My theory for the paradoxical effects that sometimes result from taking stimulants.

[Lightning-Nl]

Around every third or fourth day, I will experience paradoxical effects from taking my ADHD medication - which is Vyvanse at the moment. This is incredibly frustrating for me and while I wait for my next doctors appointment so I can get switched back to Adderall - I thought I'd spitball some idea to why this happens. After googling the mechanism behind Amphetamines paradoxical effects, I can see that there is no medical reason behind why this happens.

I happened to be looking at the ADHD medication "Guanfacine" at the same time and while it's considered a Beta-Blocker (as it has identical effects) it actually agonizes the a2a adrenergic receptor. I believe I remember reading on this forum somewhere that the mechanism behind this is due to the fact that this somehow confuses the body into believing there is too much epinephrine and norepinephrine in the synapses and therefore, somehow, induces reuptake.

While I can't find any evidence on the internet supporting this, if that's the case, is it possible that Amphetamine, especially when in lower doses and due to the fact that Dextroamphetamine has less binding affinity for the adrenergic receptors, could it possibly do the same thing?

Again, I have nothing medical to back me up - just spitballing ideas.

I might add as well - I've never gotten this effect from Adderall. I'm assuming this is due to the Levoamphetamine in Adderall as it has more binding affinity for the adrenergic receptors and less for the dopamine receptors.

 

[sekio]

neither drug has particularly high affinity for the adrenergic receptors, i don't think. it's more of an indirect agonism from monoamine release. l-amphetamine is just an order of magnitude less potent & more selective for NE release.

fairy tales i used to read told of some portion of the meth-using crowd prefering the phenylacetone biker crank (racemic d,l-meth) to the stuff made from ephedrine, because it gave a better "body high".

guanfacine and other drugs like e.g clonidine work because the a2a receptor is an autoreceptor, that is, it is used by the body to monitor levels of the ligand (i.e. epinephrine/norepinephrine). so agonizing it makes the body think there is an excess of epinephrine and it decreases endogenous release. it's kind of like pointing a hot air dryer at a thermostat. you will make the heaters in the room think it's warmer than it actually is, and they shut off.

which "paradoxical effects" are you talking about? and do these effects occur with dexamphetamine as well? maybe adderall has better pharmacokinetics (aren't some of the beads instant release?) whereas the lisdexamphetamine takes too long to build to suitable blood levels.

 

[AlphaMethylPhenyl]

I take amphetamine and experience paradoxical effects only at high doses. It can make me do relatively unproductive things (posting a lot on blue light) instead of chores, but it seems to work consistently, albeit with less euphoria, which is fine.

Not to hijack your thread, but you also said that the euphoria of amp at therapeutic doses actually BUILDS after the 'honeymoon' phase. Emphasis because this is veery intriguing, Do you have any evidence for this? I know that long-term use can manifest psychosis, which may be an extreme of increased stimulation, but euphoria?

My impression was that those with attention disorders oftentimes feel sleepy on amphetamine, simply because its an extension of the relaxation necessitated for concentration.


Hijacked again....http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2010.07073.x/full. I can't even tell if this concludes a positive or negative outcome for the drug.

 

[RobotRipping]

i definitely get sleepy on stimulants to the point i can easily take a nap after taking dexedrine. Since there's no L isomer it's just not going to be as stimulating. Which is probably why you prefer adderrall. I much prefer dexedrine because it is less stimulating.

the paradoxical effects of sleepiness or nodding out on amphetamines are probably related to low dopamine levels in the individual using such drugs. If i take something that primarily releases NE i do not get sleepy at all, just based on that i believe DA is responsible for the typical paradoxial effects experienced by ADD/ADHD patients.

 

[Lightning-Nl]

Not to hijack your thread, but you also said that the euphoria of amp at therapeutic doses actually BUILDS after the 'honeymoon' phase. Emphasis because this is veery intriguing, Do you have any evidence for this? I know that long-term use can manifest psychosis, which may be an extreme of increased stimulation, but euphoria?

I have nothing medical backing me up saying that this is the case. This is something I have experienced personally, however. Although, while looking through studies on PubMed, I came across one that showed long term use of Amphetamines, as well as Methylphenidate (although this appeared to be to a lesser extent with Methylphenidate) appeared to drastically increase overall Dopamine and Serotonin levels throughout brain, as well as heightening acetylcholine levels by up to 210% in the hippocampus and 54% in the caudate nucleus. This part was inconclusive, but they believe long term use of stimulants may also increase the amount of endogenous phenethylamine.

I'm assuming that's the reason why I experienced the euphoria actually come back and BUILD UP overtime; Since more Dopamine and Serotonin is floating around your brain, when another dose of amphetamine is taken, the extremely high levels of Dopamine and Serotonin

My impression was that those with attention disorders oftentimes feel sleepy on amphetamine, simply because its an extension of the relaxation necessitated for concentration.

That's my impression as well. People seem to think that it's because stimulant drugs affect people with ADHD differently than someone who doesn't have ADHD, but this has no medical basis, and is just outright stupid. While it don't think it's because stim affect people with ADHD differently, it could be something else...

 

[sekio]

you've still never clarified what you mean by "paradoxical effects".

which "paradoxical effects" are you talking about? and do these effects occur with dexamphetamine as well? maybe adderall has better pharmacokinetics (aren't some of the beads instant release?) whereas the lisdexamphetamine takes too long to build to suitable blood levels.

i would like to add to this, that perhaps the reason you're noticing vyvanase loses efficacy is because the "trough" blood levels, the concentration of amphetamine in your blood at the lowest point (before you take your dose in the morning, usually) remain consistently higher than those from Adderall, and as such your body just doesn't have as much time to regain equilibrium.

in the worst case, you could be starting off each day still having some level of amphetamine from the previous day in you, so eventually you can reach blood levels that are beyond what would be considered theraputic, leading to either a preponderance of side effects or loss of effects as your body develops a tolerance.

i would suspect a pharmacokinetic reason for wierd effects (or loss of effects) if the vyvanase produces typical f/x, then loses efficacy - not a physiological change, and i would not be pointing fingers at L-amphetamine. dexamphetamine on its own is pretty reliably stimulating. (if you want to go down that road, occam's razor says it's simple tolerance. anecdotally most people seem to get mostly desirable effects initially, but these can fade very rapidly with continual use, despite best-effort tolerance reduction plans, even after about 5-6 doses.)

maybe consider increasing intake of e.g. cranberry juice or other urinary acidifiers. these should help increase excretion of the amphetamines in urine, & help your body regain equilibrium faster at the end of the day. increasing fluid intake in general is probably a good thing. also consider dose reduction, or having "off days" after 2-3 days on amp.

People seem to think that it's because stimulant drugs affect people with ADHD differently than someone who doesn't have ADHD, but this has no medical basis, and is just outright stupid.

if you assume that people with AD(H)D have differences in the way their brains make, recognize, or dispose of neurotransmitters, then assuming amphetamine has a different mode of action in their brain doesn't seem "stupid" to me.

 

[Lightning-Nl]

if you assume that people with AD(H)D have differences in the way their brains make, recognize, or dispose of neurotransmitters, then assuming amphetamine has a different mode of action in their brain doesn't seem "stupid" to me.

While I don't disagree; people with ADHD have (approximately) 80% more reuptake transporters for all Monoamine neurotransmitters. What this means is people with ADHD don't have nearly enough of these neurotransmitters to function "correctly" and while I guess the brain is different in that respect, that doesn't change the pharmacological actions of Amphetamines, stimulants, or hell, any drug for that matter just because the brain happens to reuptake Monoamine transmitters much more quickly.

 

[sekio]

people with ADHD have (approximately) 80% more reuptake transporters for all Monoamine neurotransmitters.

do you have a source for that?

why would amphetamine's effects not be altered (i.e. a dose is less effective) if there is twice as much of the target protien to bind to?

 

[Lightning-Nl]

do you have a source for that?

why would amphetamine's effects not be altered (i.e. a dose is less effective) if there is twice as much of the target protien to bind to?

It's somewhere in this this video. I'll attempt to find the timestamp and edit this post when I do.



Dr. Russell Barkley is an amazing researcher and has greatly advanced our understanding of ADHD over the past 15 years.

 

[sekio]

I think you should provide something a little more substantial than one dude talking in a 3 hour lecture.

The findings on dopamine transporter levels in the striatum of patients with ADHD relative to those of comparison subjects have been inconsistent. While several of the earlier studies showed higher dopamine transporter levels in ADHD patients, some showed no difference and others indicated lower dopamine transporter levels in ADHD. Reasons for the discrepancies could be 1) differences in radiotracers or the methods used, 2) differences in patients’ characteristics, including medication history, comorbid conditions, and age, and 3) differences in study group sizes.
[...]
Two out of the nine studies showed no significant difference in striatal dopamine transporter density between the ADHD and comparison groups, while five studies showed higher dopamine transporter density in the ADHD group and two studies showed lower dopamine transporter density in ADHD. The pooled meta-analysis indicated consistent statistical evidence for greater dopamine transporter density in the ADHD group than in the comparison group in the whole striatum (Figure 3), although the magnitude of the effect size was small. The ratio of striatal dopamine transporter density in the ADHD group to the density in the comparison group ranged from 0.80 to 1.70 (Table 1), with an average value of 1.14. No laterality effect was detected.

http://psychiatryonline.org/data/Journals/AJP/20334/appi.ajp.2011.11060940.pdf

I don't think we can conclusively say that "people with ADHD have higher levels of monoamine transporters". There are such a large number of different subtypes of ADHD, and genetically there are many causes (ref).

 

[Lightning-Nl]

you've still never clarified what you mean by "paradoxical effects".

I apologies, totally forgot to respond to it! Anyways, what I mean is; instead of feeling more awake and having increased focus and motivation, I get really tired. The focus is still there, but the motivation is gone completely. I've actually never taken pure dex. I guess you could call lisdexamfetamine pure dextroamphetamine, but otherwise, I haven't taken a dextroamphetamine only drug before.

As for the Adderall, I believe that's correct. It's nearly half, if not more than half of the beads are instant release.

I don't think we can conclusively say that "people with ADHD have higher levels of monoamine transporters". There are such a large number of different subtypes of ADHD, and genetically there are many causes (ref).

Fair enough, although I assumed it was correct as I'm sure he would've said "we believe this is the way it works" instead of saying that it was absolutely the way it works.

 

[Psychedelic Jay]

Isn’t it related to the reverse tolerance of cocaine?

Coke makes me very sleepy at the end of the day verses more hyped up.

 

[AlphaMethylPhenyl]

I always thought that pure coke, such as pure MDMA, can be simply relaxing.

 

[Psychedelic Jay]

While I don't disagree; people with ADHD have (approximately) 80% more reuptake transporters for all Monoamine neurotransmitters. What this means is people with ADHD don't have nearly enough of these neurotransmitters to function "correctly" and while I guess the brain is different in that respect, that doesn't change the pharmacological actions of Amphetamines, stimulants, or hell, any drug for that matter just because the brain happens to reuptake Monoamine transmitters much more quickly.

That can’t be right?

This must be an average right?

 

[AlphaMethylPhenyl]

http://www.news-medical.net/news/2008/07/09/39870.aspx

Hope that clears things up...

 

[sekio]

This must be an average right?

The ref I pulled suggests the average is closer to 15% more DA transporters.

i don't know why you'd expect everyone to have the same number though.

 

[MrSpeedyG]

I highly doubt that theory of ADHD people having nearly double the amount of monoamine transporters... Never have I read that before.

Pure d-isomer amphetamine, especially meth, used in low doses is relaxing as hell for me and gets my mind straight as an arrow and can sleep and isn't "stimulating", but throw more in and obviously euphoria and stimulaion occur.

I think factors that influence the amount of amphetamine in the blood and other major facots like sleep quality can what cause somedays to seemingly feel paradoxical in effect even though the same dose was ingested... say you take 20mg each morning and it produces the typical effect, but somedays you take the same amount yet slept much better or much worse than usual, you ate food/drink the night before that either helped to create more acidic/alkaline conditions or the big one you ate food with your dose can all effect both the blood levels of amphetamine AND that effects that they have.

I know when I used to take d-amphetamine daily, if I had a shit night sleep the effects would be paradoxical and I would fall asleep sometimes feel a very sedated feeling and feel depressed... whereas if I had a great nights sleep I would feel good and be focussed whilst it was working.

But in terms of speaking about the typical "stimulants have a paradox effect on ADHDers and calm them down"... My above explanation doesn't account for that, but rather explains (most likely) why on SOME days you get differing effects.

I think people try focus on the fact that people with "true" ADHD must have some sort of excess or lack in dopamine transport... Most likely, but probably in a very specific portion of the brain and that lack or excess or dysfunction does not affect other parts of the brain that use dopamine or dopamine plays a role in etc. there is no real way of knowing by use speculating, that is all we can do is speculate! I think the fact that ADHD is very misunderstood and many people are heavily misdiagnosed throws a spanner or two into the works.

 

[Lightning-Nl]

I highly doubt that theory of ADHD people having nearly double the amount of monoamine transporters... Never have I read that before.

Yeah, I was incorrect about that. After looking it up again, it was not all monoamine neurotransmitters - just Dopamine transporters.