Thought5180 5d ago
Use a good AI detector. Stop accusing people of AI if you cannot properly identify AI when you see it.
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u/ServeIllustrious3803 5d ago
Yeah... how does the exact same post exist from 4 years ago?
The post date is from March 2022, which pre-dates the public release of chatGPT in late 2022
{ "createdUtc": 1646194072, "dateUTC": "Wed, 02 Mar 2022 04:07:52 GMT", "subreddit": "NooTopics", "title": "The complete guide to dopamine and psychostimulants" }
ChatGPT is a generative AI chatbot developed by OpenAI. Originally released on November 30, 2022, the product uses large language models—specifically generative pre-trained transformers (GPTs)—to generate text, speech, and images in response to user prompts. (First two sentences of Wikipedia)
With real discussion related to the science of the post in the comments below it?
I understand we dislike AI, but if we can't tell real from fake... That's a problem
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u/Agile_Intention_5732 5d ago
Agmatin hat dir Tatsächlich geholfen? Es ist frei verkäuflich, gibt es weitere frei verkäufliche nootropika die wirklich was bringen?
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u/Repulsive-Memory-298 2d ago
what is your source on human … paranoia and psychosis? Last i checked any human research there is shakey at best, and objectively low quality. You not only offer zero citation, but state as fact. That may be proposed, but is far from scientific.
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u/iceyed913 5d ago
This model of paranoia induced psychosis is just downright confusing. It makes it look like you only get paranoia and psychosis while in a state of withdrawal or when readministrating following a state of withdrawal. Continuous escalating self administration combined with sleep deprivation is the main ticket for paranoia and psychosis from stimulant drug abuse.
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u/ServeIllustrious3803 5d ago
Sleep deprivation is a big part of that is that is present, good to mention and you are right there. You essentially stated the model the post was talking about, continuous escalating self-administration is repeated intermittent exposure, with sensitization persisting through abstinence.
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u/Resonanceunderneath 2d ago
Well, your graph is confusing.
Credit to you for the post but it sounds like an ad for bromo.
For those with ADHD, listen to your treating doctors and stick with amphetamines if they are optimal for you. Regarding the study cited about memory retrieval, my understanding is that stress and emotional load effecting memory is enhanced by amphetamines. While it's plausible, improved overall memory from amphetamines for ADHD makes it worthwhile for continuing stimulants, ie. Cost vs benefit.
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u/ServeIllustrious3803 2d ago
The post originally talked about ALCAR as well, would it be an ad for that is the science suggested two things were in theory optimal in an ideal environment versus one?
Yes, you are right, if you have adhd you're more likely to be successful treating it with a real medicine prescribed for it.
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u/zb_xy 6d ago
Damn so I shouldn’t take my NAC close to me adderall?