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Mar 9 09 7:58 AM

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#2 [url]

Feb 5 10 12:08 AM

I'm hijacking this thread.

In response to Toast[us] from the thread "Receptor Effects",

"On the contrary, look up luteolin. It's a natural Dopamine Reuptake Enhancer with minor Norepinephrine Reuptake Enhancer effects too. I've tried it and at first it feels like it sucks, but when it wears off after an hour or two it feels great [but you need a 5-HT3 antagonist to block the nausea generated by the lack of the dopamine transporter, or else you won't feel euphoric after the come down].There is only one store I know of selling it. PM me if you want the source, it was kind of hard to find on Google and took several tries to find any available. Fortunately they sell in bulk and it is relatively cheap."

Don't forget about Apigenin. I'm a little confused with when you said "by the lack of the dopamine transporter". I thought it was an activator. And oh apparently Apigenin acts on the benzo receptors (Can you clear up what the difference is between the GABA and benzo receptors?), so maybe I can take this in the afternoon way before luteolin. Whatcha think?
Alibaba offers Luteolin. What about that?
Both Apigenin and Luteolin have very low oral bioavailability. What can I take to increase that? Some type of oil or cytochrome inhibitor?

This article
http://www.ncbi.nlm.nih.gov/pubmed/19815045
contradicts ur previous statement with lobelia. How blocking monoamine transporters will result in upregulation. The article says at the end, activations results in upregulation and this other article (which I've showed you before):
http://www.ncbi.nlm.nih.gov/pubmed/12776228
Shows a downregulation with the blockage of DAT transporters. Explain yourself Toast!!!

"I've read about tianeptine, the serotonin reuptake enhancer. Would be nice, but I don't think I could get it, I don't know how to order from offshore pharmacies or alibaba.com yet. I'm trying to learn how to order from alibaba so I can get some amentoflavone for 5-HT2C antagonism. All the herbs that have amentoflavone screw up its effects and make it get metabolized in like 2 minutes so you barely feel it. I'd like to use inhibitors with it, like ginger."

Doesn't amentoflavone promote alzheimers developement via inhibition of cathepsin B?

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toastus

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#3 [url]

Feb 5 10 4:10 PM

I'm hijacking this thread.
In response to Toast[us] from the thread "Receptor Effects",

Don't forget about Apigenin. I'm a little confused with when you said "by the lack of the dopamine transporter". I thought it was an activator. And oh apparently Apigenin acts on the benzo receptors (Can you clear up what the difference is between the GABA and benzo receptors?), so maybe I can take this in the afternoon way before luteolin. Whatcha think?

-kenbeaulieu1

Luteolin activates the dopamine transporter. By doing this it causes the dopamine transporter to downregulate. After it wears off you feel a dopamine build up, similar but not identical to cocaine. But dopamine reuptake inhibitors feed dopamine into the nausea center, so the downregulation induced by luteolin will do the same thing. If you want to experience euphoria after the luteolin wears off you'll need to use a 5-HT3 antagonist to block the nausea.

Apigenin is, to my knowledge, an NMDA antagonist and a Benzodiazepine-receptor Positive Allosteric Modulator. The Benzodiazepine receptor is this little spot on the GABA-A receptor that is different from other spots on the receptor that other molecules bind to. Benzo's like this little spot better than the other spots for some reason. Apigenin should cause sedation by potentiating this receptor.

I don't see a connection between apigenin and luteolin. What idea did you have about combining them?


Alibaba offers Luteolin. What about that?

-kenbeaulieu1

If you can order anything from alibaba, do it. I'm still trying to learn how to use it.


Both Apigenin and Luteolin have very low oral bioavailability. What can I take to increase that? Some type of oil or cytochrome inhibitor?

-kenbeaulieu1

Luteolin is very active in me at 50 mg. Doesn't feel like it has low bioavailability to me. I wouldn't want it any stronger. I've never tried apigenin before, though I have had effects from a gram of parsley [mild dissociation].

Oh, I just read that article, and it says apigenin is also a mild DA/NE reuptake enhancer but less potent than luteolin. Nice. I still don't know why I would use it with luteolin though.


This article
contradicts ur previous statement with lobelia. How blocking monoamine transporters will result in upregulation. The article says at the end, activations results in upregulation and this other article (which I've showed you before):
Shows a downregulation with the blockage of DAT transporters. Explain yourself Toast!!!
"I've read about tianeptine, the serotonin reuptake enhancer. Would be nice, but I don't think I could get it, I don't know how to order from offshore pharmacies or alibaba.com yet. I'm trying to learn how to order from alibaba so I can get some amentoflavone for 5-HT2C antagonism. All the herbs that have amentoflavone screw up its effects and make it get metabolized in like 2 minutes so you barely feel it. I'd like to use inhibitors with it, like ginger."

-kenbeaulieu1

I don't see a contradiction with anything I said.
http://www.ncbi.nlm.nih.gov/pubmed/19815045
"Thus, luteolin and apigenin function as monoamine transporter activators, which would improve several hypermonoaminergic neuropsychological disorders, especially cocaine dependence, through up-regulating monoamine transporter activity."

By upregulating, they mean the action of luteolin on the transporter, not the reaction the body produces in response to luteolin's presence. Luteolin boosts the transporter, causing the body to downregulate it. If you don't believe me, try it yourself. I suspect this is just a jargon-based misunderstanding. Upregulating probably means several things to them, like the action of luteolin is to upregulate the transporter while it is in the system. I know for a fact, from personal experience, that luteolin downregulates the transporter after it leaves the body. I know what it feels like and I can differentiate it from placebo. I also know that luteolin causes this by activating the transporter because I can feel it. Taking luteolin sucks but its worth it.

http://www.ncbi.nlm.nih.gov/pubmed/12776228
"Three months after initiation of treatment with methylphenidate we found a down-regulation of the post-synaptic dopamine receptor with a maximum of 20 % and a down-regulation of the dopamine transporter with a maximum of 74.7 % in the striatal system."

Oh, this is interesting. How would that work... A reuptake inhibitor causing reverse tolerance... In my experience all reuptake inhibitors cause upregulation of the transporter. I've never felt reverse tolerance, not even to methylphenidate. That would be interesting to try, but I don't want to risk my transporters, lol.

Now, it is possible that my understanding of lobelia is not correct, and that VMAT is the only transporter needed to be inhibited. Regardless, inhibition of both transporters by lobelia results in an upregulation of some type that feels like a natural amphetamine-state. It may be due purely to the VMAT, since we know upregulation of the dopamine transporter reduces synaptic dopamine and therefore sucks.

I suspect the good effect is due to VMAT upregulation, allowing each neuron to fire more transmitter per action potential. I don't know how much it is dependent on an increased supply of cytoplasmic dopamine caused by the increase in the dopamine transporter.


Doesn't amentoflavone promote alzheimers developement via inhibition of cathepsin B?

-kenbeaulieu1

That would suck. I guess I'll have to take my chances, lol. 5-HT2C antagonism is something you HAVE to experience. It's like pure magic.

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toastus

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#4 [url]

Feb 7 10 9:08 PM

kenbeaulieu1, I found a clue as to why methylphenidate downregulates the dopamine transporter.

https://en.wikipedia.org/wiki/Methylphenidate#Pharmacology


Moreover, MPH is thought to act as a releasing agent by increasing the release of dopamine and norepinephrine, though to a much lesser extent than amphetamine. Methylphenidate's mechanism of action at dopamine-norepinephrine release is still debated, but is fundamentally different from amphetamine, as methylphenidate is thought to increase general firing rate, whereas amphetamine reverses the flow of the monoamine transporters.[16][17][18][19] Although methylphenidate can be considered an amphetamine derivative, subtle differences exist in its pharmacology; amphetamine works as a dopamine transport substrate whereas methylphenidate works as a dopamine transport blocker.[14]

-Wikipedia

I looked at links sixteen to nineteen. Only sixteen mentioned anything about firing rates, and its results don't really suggest any difference between the mechanism of release between methylphenidate and methamphetamine.

To understand the effects of methylphenidate, the elective ADHD drug treatment in humans, in a dysfunctioning DA system, we realized a simple mathematical model of DA regulation based on experimental data from electrophysiological, cyclic voltammetry, and microdialysis studies. This model allows the estimation of a higher firing frequency of DA neurons in SHR rats and suggests that methylphenidate increases attentive processes by regulating the firing rate of DA neurons.

Nothing else is said on the subject from those links. So I did some more digging.

I am not sure what to make of it but I did find this:

www.ncbi.nlm.nih.gov/pubmed/12604695

Also of interest are findings that dopamine transporter inhibitors, including methylphenidate, rapidly increase 1) vesicular dopamine uptake, 2) vesicular monoamine transporter-2 (VMAT-2) ligand binding, and 3) VMAT-2 immunoreactivity in a vesicular subcellular fraction prepared from treated rats.

Also:
http://www.aapsj.org/view.asp?art=aapsj070481
Apparently reuptake inhibitors move the vesicles away from the cell wall and into the cytoplasm. This could, according to this paper, help protect against huge dopamine release by meth by moving all the dopamine away from the transporters, but I'm unconvinced. If meth blocks the VMAT, and reverses the DAT by activating TAAR, and methylphenidate moves the vesicles away from the cell wall, the dopamine wouldn't follow the vesicles because it would be prevented from entering the vesicles by the blockage of the VMAT. I think they made a jump in logic or something. If anything, methylphenidate would even further decrease the vesicular-based release of dopamine by moving the vesicles away from the cell wall... I don't get it, and I think I just went off track from this post lol. Thought it was worth mentioning though.
more on that subject:
http://www.ncbi.nlm.nih.gov/pubmed/19038779

These data suggest that after cocaine administration, D2 receptors are activated because of increased synaptic DA, resulting in a redistribution of DA-containing vesicles away from synaptosomal membranes, thus leading to less DA released after a depolarizing stimulus. These findings provide insight into not only the mechanism of action of cocaine but also mechanisms underlying the regulation of dopaminergic neurons.

Now THAT is interesting. D2 decreases the activity of cells by both increasing the expression of the dopamine transporter and by moving the vesicles away from the cell wall, to where the vesicles can't release dopamine by normal mechanisms. Therefore they effectively reduce the amount of dopamine released upon firing. Apparently D2 inhibits adenylyl cyclase, causing a drop in cAMP. This drop in cAMP must cause the movement of vesicles and increase in transporters. I think I am going to write about the receptors on HerbPedia.

Anyways, back on topic. Methylphenidate somehow increases the firing rate of neurons. I looked up if other reuptake inhibitors increase firing rate, and they cause different effects in different parts of the brain: some areas increase the rate while other areas decrease it, probably due to differences in the density of D2 and other receptors that inhibit cAMP production.

So I don't know how methylphenidate increases firing rate. It could be a TAAR agonist but I couldn't find confirmation on that. When SWIM sampled methylphenidate it seemed to be more than a reuptake inhibitor and seemed to have releasing agent effects on dopamine, due to the psychedelic aftertones from dopamine. Now, to conclude this post, if methylphenidate is a TAAR agonist it would result in a loss of dopamine transporters. www.jneurosci.org/content/21/23/9414.full.pdf

WAIT. This whole post may be for nothing and my theory be blown apart.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823365/


Four days after the course of cocaine, challenge with MDMA attenuated the MDMA-induced striatal dopaminergic neurotoxicity. Co-administration of the protein kinase C (PKC) inhibitor NPC 15437 prevented cocaine protection. At the same time, after the course of cocaine, DAT density was reduced in the plasma membrane and increased in the endosome fraction, and this effect was prevented by NPC 15437. The course of cocaine potentiated the MDMA-induced increase in extracellular dopamine and locomotor activity, following challenge 4 days later, compared with those pretreated with saline.


Repeated cocaine treatment followed by withdrawal protected against MDMA-induced dopaminergic neurotoxicity by internalizing DAT via a mechanism which may involve PKC. Furthermore, repeated cocaine followed by withdrawal induced behavioural and neurochemical sensitization to MDMA, measures which could be indicative of increased rewarding effects of MDMA.


I DO NOT UNDERSTAND WHY A REUPTAKE INHIBITOR WOULD DOWNREGULATE THE TRANSPORTER. That would just cause more reuptake inhibition. That is not a response which would balance the effect of a reuptake inhibitor and therefore return the brain to homeostasis. That would make it worse.


There is one simple way to test this out. Chronic cocaine anyone? Repeat their experiment. "Mice received a course of cocaine (20 mg·kg−1, ×2 for 3 days)." See how much your transporters, NOT RECEPTORS, have downregulated. Not sure how to tell the difference. That's why they used MDMA.


Perhaps their results were skewed by a lack of knowledge of how MDMA functions as a releasing agent by activating TAAR? They assume it is just because it interacts with the transporter in some unknown way that reverses it.


I haven't read the full study yet because I'm about to leave my house so when I get back I'll continue reading it and see how they measured the effect of MDMA after cocaine.


I DO NOT UNDERSTAND THIS. This makes no sense.

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#5 [url]

Feb 8 10 10:53 PM

               
That would suck. I guess I'll have to take my chances, lol. 5-HT2C antagonism is something you HAVE to experience. It's like pure magic.

-toastus

This is a little off topic but I think 5HT2C antagonists may actually DOWNREGULATE the 2C receptors. I was looking at 2C agonists and I found that these compounds do not lead to tolerance/upreg.
 http://en.wikipedia.org/wiki/A-372,159
http://en.wikipedia.org/wiki/WAY-161,503
http://www.ncbi.nlm.nih.gov/pubmed/10435391

http://www.socialanxietysupport.com/forum/f30/5-ht2c-antagonism-111864/index2.html#post1059665315

So wouldn't isn't the same true with antagonists?
It most likely is, http://www.ncbi.nlm.nih.gov/pubmed/11489455

The only problem is there aren't any cheap 5ht2c antagonists available. Even research chemicals have proven elusive. Agomelatine's bioavailability is incredibly weak >5% with a half-life of >2h. If chronic 2C antagonists are the goal, I don't think amentoflavone is a safe solution (because of Alzheimers promotion). I will try to find methods on increasing absorption/bioavailability of Agomelatine. Pharmacokinetics are similar to Stablon so desirable results may only come about with extremely high and consistent doses....meaning very expensive solution. Not worth it.

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toastus

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#6 [url]

Feb 9 10 12:22 AM


This is a little off topic but I think 5HT2C antagonists may actually DOWNREGULATE the 2C receptors. I was looking at 2C agonists and I found that these compounds do not lead to tolerance/upreg.
So wouldn't isn't the same true with antagonists?
It most likely is,
The only problem is there aren't any cheap 5ht2c antagonists available. Even research chemicals have proven elusive. Agomelatine's bioavailability is incredibly weak >5% with a half-life of >2h. If chronic 2C antagonists are the goal, I don't think amentoflavone is a safe solution (because of Alzheimers promotion). I will try to find methods on increasing absorption/bioavailability of Agomelatine. Pharmacokinetics are similar to Stablon so desirable results may only come about with extremely high and consistent doses....meaning very expensive solution. Not worth it.

-kenbeaulieu1

I agree, but only long term. In the short term [meaning for several hours] upregulation of 5-HT2C occurs. The next day I notice 5-HT2C has downregulated a little bit. Doing this for a long time would downregulate them as long as it's not an inverse agonist [which upregulates them]. Interestingly, agonists still downregulate them, especially bufotenine.

An agonist would be a better idea than an antagonist for long term downregulation. The downregulation would be stronger that way. Anyone know of a strong 5-HT2C agonist that doesn't interfere with other valued receptors? For example, bufotenine is also a D3 agonist and a 5-HToneA agonist, so long term wouldn't be a good idea. But Harmaline might be fine, it's a 5-HT2C agonist.

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#7 [url]

Mar 5 10 10:59 PM

I didn't want to intrude the other NZT thread too much so I'll continue here unless it's really important then I'll add onto the other thread. This thread I guess could be used as "scrap paper" for thoughts/ideas.

So ever since I started taking Adderall recreationally 8 months ago I've very slowly notied my tolerance building. It hasn't become apparent until now. I tried my absolute best to prevent tolerance. I only took it once every two weeks! Took high-dose magnesium with it. And tolerance still built! I mean really?! I rarely take it, sometimes I rotate and even wait an additional week so it's actually more like once every three weeks! This shouldn't be happening? I'm kinda disappointed this is happening. I vividly remember my first Adderall 20mg dose, I was on top of the world! Euphoric, sharp, and confident! Now today with 30mg, it's pretty noticeable and it did help quite a bit, but it is much weaker than before and the crash comes on a little sooner.

I have yet to try lobelia and blue lotus (50x 1.5 grams Toastus really?!). Is there anything else that would help? I wanna be able to completely restore my tolerance on a weekly basis.

Here's what I take on my special days: (NT=Neurotoxicity reliever)
-5 grams Turmeric w/30mg Piperine (NT)
-200mg Chelated Magnesium
-20mg-25mg Adderall IR
-500mg Ubiquinol (NT)
-2 grams Piracetam

Blue lotus looks like it costs too much if I need that high and purity of dosage. Are you sure lobelia's the magic cure? There has to be other herbs that could help.

Sorry if I came off a bit manic. I'm in the middle of a 30mg IR crash.

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#8 [url]

Mar 5 10 11:16 PM

My N-AcetylCysteine arrived in the mail last week. I was unaware of it's neuroprotective effects.
http://www.ncbi.nlm.nih.gov/pubmed/19277967 (A lot more studies google type NAC dopamine)
I'll start taking NAC daily tonight and see if it actually helps when I take AMPH again next month.

The tolerance really wasn't noticeable until shortly after dropping my veggie powder. It might have had an effect that was totally latent. Was gonna restart that anyway for overall health. I'd love for ur guys input on different herbs.

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#10 [url]

Mar 6 10 2:35 AM

Ahah yeah sure upping the dosage will bring you closer but you will never catch it again...

2 words
Psychological tolerance..well not tolerance but the lack of awe, of wow immersion, habit should i say..

You integrated this state more and more into yourself, it doesnt impressionate you anymore just like relationship to the people and environnement you live with since long time. Its a habit now, just like seeing a nude girl doesnt turn you hyper exited like it used to as a child. Neurophysiological tolerance will not help you with that at all. I really hope you have printed the experience of this state within yourself, cause it will never be back. Like as a child really feel the wow of a hike in the wood, you take the same path and feel 10% of what you've felt as a child. If you've seen a tree,house even wife your hole life you just cant see it anymore. like looking at a movie the first time then again and again and again... The printer of life has already stamp you mate, everything fellow this pattern, but cheer up! there are an infinite number of state you can meet for the first time and revisit but once you meet and feel it, you know it now, its over. Sure it will be fun again but not as religious/spiritual.

Im sure moving to bangkok and shooting Meth is a hell of an ''encounter'' but cant imagine the pain of the suckyness of the second shot...

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toastus

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#11 [url]

Mar 6 10 6:45 PM

Ahah yeah sure upping the dosage will bring you closer but you will never catch it again...
2 words
Psychological tolerance..well not tolerance but the lack of awe, of wow immersion, habit should i say..
You integrated this state more and more into yourself, it doesnt impressionate you anymore just like relationship to the people and environnement you live with since long time. Its a habit now, just like seeing a nude girl doesnt turn you hyper exited like it used to as a child. Neurophysiological tolerance will not help you with that at all. I really hope you have printed the experience of this state within yourself, cause it will never be back. Like as a child really feel the wow of a hike in the wood, you take the same path and feel 10% of what you've felt as a child. If you've seen a tree,house even wife your hole life you just cant see it anymore. like looking at a movie the first time then again and again and again... The printer of life has already stamp you mate, everything fellow this pattern, but cheer up! there are an infinite number of state you can meet for the first time and revisit but once you meet and feel it, you know it now, its over. Sure it will be fun again but not as religious/spiritual.
Im sure moving to bangkok and shooting Meth is a hell of an ''encounter'' but cant imagine the pain of the suckyness of the second shot...

-qwer27

If this is true then reactivation of NGF and upregulation of 5-HT7 would fix the whole thing.

Also NMDA antagonism.

Or spiritual work.

:)

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#12 [url]

May 24 10 10:25 PM

Ok well it's been a while since I last posted lol. Hope all of ya'll are having a good time.
 
Here is my update:
-Dropped Adderall. Didn't like the levo- (peripheral) and roller coaster change in mood due to instant release. Switched to Vyvanse. Looks safer because of slow release and absence of any levo.
 
-Deprenyl seems to upregulate DAT, SERT, etc and since AMPHs reverse them, maybe I can reset tolerance to a certain degree.  Plus it has other neuroprotective effects. I might consider the transdermal patch Emsam as it appears safer than the oral route.
 
-Dropped Solian idea. I think receptors play a limited role in tolerance and the possibility of adverse effects are pretty high. Would use blue lotus instead.
 
-Ethanol (Alcohol) upregulates SERT and MAO-A. Upregulation of SERT could in theory potentiate the empathogenic effects of AMPH on administration day. I'm not sure how upreg of MAO-A would help though. Chronic Deprenyl also eventually inhibits MAO-A due to the spillover effect. I don't know what this would do. Also, GABA is thrown in the mix.

-I still plan on using Acetyl L-Cysteine and Memantine with it (AMPH).
 
Any thoughts, suggestions, comments??
 
 
 



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#13 [url]

May 24 10 10:41 PM

    kenbeaulieu1, I found a clue as to why methylphenidate downregulates the dopamine transporter.

[url]

I DO NOT UNDERSTAND WHY A REUPTAKE INHIBITOR WOULD DOWNREGULATE THE TRANSPORTER. That would just cause more reuptake inhibition. That is not a response which would balance the effect of a reuptake inhibitor and therefore return the brain to homeostasis. That would make it worse

-toastus

MDMA possesses similarities in pharmacology with AMPHs. Soo.....less DAT (as a result of downregulation from methyphenidate/cocaine) reversed means less neurotoxicity? Is the neurotoxicity because of the reverse process itself or the extra dopamine in the synaptic cleft being metabolized? The answer to this question is crucial because an MAOI-B inhibitor such as deprenyl is neuroprotective against AMPH and MDMA? http://www.ncbi.nlm.nih.gov/pubmed/7538579
 
Wtf Deprenyl is also a weak reuptake inhibitor but upregulates DAT unlike cocaine and methylphenidate.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1571229/


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#14 [url]

May 24 10 10:57 PM

Wow apparently chronic Deprenyl actually reduces the effect of AMPH via tyrosine hydroxylase downregulation. I guess that shoots down my previous plan. Unless muhaha I find what upregulates TH. Now this means introducing yet another substance to which I have no lead on what kind of interaction it'll have with AMPH. Lithium upregulates TH. Counteract AMPH TH downreg or even out? Who knows.
http://www.ncbi.nlm.nih.gov/pubmed/9523597

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koda

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#15 [url]

May 25 10 4:17 PM

I imagine the body upregulates DAT from deprenyl from the extra dopamine hanging around from the MAO-B inhibition.  Similarly I would imagine it would downregulate the enzymes that convert amino acids to dopamine.  This may seem like a bad idea at first, but if you think about it, this means that the protein you eat will fuel the other amino acids & neurotransmitters such as serotonin etc.

Lately I have been taking a more holistic approach to the NZT thing.  I mean the body has all the tryptamines, phenylethylamines, trace amines, endorphins, cannabinoids we could ever need, in a form the body knows how to use.  The body only has so much energy it can provide thanks to out modern day living situation, stress, pollution, etc.  I wonder if we take away all the poison and negativity that puts up our shields & defense mechanisms, that our higher order neurotransmitters might show themselves for what they are.

A little supplementation & herbs certainly help too :)

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sativa

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#17 [url]

Apr 24 13 1:41 PM

It seems most people have continued on other forums! I've seen a few people from here active on dmt nexus and entheogen-network.

Posting continues on this forum though :)

The original source of most novel research that I know of on these kinds of subjects!!!!

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