Alternative To Caffeine? Dopamine Agonist Without GABA Antagonism/NMDA Agonism?

[Waynish]

Not to hijack the thread, but are there any other substances frequented here that can kill you in the quantities that caffeine can?

 

[johnwester130]

hi, thanks for this. i was thinking about this comment for the last 2 hours while i was running errands. i found a study, maybe it is the one you are referring to:

Dopamine is a commonly used pressor agent. Frequently recognized side effects other than occasional reports of pedal gangrene respond to reduction of dose. Because a number of compounds interfere with vitamin B6 and dopamine toxicity in animals is modified by B6, we studied the dopamine-vitamin B6 interaction in rabbits. Six animals received 40 mg dopamine/kg and 10 mg pyridoxine injections; 6 received dopamine and saline. Dopamine administration led to an average fall of 20% (p = 0.04) in plasma pyridoxal 5'-phosphate (PLP) levels, which declined 42% by day 5. Three days later, a 25% decrease persisted (p = 0.03). Dopamine with pyridoxine caused a PLP rise of 65% (p = 0.007), but the post-study level was 28% lower than baseline (p = 0.04). We interpret our data to mean that dopamine reduced PLP levels during and 3 days after the study, and that dopamine appeared to increase the requirements for B6. We worry that dopamine given with other drugs, ie gentamicin, digoxin and theophylline which are frequently used in critical care settings, could aggravate alterations of requirements for or body stores of vitamin B6, creating B6 deficiency.
Depression of vitamin B6 levels due to dopamine. - PubMed - NCBI



i was wondering, this is going to sound controversial, but what if porn was able to deplete b6 through it's ability to increase dopamine? or entertainment addiction or something? i think it is possible.

yes, that's it

so using lisuride may deplete b6

 

[KyleKingsly]

well i can only talk from experience, p5p is good but has completely different effects than regular b6 for me

What effects does p5p have for you in comparison to the "huge dopamine boost" you experienced from b6?

 

[ddjd]

What effects does p5p have for you in comparison to the "huge dopamine boost" you experienced from b6?

P5p makes me tired

 

[Sativa]

Another approach to restoring or 're-vitalising' brain receptor functionality is to 'up-regulate' (ie increase the number of receptors/increase receptor 'efficiency') the receptors in question. (This approach isn't suitable for all receptor families btw)

There are many ways and approaches to up-regulating aspects of the dopamine system. A lot of focus is on the D2 receptor, which is responsible for the psychoactive properties of families of drugs.

Blue Lotus seems to have broad dopamine system re-sensitising properties.

btw, coffee also acts as a PDE4 inhibitor which increases levels of cAMP which is a -

second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transduction

Forskolin also has this PDE4 inhibition property.
(PDE aka phosphodiesterase inhibitors)

 

[Lokzo]

Caffeine blocks GABA-A activity but GABA-B activity also helps to reduce anxiety. GABA-B activity is promoted by low estrogen and high progesterone (and also by meditation). High dopamine + high GABA-B = you're the smoothest guy ever.

"High dopamine + high GABA-B = you're the smoothest guy ever." - Any herbal ways to increase GABA-B receptors, or GABA-B Agonists?

 

[Sativa]

Any herbal ways to increase GABA-B receptors, or GABA-B Agonists?

A GABA-B antagonist will initially, reduce GABA-B function, and the body will compensate by increasing GABA-B receptor 'density'. (ie enhanced GABA-B functionality)

Note that a GABA-B antagonist will likely cause temporary psychoactive stimulation, followed by increased GABA-B functionality.

You can always google "GABA-B antagonist herbal" for more options!
You could target the enzyme that breaks down GABA...

Note that using a GABA-B agonist consistently will result in decreased GABA-B receptor function due to down-regulation - aka the brains response to prolonged receptor stimulation - the main factor in withdrawal.

 

[LeeLemonoil]

Allosteric Modulators of all GABA-Rs also play an important role. Negative modulators are in general intellectualy and mentally stimulating while positive modulators are calming but can lead to apathy and mental tiredness. Homeostasis is tricky

 

[Lokzo]

A GABA-B antagonist will initially, reduce GABA-B function, and the body will compensate by increasing GABA-B receptor 'density'. (ie enhanced GABA-B functionality)

Note that a GABA-B antagonist will likely cause temporary psychoactive stimulation, followed by increased GABA-B functionality.

You can always google "GABA-B antagonist herbal" for more options!
You could target the enzyme that breaks down GABA...

Note that using a GABA-B agonist consistently will result in decreased GABA-B receptor function due to down-regulation - aka the brains response to prolonged receptor stimulation - the main factor in withdrawal.

Wicked, thanks for this!

 

[KyleKingsly]

I thought GABA-B antagonists can lower one's seizure threshold, or something like that? I've definitely read that strongly antagonizing GABA is a pretty bad idea, even if the idea is enhancing GABA functionality in the long run.

Anyway, I really want to return the focus of the thread on boosting dopamine for the long run. I don't think any agonists or releasers are the way to go because they're not really sustainable in the long run. DRIs might be better, but they can downregulate dopamine transporters when used consistently.

I am very interested in hydergine since it's a partial, rather than full, dopamine agonist, and so the risk of downregulating receptors should be a lot lower. Albert Hoffman is said to have used it every day until his death, and he lived to a good old age. However, there does some to be some risk of fibrosis with it, especially since one the ingredients in that blend has been directly tied to fibrosis.

I think upregulating TH and dopamine receptors, particularly D1 and D2 is the way to go for sustainably feeling more dopamine, but there aren't many good substances that I've come across for this purpose unfortunately. I'm very interested in pursuing very low amisulpride for this purpose, but it can really raise prolactin, which makes me wary. I'm not sure if P5P and other stuff would be enough to lower it or not, but it is anecdotally supposed to be great for feeling a powerful sense of magic and appreciation for life.

 

[LeeLemonoil]

Creating acts on D1 and D2, but very mildly. I imagine it wouldn’t desensitize receptors. It also works to enhance mitochondria and ATP-synthesis very effectively. I think it’s an Allround beneficial supp in moderation!

 

[KyleKingsly]

Haha I'm assuming you mean creatine, not creating lol. Anyway yeah I love that stuff, it's one of the few things I know that boosts DHT, among other benefits. I take 5g creatine monohydrate every day with a meal.

 

[LeeLemonoil]

Creating is very good for dopamine too I reckon
Yep, top stuff Creatine

 

[ImprovingDaily]

So I've been doing some experimenting and I've had a few revelations.
*Lisuride is good for Dopamine but lacks something that Caffeine gives me. If I can separate the aspect from caffeine that helps me, but also keep the anxiety at bay, ill be set.
*Keeping caffeine at a rate where I'm good enough energy wise, but not overstepping too much into anxiety territory.
*Been messing about with P5P B6, but probably gonna try the common B6. (hydrochloride?)
*Out of all the GABA agonists, Taurine might be my favorite. I've had good results with Beta Alanine in the past so might mess about with that too.

This is an open exploration for me so I'll keep updating as I go.

 

[General Orange]

asiaticosides + caffeine + l-theanine

 

[japanesedude]

B6 gave me mild but continuous focus but P5P did not have same effects.
It always makes me edgy

 

[Light]

How do you take your coffee?

Ray said to add sugar to coffee until no adrenalin effects.

Personally 5-8 sugars in a coffee does me well.

Hey @Benyamin Bulluc,
Do you have the reference for Ray saying that?
And how did you measure your adrenalin effects?
Thanks

 

[Herbie]

Hey @Benyamin Bulluc,
Do you have the reference for Ray saying that?
And how did you measure your adrenalin effects?
Thanks

Ive listened to all the audio interviews with Ray and he mentioned it one of them, I do not recall which one.

I just go by how I feel. How high I get, psychological effects and what happens to urination colour and frequency etc. I learnt through reading and reflecting and having heightened awareness of the body

 

[Frankdee20]

Caffeine/coffee is not directly a pro dopamine substance. First and foremost, it blocks adenosine from its receptor attachment. This can free up some dopamine, yes. When we talk about dopamine compounds falling short of something caffeine gives us, well, it’s also working on acetylcholinesterase, and GABA antagonism. Theoretically, ingesting coffee over time should cause up regulation of GABA receptors and Adenosine. The only way to make GABA is via that GAD enzyme or through Transaminase inhibition. Obviously cofactors like P5P, Glutamic Acid are needed.

 

[Frankdee20]

I thought GABA-B antagonists can lower one's seizure threshold, or something like that? I've definitely read that strongly antagonizing GABA is a pretty bad idea, even if the idea is enhancing GABA functionality in the long run.

Anyway, I really want to return the focus of the thread on boosting dopamine for the long run. I don't think any agonists or releasers are the way to go because they're not really sustainable in the long run. DRIs might be better, but they can downregulate dopamine transporters when used consistently.

I am very interested in hydergine since it's a partial, rather than full, dopamine agonist, and so the risk of downregulating receptors should be a lot lower. Albert Hoffman is said to have used it every day until his death, and he lived to a good old age. However, there does some to be some risk of fibrosis with it, especially since one the ingredients in that blend has been directly tied to fibrosis.

I think upregulating TH and dopamine receptors, particularly D1 and D2 is the way to go for sustainably feeling more dopamine, but there aren't many good substances that I've come across for this purpose unfortunately. I'm very interested in pursuing very low amisulpride for this purpose, but it can really raise prolactin, which makes me wary. I'm not sure if P5P and other stuff would be enough to lower it or not, but it is anecdotally supposed to be great for feeling a powerful sense of magic and appreciation for life.

Amisulpride would raise it at higher doses yes ?