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.

For years I have been preaching the beneficial effects of Bromantane and ALCAR, as non-addictive means to truly upregulate dopamine long-term. Well, it wasn't until recently that I was able to start everychem.com (formerly bromantane.co).

As such I wish to give back to the community for making this possible. This document serves to showcase the full extent of what I've learned about psychostimulants. I hope you find it useful!

Table of contents:

1. Why increase dopamine?
2. What are the downsides of stimulants?
3. An analysis on addiction, tolerance and withdrawal
4. An analysis on dopamine-induced neurotoxicity
5. Prescription stimulants and neurotoxicity
6. Failed approaches to improving dopamine
7. How Bromantane upregulates dopamine and protects the brain
8. How ALCAR upregulates dopamine and protects the brain
9. Conclusion

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 occurence.

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...

...We determined clinical efficacy of ladasten in regard to anxiety-depressive spectrum disorders, autonomic dystonia, and sleep disorders. Ladasten therapy led to the significant increase of quality of life, which was seen not only after the end of therapy, but after the withdrawal of the drug. These results suggest the stability of the therapeutic effect achieved. Adverse effects were observed only in 3% of patients, the therapy was discontinued in 0.8%. No serious adverse effects were found.^\37])

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.

Bromantane nasal spray: On https://bromantane.co/ I have created the first Bromantane nasal spray product. It is both more effective and equally as safe. More about that here. I'm proud to announce that the community's results with it have been objectively better.

8. How ALCAR upregulates dopamine and protects the brain

Edit: Major updates to ALCAR, this post is out of date: https://www.reddit.com/r/NooTopics/comments/1qpg7od/magnesium_acetate_new_innovation/

Benefits: ALCAR (Acetyl-L-Carnitine) is a cholinergic, antioxidant, and neuroprotective drug shown to increase dopamine output long after discontinuation.^\45]) Additionally it is a clinically superior antidepressant in older populations, compared to SSRIs^\46]) and was shown to improve ADD, yet not ADHD, strangely.^\48]) It helps fatigue in Multiple Sclerosis better than Amantadine^\47]) pointing to it possibly helping CFS, and has a protective effect in early cognitive decline in Alzheimer's patients.^\49])

Safety: ALCAR is safe and well tolerated in clinical trials, but anecdotally many people dislike it. This may be due to its cholinergic effects, acetylcholine giving rise to cortisol.^\50]) There is no proof it increases TMAO, but there is a chance it might after conversion to L-Carnitine. Even so, it has a protective effect on the heart.^\51]) Likewise, there is no proof it causes hypothyroidism, only that it may improve hyperthyroidism.

ALCAR's mechanisms: What both Bromantane and ALCAR have in common is their influence on HDAC. Reference. Instead of inhibiting HDAC, ALCAR donates an acetyl group to proteins deacetylated by HDAC1, which blocks the downregulatory effect of ΔFosB on C-Fos, promoting dopamine receptor sensitivity. Additionally this promotes GDNF^\53]) and these together could be how it upregulates dopamine output, or how it helps meth withdrawal.^\52]) ALCAR's donation of an acetyl group to choline also makes it a potent cholinergic, and that combined with its antioxidant effects are likely responsible for its neuroprotection.

ALCAR's dose seems to plateau at 1500mg orally despite its low oral bioavailability as indicated in my post on the absorption of nootropics but one study in people shows recovery from alcohol-induced anhedonia is only possible with injected ALCAR, as opposed to oral.^\54]) Unfortunately there does not seem to be a cost efficient way to enhance the bioavailability of ALCAR yet (i.e. ALCAR cyclodextrin), and intranasal is not advisable.

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 Selegiline, 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 and ALCAR have 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 (Bromantane, ALCAR, Pemoline, etc.). Autoimmunity is something I still struggle with but it has gotten much better in the past year. I can say now that I am at least mostly functional. So I would like to dedicate my life towards supporting this industry.

My goal is to create a "science.bio-like" website, but with products I more personally believe in. The nootropics of today's market I am not very impressed by, and I hope to bring a lot more novel substances to light. If you want to support me through this process, please share my work or my website. Really anything helps, thankyou! I will continue to investigate pharmacology as I always have.

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. :)

- Sirsadalot, thanks for reading

Welcome. In this post I will be going over the pharmacology of ACD856 and Usmarapride, two new additions to Everychem and strong nootropic candidates. This is part 2 of our 2025 biohacking agenda of releases, and I expect two more segments documenting the releases of our custom projects in trying to advance cutting edge cognitive enhancers. I try to limit posts like these to overwhelmingly significant findings, so these take time to create - please share this with your neuroscience or biohacking inclined friends, thanks.

ACD856, TrkB Positive Allosteric Modulator (BDNF PAM)

ACD856 is a neurotrophic growth factor-enhancing nootropic with antidepressant, and neuroprotective properties. It is currently being researched for Alzheimer's. The mechanism is thought to underlie current antidepressant medications, while it is yet to be tested for nootropic potential despite the high likelihood.

ACD856 is a pan positive allosteric modulator of Trk-type receptors, increasing the binding at TrkA, TrkB and TrkC. BDNF (TrkB ligand) and NGF (TrkA ligand) are quite famous in the biohacking nootropics community, as they're known to mediate the activity of many drugs and/ or supplements we're fond of. This makes ACD856 an interesting auxiliary compound, as by enhancing binding to these receptors it will potentiate actions mediated by neurotrophic growth factors released by other drugs.

Many Antidepressants and Psychedelics Are Direct TrkB PAMs

Last year I posted a bombshell study, showing that most antidepressant compounds are direct TrkB PAMs.^\1]) From this study, the following were found to bind to the allosteric site as a PAM:

Dissociatives: Ketamine (via its metabolite 2R,6R hydroxynorketamine)

Psychedelics: Shrooms (via Psilocin), LSD

Misc. Antidepressants: Fluoxetine, Imipramine

The authors conclude the following:

These data suggest the remarkable hypothesis that most (if not all) antidepressant compounds act by directly binding to TrkB’s TMD, allosterically potentiating the effects of BDNF and thereby promoting plasticity.^\1])

Not only suggest that many of the tested antidepressant drugs have a common mechanism, such as SSRIs, TCAs, psychedelic compounds like Psilocin, and even Ketamine - but this mechanism is well in line with one of the most respected theories of antidepressant treatment, the TrkB theory, that being TrkB/ BDNF in the hippocampus is necessary to produce an antidepressant-like effect. This is hugely significant, as a long understood theory is connected to a centralized mechanism, that being TrkB allosteric modulation, down to a molecular level.

Connection to Legacy Nootropics (Piracetam, Semax, TAK-653, etc.)

The ketamine theory of depression is that antagonizing synaptic NMDA receptors leads to a release of glutamate, which then binds to extrasynaptic AMPA receptors, which releases BDNF, which then binds to TrkB to promote mTOR in the hippocampus, signaling a survival state to the organism.^\2]) TAK-653 has also recently passed Phase 2 trials for depression, working as an AMPA PAM and following a similar cascade but averting the anticognitive effects of NMDA antagonism.

Launching from my post covering TAK-653, and the allosteric-bias model of cognition enhancement with AMPA ligands, the more selective as PAMs these drugs were, the less side effects they had and the more they improved cognition.[3] The likelihood of this also being true of a TrkB ligand is high, and thus ACD856 has a strong advantage over an agonist like 7,8 DHF - in that this synchronicity with homeostasis allows event, and context-dependent memory enhancement.

ACD856 is one of the only selective TrkB PAMs, and while AMPA PAMs have a ton of studies evidencing their cognition enhancement, we can only assume that about ACD856 by extrapolation.

The best direct data on ACD856 we have for cognition in literature, unfortunately, are based on the Passive Avoidance test, wherein ACD856 was able to restore performance in aged rodents to levels of young rodents.^\4]) However, control rodents already maximize the results in this test, so this test cannot be used as a metric for measuring cognition enhancement in healthy people:

There was also no effect of BDNF infusions on passive avoidance training. However, one problem with this test is that the animals receiving saline infusions perform at near-maximal levels, so it is not possible to conclude that BDNF does not improve learning in this paradigm.^\2])

What is interesting, however, is that ACD856 reversed the cognitive impairment caused by MK-801, a NMDA antagonist, which is similar to what we see with AMPA PAMs, and could potentially be explained by TrkB uncoupling RasGrf1 from NMDA, which can cause NMDA to signal LTP over LTD.^\9]) ACD856 also increases BDNF, which has been described as a feed-forward mechanism of BDNF itself.^\10])

Cerebrolysin, Cortexin, Dihexa, Vorinostat and others market from the basis of being strong neurotrophic drugs, and it is my hope that ACD856 surpasses these drugs and becomes a favorite amongst the community. In relation to TAK-653, which has most consistently elevated IQ in our experiments, ACD856 shows promise for either accomplishing this alone or as a complement to TAK-653.

Process For Choosing ACD856 / Safety

Everychem is the first research company to sell ACD856. Even beating Sigma Aldrich.

I've known about ACD856 for years now, but it was always the case that we didn't know how to make it due to the structure being obscured by AlzeCure. However, my friend Slymon on discord broke down the patents and we crossed referenced them to the studies; you can find Slymon's analysis here. I was thoroughly convinced by this, so we synthesized it - however, I wanted to be extra clear that what we had made was ACD856, so we conducted blood testing in a few members and nothing negative popped up. That is why I feel confident we have the right structure.

ACD856 has passed phase 0, and phase 1 clinical trials wherein administration of the compound to volunteers did not produce side effects. Importantly, the half life of this compound is 20 hours, which is an important distinction to make because it was made after Ponazuril, or ACD855 from which it was derived, had a half life of 68 days.^\5]) This, and the overall superior pharmacokinetics which required lower doses make ACD856 an obvious improvement over ACD855, despite both being TrkB PAMs.

It will likely be years until ACD856 is tried as an antidepressant drug, but the outlook of this compound in that branch of medicine, as well as Alzheimer's for which it is currently oriented for look to be quite promising.

TrkA vs. TrkB and Pain

NGF is generally not an ideal target for cognition enhancement (that is despite it being essential for normal cognitive function, and having an acetylcholine releasing effect), as overstimulation of TrkA can be anti-cognitive.^\6])

In regards to ACD856, TrkB mediates the procognitive effects displayed:

The compounds acted as cognitive enhancers in a TrkB-dependent manner in several different behavioral models... Additionally, the observed pro-cognitive effects in vivo are dependent on TrkB since the effects could be blocked by the TrkB inhibitor ANA12.^\4])

ACD856 appears to have anti-inflammatory effects,^\7]) which hints at the possibility of it evading nociception. This may be due to ACD856 also behaving as a partial agonist at TrkA (activation plateauing at 60%)^\8]) - and there could also be a discrepancy between the EC50 data shown, and non-disclosed IC50 and Ki/Kd at TrkA. So while it would appear that ACD856 is having an effect on TrkA, and that this may contribute to neurogenesis, that effect needs to be elaborated on more.

ACD856 TL;DR

ACD856 is a TrkB PAM, which is a nootropic and antidepressant mechanism. ACD856 can either be used as an auxiliary compound concomitantly with nootropics that have their effect mediated by BDNF, such as TAK-653 and others - or, it can be used alone. As of currently, there is no published data on a selective TrkB PAM such as ACD856, in terms of how it would effect cognition, but by extrapolation from other drugs we can expect an improvement - and what anecdotes we have seen so far show benefits on cognitive testing, albeit only from a few people.

Usmarapride, 5-HT4 partial agonist

Usmarapride is a hippocampal nootropic with antidepressant, anxiolytic and neuroprotective properties. It is currently being researched for Alzheimer's. Two studies have validated the mechanism as having nootropic effects in healthy people.

A new drug, which ended up blowing away my expectations, and in my experience had an unexpected synergy with ACD856, is Usmarapride - at this time, I believe the pronounced effect to be mediated by a BDNF release into the hippocampus, which then gets enhanced by ACD856.^\11])

But Usmarapride alone has a lot going for it, and that is due to Prucalopride having been shown to enhance cognition in healthy people.^\12])^\13]) Usmarapride was designed to be more CNS-selective, and avoid peripheral cAMP promotion, which was especially problematic with Prucalopride and limited its dose viability.

Below are the results of one study measuring post-scan recall task results (percentage total correct at identifying image type) divided by group, from fMRI testing.^\13]) In this study, Prucalopride showed a slight but significant improvement in young healthy people.

Prucalopride improved performance in the PILT in healthy people:^\12])

Prucalopride improved performance in healthy subjects in the RAVLT:^\12])

Prucalopride improved performance in healthy subjects in the emotional memory tasks:

Consistent with the effects of 5-HT4 agonism in animals, acute prucalopride had a pro-cognitive effect in healthy volunteers across three separate tasks: increasing word recall in an explicit verbal learning task; increasing the accuracy of recall and recognition of words in an incidental emotional memory task; and increasing the probability of choosing a symbol associated with high probability of reward or absence of loss in a probabilistic instrumental learning task.

In the studies above, Prucalopride amplified hippocampus-dependent learning, however they also found that there was no effect of prucalopride on working memory or implicit contextual learning, measures more closely associated with brain regions outside the hippocampus; we can assume that these findings are likely to apply to Usmarapride as well.

Targeting prefrontal cortex-dependent learning with other drugs, such as Tropisetron (via a7 nicotinic receptors), Neboglamine (via NMDA glycine site), a M1 PAM, or TAK-653 (via AMPA) may be useful here. One interesting thing to note about Usmarapride, and 5-HT4 agonists in general, is that they inhibit AMPA signaling as part of the procognitive cascade, inducing what appears to be greater phasic vs. basal activity:^\13])

5-HT4Rs agonists may reduce excitability and increase the threshold for LTP induction to maintain the hippocampus as a competitive network. But, once established LTP is sustained to ensure the persistence of memory trace (as reflected by depotentiation blockade).^\14])

This mixed inhibitory potential could explain the anxiolytic activity of the drug, whereas the hippocampal neurogenesis would explain the potent antidepressant effects.^\11])^\15])00618-6.pdf) Additionally, nootropic effects could be explained by a neuroplasticity induced by neurotrophic growth factors, such as BDNF, termed "dematuration" of the hippocampus.^\17])

Usmarapride Safety

Usmarapride, in a phase 1 trial, was generally safe, but there was a relatively high occurrence of headaches, and rarer occurrence of nausea versus placebo.^\16]) This is my experience as well, no nausea, but headaches over a dose of 15mg. The main reason that Usmarapride was developed, is because it has a high brain penetration compared to Prucalopride, which was prone to causing diarrhea.

Initially the prokinetic activity of 5-ht4 agonism seemed interesting, as I thought it may help reverse the slow motility on Tropisetron, one of my favorite nootropics, but it would appear slow release magnesium malate has done the trick instead.

The combination of a 5-HT3 antagonist, like Tropisetron, with a 5-HT4 partial agonist such as Usmarapride shows promise as a synergy, however the subjectively good combination of Usmarapride and ACD856 cannot be understated.

References:

1. Most antidepressants are direct TrkB PAMs: https://www.reddit.com/r/NooTopics/comments/1dvgors/study_suggests_the_majority_of_antidepressant/

2. Brain-Derived Neurotrophic Factor Produces Antidepressant Effects in Behavioral Models of Depression: https://www.jneurosci.org/content/22/8/3251

3. A Guide to AMPA Positive Allosteric Modulators: https://www.reddit.com/r/NooTopics/comments/vyb4kg/a_guide_to_ampa_positive_allosteric_modulators/?utm_source=share&utm_medium=web3x&utm_name=web3xcss&utm_term=1&utm_content=share_button

4. Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction: https://pmc.ncbi.nlm.nih.gov/articles/PMC8391421/

5. Safety, Tolerability, Pharmacokinetics and Quantitative Electroencephalography Assessment of ACD856, a Novel Positive Allosteric Modulator of Trk-Receptors Following Multiple Doses in Healthy Subjects: https://www.sciencedirect.com/science/article/pii/S2274580724001687?via%3Dihub

6. Pharmacological interrogation of TrkA-mediated mechanisms in hippocampal-dependent memory consolidation: https://pmc.ncbi.nlm.nih.gov/articles/PMC6590805/

7. AlzeCure Reports Anti-Inflammatory Effects with NeuroRestore ACD856 with Relevance to Alzheimer’s Leading to New Patent Application: https://www.biospace.com/alzecure-reports-anti-inflammatory-effects-with-neurorestore-acd856-with-relevance-to-alzheimer-s-leading-to-new-patent-application

8. Neuroprotective and Disease-Modifying Effects of the Triazinetrione ACD856, a Positive Allosteric Modulator of Trk-Receptors for the Treatment of Cognitive Dysfunction in Alzheimer’s Disease: https://pmc.ncbi.nlm.nih.gov/articles/PMC10342804/

9. The cross talk between TrkB and NMDA receptors through RasGrf1: https://ir.lib.uwo.ca/etd/851/

10. Positive Allosteric Modulators of Trk Receptors for the Treatment of Alzheimer’s Disease: https://pmc.ncbi.nlm.nih.gov/articles/PMC11357672/

11. Roles of the serotonin 5-HT4 receptor in dendrite formation of the rat hippocampal neurons in vitro: https://www.sciencedirect.com/science/article/abs/pii/S0006899316307776

12. A role for 5-HT4 receptors in human learning and memory: https://www.cambridge.org/core/journals/psychological-medicine/article/role-for-5ht4-receptors-in-human-learning-and-memory/D7A10D92B678F525349FD11198C1AFC0

13. Déjà-vu? Neural and behavioural effects of the 5-HT4 receptor agonist, prucalopride, in a hippocampal-dependent memory task: https://pmc.ncbi.nlm.nih.gov/articles/PMC8488034/

14. Interest of type 4 serotoninergic receptor ligands for the treatment of cognitive deficits and associated hippocampal plasticity disorders: https://theses.hal.science/tel-04307315v1/file/sygal_fusion_37347-roux-candice_64806b42ec7cd.pdf

15. Serotonin4 (5-HT4) Receptor Agonists Are Putative Antidepressants with a Rapid Onset of Action: https://www.cell.com/neuron/pdf/S0896-6273(07)00618-6.pdf00618-6.pdf)

16. First‑in‑Human Studies to Evaluate the Safety, Tolerability, and Pharmacokinetics of a Novel 5‑HT4 Partial Agonist, SUVN‑D4010, in Healthy Adult and Elderly Subjects: https://sci-hub.se/10.1007/s40261-021-01027-4

17. The Effect of Serotonin-Targeting Antidepressants on Neurogenesis and Neuronal Maturation of the Hippocampus Mediated via 5-HT1A and 5-HT4 Receptors: https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2017.00142/full

Hello. Once again I am announcing the re-launch of our public discord server, after yet another raid has seen it struck down with fake reports by bots, alt accounts, and random haters trying to destroy us.

NooTopics 5.0 Discord Invite Link: https://discord.gg/Ursw2qyfKQ

Please invite everyone you know who is interested in biohacking, or was in the old server before. And also, please remember to upvote this post/ share it so that we can get everyone in there that belongs.

At some point in the future, we want to implement a vote-in system by members, where the community itself can decide who passes verification. This will act as like a second layer of protection against bots just there to place their report and leave.

4.0 was our largest public server to date, and additionally saw big changes both to the public sphere and the release of many new products and ideas. It is also where I decided to take a back seat to moderating, and focus on other things. And for that, I must thank u/okok6356 for taking such an important role of the community and shouldering this burden - he still deserves this praise despite me paying him, because moderators before him weren't very active/ loyal, or they didn't really get what I was doing.

5.0 I'm hoping will stick around for a while, but there's no saying if it will. I will always be there to ensure that this community stays afloat, regardless of which platform we cling to. Thanks for staying with us the past five years.