34 replies to this topic

[Mind_Paralysis]

The article seems relevant but won't a D4 agonist just downregulate the D4 receptors in the end? If there's a -/- mutation which already decreases novelty seeking behaviour and causes cognition problems, then that would be bad. Also, A-412,997 is insanely expensive and in very low quantities as far as I can see.

 

The D4-receptor is an interesting case, because it appears as if it is unusually resistant to homeostatic changes, meaning that it is actually immensely hard to either up or down-regulate it. It's a very unusual trait within neurotransmitter -receptors, but it's not entirely unheard of - Melatonin-receptors actually appear to be fairly hardy as well (alltho' not to as dramatic an extent), and even tho' many get tolerance towards exogenous melatonin, it does not appear to be permanent at all, and can be easily reversed with Valproic Acid.

 

So no, D4-agonism won't downregulate the D4-receptors - the reasons why some receptors in the brain is less responsive to stimuli and tolerance is as of yet... unknown, though. I actually learned this here at Longecity, and it was quite surprising to learn this about MT and D4 -receptors, but this is the truth, this is the cutting edge - every receptor is not made from the same cloth, it would appear.

 

The idea of a -/- mutation is interesting however... but I believe that the research so far, in the dopamine-hypothesis of Schizophrenia, is that it is as a matter of fact the D2-receptors that are involved in the disorder, and not the D4 -receptors. It may be that D4 -agonism may actually be treating the negative symptoms in a round-about way, and not directly.

 

Since D4 handles cognition, it may simply be that it's simply because it's the one D-receptor not involved in the disorder, that agonising it won't trigger symptoms, and hence, you can reverse some of the problems that are caused by the Low-dopamine phases of the disorder.

"Schizophrenia: More dopamine, more D₂ receptors"

http://www.ncbi.nlm....icles/PMC33999/

 

It should also be noted that the dopamine-hypothesis have strong competition from the Glutamate-hypothesis concerning Schizophrenia - and the unifying hypothesis, the Kynurenic Acid Hypothesis, is gaining ground and looks to actually be replacing both of them in the next decade or so - there are already several Kyna-based medications for Schizo being developed, if they work, then we know the two earlier ones were bull-sh*t. (a bit like the Serotonin-hypothesis in depression)

 

In closing, as far as I know, no extremely short variation of the DRD4 -gene have as of yet been identified to be connected to any disease, in fact, it seems to be the opposite. It should be noted, the D4-receptor is the least common D-receptor in the CNS, and it can only be found in the brain, the PFC to be accurate, which is again, a very atypical feature of a neurotransmitter receptor.

Edited by Stinkorninjor, 02 November 2015 - 01:13 AM.

[Mind_Paralysis]

But yeah, you're very correct in that A-412,997 is not very practical as a treatment-option at the moment... the cost is indeed astronomical. However, it's definitely something to keep a look at, and see what the future results will bring, if they ever truly do test it further.

 

And hey, maybe we'll be lucky, and somebody finally organizes a group-buy? Much like other cognitive-enhancing drugs, it might just need a kickstart in the market before it can finally be procured. = )
 

I mean, look at Fasoracetam and NSI-189 - nobody had a CLUE about these drugs until only a few years back, and they were unavailable and super-expensive at first, but eventually they came to market. Fasoracetam in perticular shot straight out of obscurity following some recent research and our threads here on Longecity (which prompted the nootropics-sellers to begin synthesis, as they noted a potential market).

[themadscientist]

I hate to say it, but if you want to see any real improvements or results then you only have one option: Cerebrolysin. Taking vitamin supplements will never get you back to baseline. Do two cycles of 5 ml every other day for 2 months, but also perform cardio daily and keep your brain working, and you will start to see improvements by the 3rd week. This is not a cheap or painless process—it involves IM injections—but if you look at the literature and experiences posted here, you will see it's the most effective option currently available.

Edited by themadscientist, 05 November 2015 - 01:35 PM.

[sativa]

Found this paper recently and it made me wonder that the effects arent well researched and that the effects of Cannabis might have chronic consequences even to those who havent smoked in the adolescence
...
I´m happy for any thoughts and inputs

Ex cannabis smoker here. I've fully recovered all my faculties using some neat pharmacology

Cannabis (or marijuana) is a very useful tool for creative thinking and expanded logic (Studies have shown). But Studies have also shown that, although cannabis doesn't kill brain cells, marijuana's effects reduce memory function in a few different ways.
Some benefits of this supplement include: Reversing some tolerance, reversing memory loss, speeding detoxification of THC, correcting some hormonal effects, potientially helping immune system, and improving overall memory.

Main ways Cannabis reduces memory:
1. Residual CB1 agonist release from fatty cells.
2. cAMP/ CREB (Chemical responsible for Long-Term memory potential) decrease will result in less memories being encoded.
3. NGF (Nerve Growth Factor) decrease lowers the maintenance and growth of new neurons.
4. Decrease in Glutaminergic brain activity (via GABA) (causes a lowered mental energy and could make someone lazy/tired).

Ingredients:
Dihydromyricetin Extract
A natural proven intoxication blocker. Studies show this type of chemical diminishes all memory impairments caused by THC. Contains a chemical called ampelopsin that influences GABA(a) receptors in an inhibitory fashion. This compound not only reverses memory effects caused by GABA, it also prevents long term anxiety caused by THC. This compound can be used to reverse even non-drug induced anxiety. 8' 13'

American Ginseng
Proven to increase metabolism of THC to its inactive version 11-nor-9-carboxy. This means american ginseng is a working detox. Prevents CB1 activation after intoxication, reducing ones tolerance. American Ginseng also contains CB1 Inverse agonist falcarinol (Studies show it reverses CB1s effects at certain sites). Some slight hormonal type improvements have also been noted. American Ginseng also increases dopamine production in certain areas of the brain improving memory and tolerance. American Ginseng also works as a choline uptake enhancer exactly as Aniracetam, Piracetam and most of the other racetams (nootropics) do. 7' 10' 11' 17'

Lysine
This natural compound has been found to relieve anxiety and stress in the gut without effecting gaba receptors or memory! Marijuana has been shown to increase stress and anxiety aswell as weaken the immune system. Lysine helps to reverse both of these aspects.
9' 18' 19' 20' 21' 22'

Bacopa Extract
Bacopa has been shown to increase working memory as well as long term retention. Bacopa also reduces the possibility of seizure. This makes overdose from Dihydromyricetin nearly impossible even at unsafe amounts. Bacopa has also been shown to reverse amnesia caused by gaba down regulation with an unknown mechanism. Bacopasides has also been found to thwart brain inflammation caused from smoke and lipoxygenase. 1' 6' 9'

ALCAR (Acetyl-L-Carnitine)
Studies have shown it is very beneficial with boosting the effects of NGF. Studies show it helps ATP production. Uridine relies on ATP to exert its effects, thus proving synergistic effects between the two. Aceytl-L-Carnitine also works synergistically with l-glutamine, increasing the activation of glutaminase, the enzyme responsible with converting glutamine into glutamate (most abundant neurotransmitter in the brain). Studies also show it improves mental performance greatly. 12' 14' 16'

[Flex]

Ex cannabis smoker here. I've fully recovered all my faculties using some neat pharmacology

Thank You a lot. I missed this and several other posts, so excuse me for the late response.

I found also something interresting recently:

 

Pregnenolone Can Protect the Brain from Cannabis Intoxication
http://www.ncbi.nlm....les/PMC4057431/

...(THC) substantially increases the synthesis of pregnenolone in the brain via the activation of type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals an unknown paracrine/autocrine loop protecting the brain from CB1 receptor over-activation..

Enhancing Brain Pregnenolone May Protect Cannabis Intoxication but Should Not Be Considered as an Anti-addiction Therapeutic: Hypothesizing Dopaminergic Blockade and Promoting Anti-Reward

http://blumsrewardde...nneth-blum.html

 

Pregnenolone is not the answer

..However, in contrast to these effects the sulfated Pregnenolone has been shown by Vallee’s group [3] to increase both dopamine release and the dopaminergic response to morphine in the rat NAc [24]. The dopamine release effect of the sulfated Pregnenolone seems to be incongruent and unresolved relative to their current hypotheses...

I´m not sure about this typo, I mean is this a red flag ? though the Journal name is per sé interresting:

Journal of Reward Deficiency Syndrome and Addiction Science (JRDSAS) (Formerly Journal of Reward Deficiency Syndrome)

 

Moreover, it is known that THC induces inhibition of GABA/glutamate release through an interaction with MDMA receptors [23] allowing for "dopamine homeostasis." These particular THC effects were significantly attenuated by Pregnenolone

Interrestingly pregnenolone seems to counter THC overdoses

Scientists Explain Why Marijuana Users Never Overdose

http://www.leafscien...never-overdose/

 

Also I wonder whether Pregnenolone is partialy responsible for the anxious and feminine-like effects of THC

Edited by Flex, 14 August 2016 - 03:31 PM.