21 replies to this topic

[chris106]

First of all - my knowledge of brain-chemistry / neuroscience in general is still very sub-par.
The tiny bit of what I know, I got from lurking these forums for a few months. Not trying to sound like an apologist here, but there's still one burning question on my mind I'd like to discuss with you guys (or at the very least initiate a discussion)


I've had my experiences with a fair share of stimulants - Ritalin in pretty much all forms and shapes, DL-Amphetamine, plain Dexamphetamine, Modafinil (Modalert) and Armodafinil (Wacklert).

The only one I seem to be able to somewhat tolerate for longer periods of time is Modafinil. But in the end they all have one anoying thing in common -
the sympathetic side-effects!

I'm talking about postural hypertension, stiff muscles and decreased fine motor skills, dry mouth (dry mucous membranes in general) to the point where the voice starts cracking unvoluntarily, and dehydration - just to name a few.

I recently came across a new type of substances which seems to be promising regarding ADD and daytime sleepiness -
Histamine-3 autoreceptor antagonists/ reverse-agonists. (Yadayada just recently opened a thread regarding Ciproxifan - very interesting read!)
I'd also like to try a few other candidates for raising dopamine like Selegiline or Rasagiline if I can get my hands on them.

Now my question is:

Though through different working mechanisms and paths, all these different substances achieve a (more or less) similar goal: Raising catecholamine levels, especially in the PFC (oversimplification - so correct me if I'm wrong).
Is it inevitable that ANY substance which achieves this goal - no matter through which mechanisms, or how specific in targeting certain receptors, be it through agonism, antagonism or re-uptake inhibiton - will allways cause these side effects in the end?

Or do they only occur when said goal is achieved through certain mechanisms of action, and can be avoided through others?

Wouldn't it be interesting if there was some kind of stimulant ( or maybe even something in the lines of SAMe or other substances that doesn't even classify as a plain stimulant), that achieves the positives without said negatives?
Or are we damned to minimize the sides by countering them with additional substances and supplementation?


I hope this topic will be of interest for other, more knowledgeable members of this forum, too - Would love to hear your thoughts on this!

Edited by chris106, 05 June 2013 - 05:33 PM.

[Reformed-Redan]

Check out BPAP. Interesting stuff. Pitolisant is also interesting as something to look into in the future.

[chris106]

Definetely, following both those threads

But I was thinking about something readily available now - sadly I don't have the resources to invest in a group buy right now...

[norepinephrine]

BPAP sounds really intriguing; it's a shame it can't be bought like deprenyl.

Edited by norepinephrine, 05 June 2013 - 07:25 PM.

[xks201]

I read from the creator of deprenyl that it inhibits the negative side effects you mentioned off amphetamines. I'm not sure if that is true or not. It definitely is not true over a period of weeks after you have finished taking deprenyl in my experience.

[KoolK3n]

To answer the topic thread question: Carbidopa

[lammas2]

To answer the topic thread question: Carbidopa

Source maybe?

[KoolK3n]

Source maybe?

Source for what? If you're confused, Wikipedia Carbidopa. It lessens the impact of dopaminergic drugs in the peripheral nervous system by inhibiting dopamine synthesis but not in the central nervous system. This happens because it does not cross the blood brain barrier.

[lammas2]

Source maybe?

Source for what? If you're confused, Wikipedia Carbidopa. It lessens the impact of dopaminergic drugs in the peripheral nervous system by inhibiting dopamine synthesis but not in the central nervous system. This happens because it does not cross the blood brain barrier.

I know about levodopa/carbidopa combination, but are you saying that carbidopa used with ANY dopaminergic stimulant reduces negative side effects, like high BP etc?

[brainslugged]

I read from the creator of deprenyl that it inhibits the negative side effects you mentioned off amphetamines. I'm not sure if that is true or not. It definitely is not true over a period of weeks after you have finished taking deprenyl in my experience.

If you do this, please be very careful.

Combining selegiline and amphetamines could easily lead to psychosis if you overestimate the dosage. I have heard that selegiline does reduce side-effects, and increases the duration of amphetamines by a factor of about 1.5 (so, they last for the normal length plus half of the normal length), though.

Maybe you could try taking sulbutiamine with a stimulant? That would reduce actions on D1 and may help since D1 activation may have negative effects on reflexes and stuff.

[chris106]

Wow, this thread actually has taken off

I read from the creator of deprenyl that it inhibits the negative side effects you mentioned off amphetamines. I'm not sure if that is true or not. It definitely is not true over a period of weeks after you have finished taking deprenyl in my experience.

If you do this, please be very careful.

Combining selegiline and amphetamines could easily lead to psychosis if you overestimate the dosage. I have heard that selegiline does reduce side-effects, and increases the duration of amphetamines by a factor of about 1.5 (so, they last for the normal length plus half of the normal length), though.

Maybe you could try taking sulbutiamine with a stimulant? That would reduce actions on D1 and may help since D1 activation may have negative effects on reflexes and stuff.

Very interesting, I would never have even guessed that taking Deprenyl could cancel out amphetamine side-effects. While it sounds interesting in theory, I guess I would never even dare to try this, though

However Sulbutiamine mixed with a stimulant sounds promising at first glance...

I should also add that personally, I'm never touching amphetamines or MPH ever again.Like mentioned before, I for myself would look for other, newer forms of stimulants or "stimulant like substances". Because while my question was adressing the limitation of emidiate side effects, long-term saftey and toxicity would be concerns too, of course.
And while I think it would be possible to dull down sympathetic side-effects of amphetamines temporarely, I guess that wouldn't make the drug itself less harmfull or neuro-toxic in the long run...
Of course others might think different about the risks of amphetamines or Methylphenidate( which in itself is safer, regarding at least toxicity, of course) - so points regarding these coumpounds are still absolutely valid to the conversation - Just an aspect I wanted to point out.

Which leads me to my next question - Regarding SAM-e - does it even qualify as a from of stimulant ? I know it somewhat works for depression, but is it actually rather serotonergic or dopaminergic? I wonder if it's wort a shot for someone struggling with regular stimulants?

Edited by chris106, 06 June 2013 - 09:31 PM.

[chris106]

Source maybe?

Source for what? If you're confused, Wikipedia Carbidopa. It lessens the impact of dopaminergic drugs in the peripheral nervous system by inhibiting dopamine synthesis but not in the central nervous system. This happens because it does not cross the blood brain barrier.

Jeez, extremely tired and almost forgot to mention - I will definetely look this up, first thing tomorrow! Really curious if this is something that would actually be managable when put to the test!

Thanks to all you guys for your input sofar!

[KoolK3n]

Source maybe?

Source for what? If you're confused, Wikipedia Carbidopa. It lessens the impact of dopaminergic drugs in the peripheral nervous system by inhibiting dopamine synthesis but not in the central nervous system. This happens because it does not cross the blood brain barrier.

I know about levodopa/carbidopa combination, but are you saying that carbidopa used with ANY dopaminergic stimulant reduces negative side effects, like high BP etc?

In theory, it should work with any dopaminergic drug but not a lot of people have taken carbidopa without the l-dopa attachment so caution is warranted if one was to go down this route.

[KoolK3n]

To add-on and clarify to my previous post, it would reduce some of the peripheral side effects, not eliminate them. Some dopamine stimulation will still cause problems. Personally, when I use DA stimulants recreationally, the addition of a long lasting benzo like Klonopin eliminates most if not all of the negative side effects of DA drugs both peripherally and centrally.

Edited by KoolK3n, 07 June 2013 - 03:07 AM.

[Major Legend]

To add-on and clarify to my previous post, it would reduce some of the peripheral side effects, not eliminate them. Some dopamine stimulation will still cause problems. Personally, when I use DA stimulants recreationally, the addition of a long lasting benzo like Klonopin eliminates most if not all of the negative side effects of DA drugs both peripherally and centrally.

I can double confirm this - however this is not really a daily/longterm solution as both DA stimulants and benzos build tolerance (DA stimulants much faster than benzos), you also need to dose higher benzo's to eliminate the side effects of DA stimulants, not to mention you need to dose Benzo's for the combined duration of the DA stimulants up and down extending the benzo use for far too long.

As I already suggested to chris in a private message that my preferred solution is using a cocktail of natural stimulants (whatever you wish to choose) + sugar intake (dextrose and glucose) which increases metabolism in all areas of the brain - this is far more preferable as the effect is spread out more evenly among the various different stimulatory processes (whatever they may be) (I discuss this in another thread named confidence and self esteem). I feel that in some ways the ADHD brain is unable to "switch on fully". I find that this "boost" on mondays increases my "on" throughout the week (but its not perfect by any mean, I have tolerance issues too, still far from the normal/peak functional human being and my monthly costs are ridiculous). Needless to say this "spread out" stimulation approach creates a much more natural, confident and sociable subjective feel for me than amphetamines (though I would say amphetamines are better for productivity).

The body is also hugely suspicious of large dopamine responses:

1) Because dopamine is associated with reward, at least the feeling of satisfaction the body has an almost reflex response to sudden spikes of dopamine, in the sense that it will down shift very quickly to avoid the trap of experiencing pleasure too much , this is a natural evolutionary response - as a creature that is constantly in pleasure will do nothing to survive ( at least in the primitive survival sense anyways). This is on a both motor control level as well as a psychological level.

2) according to my knowledge people with issues of low dopamine in the PFC, actually have a genetic disposition to having a malfunction in producing enough dopamine, well receptor sites that release dopamine I guess (there was something about asymmetry like the release is unbalanced between the hemispheres or something in the hippocampus or striatum) - messing with dopamine in these individuals who already have problems with dopamine regulation will likely to lead to further problems down the line (parkinsons, tremors, even worst ADHD,lethargy)

3) personal experience of messing with deprenyl and comt inhibitors (not together by the way - I would be dead) , has damaged my dopamine system to some extent. I had walking/posture problems and parkinson symptoms, probably because my dopamine system is not working properly in the first place due to genetic reasons. In individuals where these systems are not misaligned they may not get these side effects. Fortunately I have since recovered from these symptoms.

Solutions:

1) BPAP is promising as deprenyl had an amazing effect on me for reasons unknown, but it only lasted a day, at the time of research approx 2 years ago - I believe I figured out that the effect may be due to something BPAP produces exclusively (forgot the name of that particularly process)

2) Targeted lasers

3) Testosterone perhaps.

In conclusion: DA drugs are very dangerous, take caution before experimenting. Not long ago there was a guy called G4D who experimented with pramipexol for social anxiety and ended up with a screwed up brain where he had parkinson like symptoms and total lethargy day in, day out. If in doubt stick to amphetamines and even just supplements.

Edited by Major Legend, 07 June 2013 - 04:26 AM.

[Reformed-Redan]

Anyone interested in BPAP just PM me. Might squeeze in a spot.

[KoolK3n]

I can double confirm this - however this is not really a daily/longterm solution as both DA stimulants and benzos build tolerance (DA stimulants much faster than benzos), you also need to dose higher benzo's to eliminate the side effects of DA stimulants, not to mention you need to dose Benzo's for the combined duration of the DA stimulants up and down extending the benzo use for far too long.

In conclusion: DA drugs are very dangerous, take caution before experimenting. Not long ago there was a guy called G4D who experimented with pramipexol for social anxiety and ended up with a screwed up brain where he had parkinson like symptoms and total lethargy day in, day out. If in doubt stick to amphetamines and even just supplements.

Yes, tolerance is obviously an issue. This is why I only use the two recreationally (once a month) as stated in my previous post. The typical dose for Klonopin when taken with a moderate dose of a DA stimulant is .25-1mg. More than this and the Klonopin most likely overpowers the stimulant. Because Klonopin has a pretty long half-life, the favorable stimulant is Vyvanse. This combo would last for most of the day with a smooth rise and smooth comedown. Unlike for example an Adderall IR and Xanax combo. I've tried all these drugs in varying mix and matches. Nothing can beat the Vyvanse and Klonopin combo. It truly is the holy grail of cognitive enhancement with limited neurotoxicity. Too bad tolerance creeps up...but for you Major Legend, it truly does look like you have dopamine issues. I was speaking for people who are relatively healthy.

Edited by KoolK3n, 07 June 2013 - 10:35 PM.

[chris106]

Just to clarify:

Even though most of you obviously got what I meant in the thread-title, by "sympathetic side-effects" I of course actually meant to say peripheral side effects!
Not sure if it's just two terms for the same thing, or if there's an actual difference.

Well, english not being my first language and all ... >_<'

[Flex]

Afaik:

Noradrenaline reputake inhibitors.

The Dopamine uptake in the PFC is controlled via NE transporters. instead of DAT like in the Limbic system.

A Seroquel metabolite is afaik a PFC selective NET but You can use anything that blocks NET.

 

Perhaps there are different ways but I´m not sure:

a2 agonism or antagonism + the resulting change in CAMP, perhaps D3 inhibition which increases 5-htp in the PFC, D4 activation, 5-ht2c activation (?)

or Glutamate via either Nmda or Ampa ( dont know which one )

 

[Flex]

One important thing, do NEVER mix a2 antagonists with Glutaminergic stuff! This leads to overstimulation via glutamate and therefore to cell death

[Flex]

One important thing, do NEVER mix a2 antagonists with Glutaminergic stuff! This leads to overstimulation via glutamate and therefore to cell death

[Flex]

One important thing, do NEVER mix a2 antagonists with Glutaminergic stuff! This leads to overstimulation via glutamate and therefore to cell death