3 replies to this topic

[Sirsadalot]

Increasing dopamine without tolerance or addiction:

Hey guys. I've been hoarding all this information for the past year, and I think it's time I release it to the public. Bromantane and ALCAR are the most promising dopaminergics on the market, and this post will explain why.

For those of you confused about dopamine:

To put it simply, it's the motivating neurotransmitter. And this bleeds into things such as optimism, confidence, social interaction, mood, learning etc. It would take 10 posts to go over everything dopamine does, so hopefully you accept the generalization.

Here's a simplified version of the dopamine/ CREB cascade:

Dopamine --> D1 activation --> Adenylate Cyclase --> Cyclic Adenosine Monophosphate (cAMP) production --> Protein Kinase A --> CREB (key factor in learning and memory) --> (ΔFosB --> inhibits C-Fos), Dynorphin (inhibits dopamine release), (Tyrosine Hydroxylase activation --> more dopamine), and so much more.

Your idea of dopamine receptor upregulation may be wrong.

So many things are said to "upregulate dopamine receptors", but what does that truly mean? Well it's not so simple. Usually receptor upregulation just hints at temporarily lowered neurotransmitter causing increased sensitivity to maintain homeostasis. So keep that in mind when discussing Uridine. This source for instance. Or Sulbutiamine. So besides Uridine being GABAergic, that has to be part of Nootropic Depot's motivation to include it in the sleep support stack. Reviews are mixed, but I felt sedated by Uridine Monophosphate.

Cocaine upregulates dopamine receptors. And I'll reference this study later. But basically the transition of CREB to ΔFosB and Dynorphin, leading to a depletion of CREB and dopamine is evidence of tolerance to cocaine. So looking at receptors alone is SIMPLISTIC, especially when you consider receptor the inhibitory role of D2 receptors which people here misconceive to be a good thing. It's almost as simplistic as assuming Tyrosine Hydroxylase upregulation is why Bromantane is so great, which is one of many misconceptions I had when I wrote this post. It's the mechanism that makes it great, not just downstream activity.

And by the way, 9-Me-BC still has no safety data at all, nor is it truly proven to sensitize the brain to dopamine after discontinuation. It's a neurogenic with MAOI properties, and that would basically explain the anecdotes. But receptor upregulation and sensitization is up for debate.

I still believe L-Tyrosine, L-Phenylalanine and DLPA are useless for dopamine biosynthesis.

Revert to the old post for more evidence. But these can be used for thyroid hormone production surely, or if one is L-Phenylalanine deficient or otherwise metabolically impaired. Which is rare.

Fun fact about DLPA: D-Phenylalanine is like the "anti" L-Phenylalanine. Enkephalin inhibits dopamine synthesis, and like I expressed in my former post, adding more of the building block means nothing if you don't upregulate this enzyme. And L-Phenylalanine has no trouble converting to L-Tyrosine. The addition of L-Phenylalanine, however, prevents the weight loss seen with D-Phenylalanine.

Bromantane, ALCAR and Histone deacetylase (HDAC)

Relating back to ΔFosB, one interesting thing I found is that ΔFosB mediates dopamine desensitization through some dopaminergic drugs by recruiting Histone Deacetylase 1 to C-Fos thus decreasing its mRNA, and C-Fos is a transcription factor necessary for dopamine's effects. This also supports some things I've said in the past about Methylphenidate possessing less withdrawal than adderall, as it appears to suppress C-Fos less. C-Fos mediates neuronal plasticity, whereas ΔFosB decreases plasticity, so the loss of C-Fos means that the reward circuit for dopaminergics would become ingrained and resistant to updating. ΔFosB leads to CDK5 which upregulates D1 and downregulates inhibitory D2 receptors. This explains the upregulation of D1 from Cocaine, despite the withdrawal from other factors. But it doesn't explain sensitization from Bromantane and ALCAR, which I will explain now.

ALCAR is a true dopamine sensitizing agent.

In relation to ΔFosB, ALCAR donates acetyl groups to deacetylated proteins which acts similar to a HDAC inhibitor (HDACI). ALCAR increases BDNF and therefore ERK1/2 (a slow transcription factor) and through that may upregulate D1. This is supported by this source and this source displaying a D1 upregulation beyond baseline, with no changes to D2 receptor density. This upregulation of D1 activity leads to a continuation of PKA --> CREB activation and thus and positive feedback loop with DARPP-32, phosphorylating it at Thr34 over Thr75, when Thr75 phosphorylation inhibits PKA as evidenced here resulting in a tyrosine hydroxylase upregulation and upregulated dopamine output long-term with no tolerance as ALCAR doesn't ΔFosB and so CDK5, and therefore upregulates D1 differently than cocaine.

Now I'd like to dispell some rumors about ALCAR. It is safe. There isn't anything proving it upregulates TMAO, which isn't healthy, however it may be hydrolyzed to L-Carnitine and SCFA by the esterase HocS (hydrolase of O-acylcarnitine, short-chains) and there's some evidence that L-Carnitine increases TMAO such as this and this. But if you're a hypochondriac, and let's be honest we all are at times, fish oil may prevent this and you should probably be taking that anyways for the health benefits. And ALCAR was well tolerated in a trial consisting of 358 Alzheimer's patients.

If you want more advice on ALCAR, it appears to have dose-dependent effects on anxiety and saturates the mitochondria at just 1500, and I discuss that more in my oral bioavailability post. I believe there was another post on ALCAR and anxiety saying 500mg or 1000mg either decreased or increased anxiety, however I can't find it anymore.

Bromantane is a true dopamine sensitizing agent.

You know me... I'm the Bromantane guy. But that's because Bromantane is not only an effective mild stimulant, but it's safe and comes with virtually no withdrawal or addiction. Now I'm just going to quote the wikipedia here directly, but not link the wikipedia because organizations have been tampering with nootropics pages (Piracetam and as someone else recently mentioned Curcumin).

Clinical success: 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. The therapeutic benefit against asthenia was notably observed to still be present one-month after discontinuation of the drug, indicating long-lasting positive effects of bromantane. Source.

Atypical mechanisms: Bromantane acts via indirect genomic mechanisms to produce a rapid, pronounced, and long-lasting upregulation in a variety of brain regions of the expression of tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AAAD), key enzymes in the dopamine biosynthesis pathway.[10][18][19] For instance, a single dose of bromantane produces a 2- to 2.5-fold increase in TH expression in the rat hypothalamus 1.5- to 2-hours post-administration.[20] The biosynthesis and release of dopamine subsequently increase in close correlation with TH and AAAD upregulation.[10][18][19]

No tolerance or addiction: As such, bromantane has few to no side effects (including peripheral sympathomimetic effects and hyperstimulation), does not seem to produce tolerance or dependence, does not show withdrawal symptoms upon discontinuation, and displays an absence of addiction potential, all of which are quite contrary to typical psychostimulants.[1][9] In accordance with human findings, animals exposed to bromantane for extended periods of time do not appear to develop tolerance or dependence either.[22]

Bromantane's real mechanism of action: What they don't mention here is that Bromantane is a HDACI. But let's not make any blanket statements about HDACIs here, as they vary greatly in terms of end results. Some are even toxic and have many side effects. Rather, it seems as though Bromantane is unique in that it is simultaneously a HDACI and safe. And although this is my own conclusion, this paper suggests the increase in striatum BDNF and following ERK1/2 expression underlies Bromantane's long-term dopaminergic effects. I believe Bromantane, through HDAC inhibition, suppresses ΔFosB and upregulates D1 through ERK1/2, leading to higher dopamine sensitivity over time. This would also explain the lack of withdrawal and addiction.

The beta amyloid/ alzheimer's scare: Relating to the 10-fold increase in Beta Amyloid, this is only seen at 50mg/kg in rats. So roughly ~3237mg according to the allometric scaling calculator. The standard dose of Bromantane is 50-100mg. It's likely irrelevant at these doses. And human studies suggest it is a very safe drug.

I'd like to bring light to something not well understood about Bromantane, and that is its ability to improve sleeping patterns:

Bromantane was also noted to normalize the sleep-wake cycle. The authors concluded that "[Bromantane] in daily dose from 50 to 100 mg is a highly effective, well-tolerated and [safe] drug with a wide spectrum of clinical effects. Therefore, this drug could be recommended for treatment of asthenic disorders in neurological practice." Source.

AAAD is the second enzyme for melatonin synthesis, melatonin induces enkephalin synthesis and release and Carboxypeptidase E is found upregulated by Bromantane. This also shines some light on B6's involvement in ZMA (it upregulates AAAD) and AAAD's apparent synchrony with the sleep-wake cycle. My hypothesis is confirmed by this source. Additionally, Bromantane is a GABA reuptake inhibitor at GT3, meaning GABA is increased by Bromantane, adding to its anxiolytic effects.

So while Bromantane is stimulating, in many ways it is inhibitory. Piracetam may counteract some of the GABAergic mechanisms of Bromantane, but make sure to take 4-8g. One interesting take is Pemoline for the purpose of AAAD inhibition to counteract the melatonin increase.

Pemoline is a mysterious, possible dopamine sensitizing agent... And great for ADHD?

Pemoline is a controversial drug, but it's reasonable to assume it was wrongfully banned by the FDA. As this study suggests, it is well known for being free of addiction and withdrawal (though I haven't investigated why, as there's no incentive so long as it's outlawed). Its mechanism has been a mystery, but research disproves the possibility of it being a catecholamine reuptake inhibitor and instead suggests it is an AAAD inhibitor. This would be consistent with the atypical responses and higher dopamine in the frontal lobe.

Furthermore this helps explain its use in treating ADHD, as beyond its dopaminergic effects, melatonin was seen upregulated in children with ADHD.

To those entertaining the claims that it's liver toxic, I question the significance. Accordingly only 1-3% of children developed abnormally high liver enzymes. And in one study enzymes recover afterwards. In the 21 years it was prescribed as a prescription drug, only 9 deaths were reported. Of those deaths 4 of them were taking other prescription drugs, and one was an overdose which seems absurd given how difficult that would be dose-wise.

Cyclazodone is a Pemoline derivative, but requires much more evidence and should demonstrate likeness to Pemoline before use.

PKC's link to dynorphin and my failed experiment.

When looking into Bromantane's pharmacology I considered dynorphin reduction as a possible mechanism. For a while I was convinced it played a role due to dynorphin's role in addiction and dependence, as well as connection to CREB.

I learned that PC2 causes dynorphin biosynthesis. That PKCδ increases PC2 and inhibition of PKCδ upregulated Tyrosine Hydroxylase for days as opposed to minutes like CREB. Later direct links between PKC and dynorphin. There's studies showing PKCδ inhibition mimicks the dopaminergic activity of alcohol without causing a dependency. And more.

Naturally I searched for a PKCδ inhibitor, analyzing a ton of herbs in the process, but failed to find any redeemable options. I decided to order Rottlerin, or its parent herb "Kamala", where I opted to perform my first chemistry experiment - an extraction of Rottlerin using ethanol and ethyl acetate. After staining many valuable things with this extreme red dye, I eventually produced powdered rottlerin. After using it a few times and getting no perceivable benefit, I decided it was a lost cause due to the questionable safety profile of this chemical. My friend also made a strong tea from the known nonselective PKC inhibitor Black Horehound, and claimed it produced psychedelic-like effects. Nonselective PKC inhibitors also have antipsychotic effects.

TL;DR?

Bromantane and ALCAR are the best substances available for dopamine upregulation. Also I really want to get into the supplement industry, or something involving science, so please message me if you have an opportunity for me. Currently looking for work. Thanks.

- Sirsadalot

 

[BlueSkies]

** BUMP **

[frederickson]

Another bump for any thoughts on this well-articulated approach...

[gamesguru]

Before accepting that "Bromantane and ALCAR are the best" I would need to know this were true, i.e. we rule out the possibility that there are no better options.

But correcting dopamine is a hotly debated issue, asking a variety of practitioners would result in a variety of answers.  Depending with whom you consult, you could end up with a wildly different set of solutions.

 

 

ALCAR afaik only corrects the age-related dopamine decline, which affects risk taking and reward, and you can read more about here^[1] and here^[2].  For someone under 40 it likely has little to no benefit.

ALCAR doesn't always reduce anxiety, in fact it often makes it worse.  There is little to no indication of dosing in your post, and this is a potentially important matter to resolve before advocating use.

Upgregulating TH is also a double-edged sword. Lots of things in that boat.. epidemii^[3], CBD, Nobiletin (from citrus). However, many have reports of tolerance and none has emerged as an effective ADHD or addiction treatment option.  I would need to know the reason bromantane is an exception to this, or if there are any other secondary mechanisms which could contribute to an exemplary effect.

 

 

 

There are other options to consider as well.

 

Any partial agonist at D2 will have some benefit in displacing the more potent dopamine and therefore in boosting receptor levels and baseline activity, probably the foremost today is CBD^[4].  Such partial agonists have shown benefits in treating addiction, schizophrenia and anxiety.  ADHD-specific studies are lacking.

Phenylalanine can be supplemented modestly at 500-1000 mg daily, between meals.  It's an essential amino acid and a precursor, being converted first to tyrosine and finally dopamine (similar to tryptophan -> 5-HTP -> serotonin).

Ginkgo has shown pretty consistent effects with increasing dopamine and acetylcholine in the prefrontal cortex, an area commonly associated with working memory, executive control and ADHD-dysfunction.  Taking it has also shown some effectiveness in treating childhood ADHD & schizophrenia, disorders commonly associated with dopamine and glutamate dysfunction.

Exercise, meditation, partaking of an ongoing education, and cultivating an active social life— many things are sure to enhance one's appreciation and satisfaction with life, and to help achieve a more normal state of being.

 

The preoccupation to think in purely pharmacologic terms often distracts from the inquiry as a whole, and unfairly simplifies life factors and expectations of effect which may have a powerful and mysterious influence all their own.  I've learned not to take my experiments too seriously; to be patient and discerning; not to rush conclusions, and not to neglect external factors (or my own biases) in the analysis.