18 replies to this topic

[thedevinroy]

Guanfacine is the amazing blood pressure medication that has been discovered as a powerful element in a synergistic treatment for ADHD. It works by activating the Adrenal Alpha 2 receptors in the prefrontal cortex, reversing the effects of cAMP overload. (http://www.longecity...efrontal-cortex) After reading that cAMP closes connections in the PFC, I suddenly realized that I have been making my ADHD worse.

I'm a caffeine addict and have been for years. Caffeine is an adenosine blocker which in turn causes an increase in dopamine and norepinephrine. This is great for ADHD. However, it also increases cAMP. Increasing cAMP in the PFC like caffeine actually inhibits the PFC from making proper connections. Norepinephrine opens these channels via the adrenal alpha 2 receptor. Therefore, a way to combat caffeine is either with more norepinephrine, less cAMP, or an agonist at the adrenal alpha 2 receptor.

I enjoy caffeine and will ignore all attempts at convincing me to quit. My grandmother drank 6-12oz of coffee every morning and lived to be 93.

I'm not a big fan of medications, because they are expensive, a complete hassle, and covered in the green slime of pharmaceutical greed. I'd much rather find a natural alternative to the ill effects of caffeine... something like an alpha 2 agonist like Guanfacine (Intuniv). Are there any that you know of?

[thedevinroy]

Maybe I should just rub some inosine on my forehead to reverse cAMP overload only in the PFC ...

Haha, just kidding. I thought of that one in my sleep. I highly doubt that would work as well as it did in my dreams.

Edited by devinthayer, 03 July 2011 - 02:27 PM.

[abelard lindsay]

But, isn't increasing cAMP how PDE inhibitors improve long term memory?

[thedevinroy]

But, isn't increasing cAMP how PDE inhibitors improve long term memory?

The converse is also true. Anticholinergics increase concentration.

cAMP isn't a bad thing at all. It's just that it short circuits the prefrontal cortex, decreasing concentration. This is fine for the normal person at a normal dose of caffeine, but makes things difficult with those who have low levels of norepinephrine, like those with ADHD.

[abelard lindsay]

The converse is also true. Anticholinergics increase concentration.

ahhh... No they don't. You don't ever ever ever want to take anti-cholinergics. They are often used in nootropics studies to test if a nootropic drug is powerful enough to *reverse* their negative effects on cognition.

http://en.wikipedia....Anticholinergic

Possible effects [of anti-cholinergics] in the central nervous system resemble those associated with delirium, and may include:

* Confusion
* Disorientation
* Agitation
* Euphoria or dysphoria
* Respiratory depression
* Memory problems[2]
* Inability to concentrate
* Wandering thoughts; inability to sustain a train of thought
* Incoherent speech
* Wakeful myoclonic jerking
* Unusual sensitivity to sudden sounds
* Illogical thinking
* Photophobia

cAMP isn't a bad thing at all. It's just that it short circuits the prefrontal cortex, decreasing concentration. This is fine for the normal person at a normal dose of caffeine, but makes things difficult with those who have low levels of norepinephrine, like those with ADHD.

Ok "Short-Circuit" is not the most scientific term when talking about neuro-chem. I looked around for the caffiene + cAMP study and found this:

Mol Cell Neurosci. 2011 Apr;46(4):742-51. Epub 2011 Feb 19.
Sleep deprivation prevents stimulation-induced increases of levels of P-CREB and BDNF: protection by caffeine.
Alhaider IA, Aleisa AM, Tran TT, Alkadhi KA.
Source

Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA.
Abstract

It is well known that caffeine and sleep deprivation have opposing effects on learning and memory; therefore, this study was undertaken to determine the effects of chronic (4wks) caffeine treatment (0.3g/l in drinking water) on long-term memory deficit associated with 24h sleep deprivation. Animals were sleep deprived using the modified multiple platform method. The results showed that chronic caffeine treatment prevented the impairment of long-term memory as measured by performance in the radial arm water maze task and normalized L-LTP in area CA1 of the hippocampi of sleep-deprived anesthetized rats. Sleep deprivation prevents the high frequency stimulation-induced increases in the levels of phosphorylated-cAMP response element binding protein (P-CREB) and brain-derived neurotrophic factor (BDNF) seen during the expression of late phase long-term potentiation (L-LTP). However, chronic caffeine treatment prevented the effect of sleep-deprivation on the stimulated levels of P-CREB and BDNF. The results suggest that chronic caffeine treatment may protect the sleep-deprived brain probably by preserving the levels of P-CREB and BDNF.

Copyright © 2011 Elsevier Inc. All rights reserved.

Not bad...

Caffeine modulates CREB-dependent gene expression in developing cortical neurons.
Connolly S, Kingsbury TJ.
Source

Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
Abstract

The Ca(2+)/cAMP response element binding protein CREB mediates transcription of genes essential for the development and function of the central nervous system. Here we investigated the ability of caffeine to stimulate CREB-dependent gene transcription in primary cultures of developing mouse cortical neurons. Using the CREB-dependent reporter gene CRE-luciferase we show that stimulation of CREB activity by caffeine exhibits a bell-shaped dose-response curve. Maximal stimulation occurred at 10mM caffeine, which is known to release Ca(2+) from ryanodine sensitive internal stores. In our immature neuronal cultures, 10mM caffeine was more effective at stimulating CREB activity than depolarization with high extracellular KCl (50mM). Quantitative real-time PCR analysis demonstrated that transcripts derived from endogenous CREB target genes, such as the gene encoding brain-derived neurotrophic factor BDNF, are increased following caffeine treatment. The dose-response curves of CREB target genes to caffeine exhibited gene-specificity, highlighting the importance of promoter structure in shaping genomic responses to Ca(2+) signaling. In the presence of a weak depolarizing stimulus (10mM KCl), concentrations of caffeine relevant for premature infants undergoing caffeine treatment increased CRE-luciferase activity and Bdnf transcript levels. The ability of caffeine to enhance activity-dependent Bdnf expression may contribute to the neurological benefit observed in infants receiving caffeine treatment.

Do you have a pubmed link for the negative caffeine/camp interaction study?

Edited by abelard lindsay, 04 July 2011 - 05:32 AM.

[thedevinroy]

Caffeine is an adenosine receptor antagonist. When the receptor is activated, it reduces cAMP. Caffeine readily crosses the BBB, so blocking adenosine receptors in the prefrontal cortex is going to happen, resulting in the increase in cAMP.

Take a Look at This Search on PubMed: http://www.ncbi.nlm....anfacine%20cAMP

The one of interest is the second one down:
Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex.

I'm not saying caffeine is bad, I just would want to take it with something like guanfacine knowing what I know now about how cAMP affects the PFC. I suppose anything that increases norepinephrine in the CNS would work, but I thought it interesting that almost all alpha2 receptor agonists on wiki were man-made with the exceptions of Ephedrine, human monoamines, and ergotamines (which I believe are toxic).

On a side note, Forskolin increases cAMP, too. I believe these affects are more peripheral than central.

As far as for DMAE and anticholinergics, check out this post and get back to me: http://www.longecity...dpost__p__33416 .

I do believe DMAE to be anticholinergic in some sense. It does not raise ACh levels, but it does choline levels. http://www.ncbi.nlm....v/pubmed/850128 Therefore, it is suspected to use some of the same pathways.

Edited by devinthayer, 04 July 2011 - 04:14 PM.

[abelard lindsay]

Caffeine is an adenosine receptor antagonist. When the receptor is activated, it reduces cAMP. Caffeine readily crosses the BBB, so blocking adenosine receptors in the prefrontal cortex is going to happen, resulting in the increase in cAMP.

Take a Look at This Search on PubMed: http://www.ncbi.nlm....anfacine%20cAMP

The one of interest is the second one down:
Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex.

Thanks for point out guanfacine. It's an interesting new direction in cognitive enhancement.

As far as for DMAE and anticholinergics, check out this post and get back to me: http://www.longecity...dpost__p__33416 .

I do believe DMAE to be anticholinergic in some sense. It does not raise ACh levels, but it does choline levels. http://www.ncbi.nlm....v/pubmed/850128 Therefore, it is suspected to use some of the same pathways.

I read that thread and the assertion that DMAE was an anti-cholinergic was not sourced. Here's a study that shows that it counteracts the effects of the rather nasty anti-cholinergic Scopolamine.

http://www.ncbi.nlm....pubmed/19756528

[thedevinroy]

Abelard Lindsay, your contributions are awesome. I love arguing in a civil manner for the sake of science and humanity. Without resistance, there is no strength.

Thanks for point out guanfacine. It's an interesting new direction in cognitive enhancement.

Thanks. I think it has potential.

I read that thread and the assertion that DMAE was an anti-cholinergic was not sourced. Here's a study that shows that it counteracts the effects of the rather nasty anti-cholinergic Scopolamine.

http://www.ncbi.nlm....pubmed/19756528

Thank you. Interesting that the DMAE salt also contained pyroglutamate - an excitatory amino acid claiming to having slight nootropic effects, especially when combined with racetams. The effects could be due to a combination of the two. Are there studies done with a different salt of DMAE?

Edited by devinthayer, 05 July 2011 - 01:32 PM.

[thedevinroy]

Found one: Octopamine, specifically its m-isomer, Norfenefrine. It's found as an important neurotransmitter in invertebrate neurology, in trace amounts in vertebrates, and in trace amounts in bitter orange. http://www.ncbi.nlm....pubmed/11053214

Looking for a good source of pure compound, but coming up short on the consumer market. It's in some fat-burning formulas, probably for it's alpha-1 receptor affinity. Perhaps I can find a standardized extract form... any help?

Another study here: http://www.ncbi.nlm..../pubmed/2503224

Edited by devinthayer, 05 July 2011 - 03:57 PM.

[tlm884]

Here are my two cents. Its probably easier to obtain gaunfacine or clonidine then it is to obtain a compound you need to have synthesized.

[tlm884]

Here are my two cents. Its probably easier to obtain gaunfacine or clonidine then it is to obtain a compound you need to have synthesized.

[thedevinroy]

Just found out that an over-the-counter nasal spray contains Oxymetazoline, which is an alpha 1 & 2 agonist, lasting up to 12 hours. It's not natural, but easier to come by than getting a prescription... which I already said I didn't want to do.

EDIT: Just found out that Oxymetazoline has 50% anticholinergic action at 1.22uM in myenteric plexus-longitudinal muscle preparation of guinea pig ileum. http://www.ncbi.nlm..../pubmed/7903384 ... whatever the hell that means. Probably antagonizes muscarine receptors since its in muscle tissue.

EDIT: Alpha Adrenergic drugs including clonidine and guanfacine inhibit acetylcholine binding to muscarine receptors. http://www.ncbi.nlm..../pubmed/1980330 ... must be a common problem.

Edited by devinthayer, 05 July 2011 - 05:57 PM.

[thedevinroy]

Found a new one: Agmatine. It is a byproduct of arginine... or somehow related. It is an alpha2 agonist and exhibits anti-hypertensive properties... which is good for a stim combo. Source: http://www.ncbi.nlm....pubmed/12907314

More: http://en.wikipedia.org/wiki/Agmatine
It inhibits NO synthase, thereby raising levels of NOS by inhibiting its break down. This is useful for working out. It's also an NMDA antagonist, therefore has potential to help hyperactivity and possibly anxiety.

Looks like I found my 'cold herb' in my remedy.

EDIT: http://www.sciencedi...526590004000860 [The endogenous NMDA antagonist and NOS inhibitor agmatine inhibits spinal long term potentiation (LTP)]

Edited by devinthayer, 07 October 2011 - 07:11 PM.

[manic_racetam]

So is the basic theory that Guanfacine regulates the increased cAMP caused by the stimulants... giving you the focusing stimulation of dopamine without the over-production of cAMP?

[thedevinroy]

So is the basic theory that Guanfacine regulates the increased cAMP caused by the stimulants... giving you the focusing stimulation of dopamine without the over-production of cAMP?

So it appears: http://www.ncbi.nlm....les/PMC1783631/

EDIT: Most stimulants don't increase cAMP, just xanthine derivatives like caffeine.

EDIT: Dopamine is thought of as stimulating, but it is actually the inhibitory dopaminergic pathways that are at fault in ADHD. Receptor #4, version 7, needs an upgrade. In order to "fix" ADHD, you must decrease cAMP, decrease NMDA receptors, and increase AMPA receptors. Dopamine and norepinephrine help with that a lot... via D4 dopaminergic receptor and Alpha2A Adrenergic receptor. GABA-B receptor may be involved for anxiety-related ADHD.

Edited by devinthayer, 07 October 2011 - 09:16 PM.

[Flex]

Berberine is an alpha 2 partial agonist and a nmda antagonist (wikipedia) and its easy to obtain.
in addition it poses despite its affinity to nmda receptors an antipsychotic action.
i know this topic is old, but i wanted to give a answer anyway

[protoject]

good one, thanks

[Flex]

I´ve found a another one.

Oxymetazoline;

its OTC aviable in Topical decongestants, at least in Germany.

Its, according to Wikipedia, a partial Alpha2 agonist and an Alpha1 agonist, which unfortunaetly elevates Bloodpressure.

Bloodpressure can be serious and cause i.e. Brainbleeding, so dont overdo !!

[chris106]

Very interesting thread! Can't believe I'm just finding this now.
Too bad devinthayer (OP) hasn't been heard of in a long time... I really hope he found something that works for him and is now living the good life

However, I came to this thread because I'm hypothesizing that the CILTEP stack doesn't quite work for me because of my ADD (mind you - ADD-PI, not ADHD as OP has)
which begs the question - would an alpha 2 agonist like Guanfacine also work for someone who has ADD-PI rather than ADHD?

I find it difficult to find explanations for what mechanisms are impaired in the brain with ADD-PI in compariosn to ADHD (where it's mainly dopaminergig signalling issues in the PFC).

My main problem is, that the terms ADD and ADHD are often used loosely, as if it were the same thing. And sometimes they get intertwined, even in studies - making it unclear which one is actually being talked about...

So does anyone who has ADD (ADD-PI) know about the usefullness of Alpha 2 Agonsits or has even tried them?