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Amphetamine microdose sensitizes the dopamine system

anhedonia amphetamine

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#1 jaiho

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Posted 04 March 2016 - 08:22 AM


http://www.jneurosci...1/9579.full.pdf

 

Credited to a post on reddit.

 

While high-dose stimulant use leads to tolerance, very low dose stimulant use leads to reverse tolerance, which can be permanent.

Tests in human subjects has shown that after been given a low dosage of Amphetamine, the subjective high rating from a large dose of Amphetamine has nearly doubled. In rats, dopaminergic supersensitivity from low-dosage stimulant exposure lasts at least 12 days, and in primates, this hypersensitivity been demonstrated to last at least 2.5 years postwithdrawal.
This means that very low doses of stimulants can permanently increase the brain's sensitivity to dopamine (by increasing dopamine receptors in the high sensitivity state). This can result in long-term increase of self-confidence, motivation and focus.
Now you probably ask yourself - what's so bad about that? Having permanently elevated dopamine sensitivity and 0 stimulant tolerance? That sounds good, right?
Well, it has a dark side. Persistent dopaminergic supersensitivity has a number of negative consequences:
 

  • Impairment of sleep quality. This can result in sleep loss and tiredness during the day.
  • Motor tics. Since dopamine controls movement, an increase of dopamine sensitivity in the basal ganglia and the motor cortex can lead to involuntarily muscle movements.
  • Irrationality. Too much dopamine in the striatum and the nucleus accumbens can make emotion override logical decisions made in the prefrontal cortex.

So, yeah, be careful with very low doses of stimulants. It has been demonstrated countless times that very low doses instantly diminish tolerance, cause long-lasting dopaminergic supersensitivity and increase sensitivity to stimulants administered in the future.
If anyone is wondering about why this happens on the neurochemical level, it is because stimulants, when given in very low dosages, are unable to activate their sites of action to increase monoamines. 
For example, Amphetamine is a full agonist to TAAR1 (that's what makes it release dopamine, in addition to a few other receptors). In high doses, this works great and the usual effects are felt, but when the dosage is too low, Amphetamine is unable to activate this receptor, but it still binds to it. The result? TAAR1 antagonism, which means less dopamine is released. As an homeostatic and hormetic response, dopamine receptors IMMEDIATELY increase their sensitivity and this effect is significantly felt when the next dose of the stimulant is administered.
Here's a couple of anecdotes of this happening (one is about MDMA - while MDMA is not a stimulant, it's an amphetamine and shares similar mechanisms of actions with other amphetamines):
Adderall (Source):

The first few times I tested this out, I took the small dose first and then a larger dose later. (Even though I coincidentally discovered his posts after I got the effect). This time I took 10mg Adderall, at 4.55 am this morning, felt like the normal dose I usually took. 3.5 hours later, I took 1mg Adderall (honestly probably less than 1mg). I got really motivated and accomplished more studying than I had in weeks. I took another 1 mg (probably less) 2 hours later when the motivation was wearing down. I got the same effect for several more hours. I took another 1 mg around mid-day (maybe a little later). I should not have done that. It's 5.17 pm here right now. I felt like I had taken the largest dose of Adderall I have ever taken before (and I have taken up to 100mg in times of final exams.) I was extremely irritable for the past 2-3 hours and had an extreme amount of energy. My chest was very tight and I just felt crazy, like I overdosed. I am crashing pretty bad right now and the last time I felt this way on Adderall was some time around when I started. My pupils are also really dilated. Now, can anyone help tell me if this is hormesis? It sounds like it but I don't really know what's going on. In total I took about 13mg for the most, which felt like over 100mg. I did more work than I have done in weeks-months and I didn't eat anything for the day. I can't remember the last time Adderall gave me that effects, maybe the first few months. BTW, these posts and what I did are real. I made a mistake and posted from this troll account the first time I replied to OP's Hormesis posts so I guess I just continued with this account.

MDMA (Source):

I'm not too sure of taking it [MDMA] a few days before, but I once took a small amount at around 11am, didn't feel much apart from a little bit of jitters and chattiness... then at around 6pm took the same amount and I started rolling hard! I was grinding my teeth, unable to sit still, eye wobbles, slight visual distortion, ridiculous empathy! haha, great experience, but have no idea why

Another one of MDMA (Source):

Unfortunately all I have are anecdotes, which can be unreliable at times. One acquaintance of mine swears by it, though. He would take 20-30mg as a primer dose the day before. I think some people were talking about it on either bluelight or drugs-forum too.

TL;DR: Low doses of stimulants can permanently increase the brain's sensitivity to dopamine, resulting in consequences like stimulant supersensitivity, sleep loss and motor tics. Be very careful with stimulant dosing - obviously don't take high doses that are neurotoxic, but don't take doses that are too low to cause sensitization.

 

 

Very interesting. this might be beneficial for Anhedonia. has anyone tried?


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#2 medievil

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Posted 04 March 2016 - 05:26 PM

I noticed this myself once with ethylphenidate, i had barely any left and for some reason like a little ting smalle then a crumb produced full blown effects, normally all togheter it was one dose and it lasted days. I gotta try this as i cant live life as i need to spend all my money on stims to function.

 

 

 

  • Impairment of sleep quality. This can result in sleep loss and tiredness during the day.
  • Motor tics. Since dopamine controls movement, an increase of dopamine sensitivity in the basal ganglia and the motor cortex can lead to involuntarily muscle movements.
  • Irrationality. Too much dopamine in the striatum and the nucleus accumbens can make emotion override logical decisions made in the prefrontal cortex.

Ne is what stimulates you, i know this from amfolenic acid, also ldopa put me to sleep all day also severe nausia crap.

 

Ppl dont get motor tics from stims, why would do from a more sensitive da system? if im correct da only causes motor tics in certain disorders

how would increased da sensivity cause the same effects as taking a stim, its not that effectivem that said in health individuals stims increase motivation, learning and imo have a positive effect on decission making as they havent been sensitised to the addiction system like addicts where stims cause stupid decission making, except fucking hookers thats never a bad decission.



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#3 stefdude

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Posted 26 May 2018 - 10:08 AM

Anyone tried this?I'm about to try it myself.



#4 John250

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Posted 26 May 2018 - 04:50 PM

Well shoot I might have to give this a try today. What if you are already on higher doses? Also I’m a little skeptical on the word “permanent.” I think it’s pretty hard to “permanently” decrease or increase anything the body usually adapts.

#5 stefdude

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Posted 26 May 2018 - 07:47 PM

Well shoot I might have to give this a try today. What if you are already on higher doses? Also I’m a little skeptical on the word “permanent.” I think it’s pretty hard to “permanently” decrease or increase anything the body usually adapts.

 

Permanent results are said to have been noticed in rodents.I doubt it will be permanent, but it could be a year.I think that you might need a higher microdosing if you are already in high doses?How much do you take?Is it adderall?



#6 John250

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Posted 26 May 2018 - 08:09 PM

Well not really high doses but I take 60mg Vyvanse(=24mg dextroamphetamine) in the morning and 20-40mg adderall in the day. Today I took my vyvanse at 7:30am and around 11am I just tried 1.5mg adderall sublingual. About 30min later I noticed I didn’t crash as bad. Vyvanse is not time released like most doctor say and I absorb it really quickly. Around 12pm I took 0.5mg adderall sublingual. I will say that so far I have noticed I’m not crashing like I normally would. I don’t really feel intense focus and motivation like when I take a full 20 mg but surprisingly the crash hasn’t came on. I’m definitely going to experiment with this protocol more.

I wonder what “low dosing“ is for humans? I am 109kg

Edited by John250, 26 May 2018 - 08:12 PM.


#7 stefdude

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Posted 27 May 2018 - 12:15 PM

Not sure.Try up to 5mg adderall.
I'm testing this with pure amphetamine sulfate (racemic).I have low tolerance and I was using it 1-2 times per week, when needed.15-25mg dosage.

So now I've made 3mg dosages (max 1.5mg dextro) and I'll take 1-2 per day at least 6 hours apart.
78kg

#8 stefdude

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Posted 30 May 2018 - 07:34 AM

I've seen very good results so far.3mg racemic amphetamine, twice/day.The problem is I wake up after 5-6 hours (7-8 hours before) and I notice some memory decline and lack of patience.It's too soon to judge though.I don't know if I should continue microdosing, I'll probably stop for now.

 

It's so unbelievable and strange that I'm thinking, could that be just placebo?How is it possible that noone suggests this?



#9 John250

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Posted 30 May 2018 - 04:20 PM

This is definitely interesting and definitely has some sort of impact. I need to keep experimenting but normally I crash very hard when my Vyvanse wears off after 3-4 hours yet 2.5-5mg adderall has significantly reduce the crash. Yesterday about 4 hours after my vyvanse I took 5mg adderall and lost track of time as I had a few meetings to attend. About 2 hours went by and I realized wow I’m not crashing at all right now. I did not get the high that I normally get from a 20-30 mg adderall dose but got no crash. About an hour after that I took 20 mg Adderall, got the high, but crashed pretty hard about two hours after. I will be experimenting with this protocol over the next few weeks for sure.

#10 stefdude

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Posted 04 June 2018 - 09:03 AM

On Saturday night I took a previously common dose of amph to handle a night out until the morning, 30-35mg.Didn't find it enhanced at all, just normal effects for that dosage.Not sure what this means but if the receptors were indeed sensitized it should have felt stronger.I'll keep testing the micro dosing schedule.



#11 John250

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Posted 04 June 2018 - 04:13 PM

On Saturday night I took a previously common dose of amph to handle a night out until the morning, 30-35mg.Didn't find it enhanced at all, just normal effects for that dosage.Not sure what this means but if the receptors were indeed sensitized it should have felt stronger.I'll keep testing the micro dosing schedule.


I think it’s because 30-35mg is way to high to be considered a microdose. Next time try 5mg sublingual and see what you feel.

#12 stefdude

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Posted 04 June 2018 - 04:24 PM

I think it’s because 30-35mg is way to high to be considered a microdose. Next time try 5mg sublingual and see what you feel.

 

I was taking 3mg doses 2x day for 5-6 days and felt what I posted above.So if the receptors were indeed sensitized then the 35mg dosage should have been felt quite more, it didn't.Also, you shouldn't be able to feel the microdose, that's the point.I continue the microdosing, 4mg 3x day this time.We'll see.



#13 John250

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Posted 04 June 2018 - 05:53 PM

I was taking 3mg doses 2x day for 5-6 days and felt what I posted above.So if the receptors were indeed sensitized then the 35mg dosage should have been felt quite more, it didn't.Also, you shouldn't be able to feel the microdose, that's the point.I continue the microdosing, 4mg 3x day this time.We'll see.


That’s what I noticed that 3-5 mg doses. Didn’t really “feel“ it but didn’t feel a crash either like I normally do. I didn’t use it long enough at that dose to know if it decreased tolerance at a higher dose yet though.

#14 John250

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Posted 05 June 2018 - 07:54 PM

The past 3 days I have had some body aches from weight training so I used a very low dose of OxyContin. Only 3-5mg. I don’t like opiates as they always make me nauseous and they actually cause me to get grumpy and short tempered which is odd. Even at only 5 mg I actually get pretty high and it lasts a long time around 5-6hrs. Anyway something interesting I’ve noticed is the following day I find that I don’t need nearly my normal amphetamine dose. I only need about half if that. Not sure what the correlation is but I figured I would share.

#15 stefdude

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Posted 13 June 2018 - 09:21 AM

Well, the sleep problems are constant now.That's a big difference.I can sleep 5-6 hours only, once a week maybe I'll get 7-7.5 (actually, no.that was with xanax help because I couldn't handle another sleepless day in a row) while a couple of days could be less than 5 even.The plus is that I don't have symptoms of low dopamine any more, no easy tiredness, no sleepiness, day and night literally.With that ammount of sleep I should be a zombie that can sleep in a chair.I have to figure out how to solve this because it's not enough sleep and I can feel it.The exceptions that I can sleep more I'm in a perfect state the next day.Still I prefer that new balance than my old but I have to sleep more somehow.

 

I try to keep xanax at max twice per week, I need a viable solution.No smartphone or hard thinking before bed (although I have blue light filters), no caffeine at afternoon, no midday sleep, perhaps some 5-htp and melatonin.I think I can do it if I control my mind and avoid hard thinking.



#16 John250

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Posted 13 June 2018 - 03:53 PM

Well, the sleep problems are constant now.That's a big difference.I can sleep 5-6 hours only, once a week maybe I'll get 7-7.5 (actually, no.that was with xanax help because I couldn't handle another sleepless day in a row) while a couple of days could be less than 5 even.The plus is that I don't have symptoms of low dopamine any more, no easy tiredness, no sleepiness, day and night literally.With that ammount of sleep I should be a zombie that can sleep in a chair.I have to figure out how to solve this because it's not enough sleep and I can feel it.The exceptions that I can sleep more I'm in a perfect state the next day.Still I prefer that new balance than my old but I have to sleep more somehow.

I try to keep xanax at max twice per week, I need a viable solution.No smartphone or hard thinking before bed (although I have blue light filters), no caffeine at afternoon, no midday sleep, perhaps some 5-htp and melatonin.I think I can do it if I control my mind and avoid hard thinking.


Are you still using amphetamines and if so what’s your current dosing protocol?

#17 stefdude

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Posted 13 June 2018 - 10:30 PM

Are you still using amphetamines and if so what’s your current dosing protocol?

 

No, I have 1 week that I completely stopped.Before that I was dosing 3mg twice a day for 5 days.So my total experiment was 5 days 3mg twice (1st week), 5 days 4mg x3/day (2nd week) and 5 days 3mg twice (3rd and final week).



#18 John250

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Posted 14 June 2018 - 12:36 AM

No, I have 1 week that I completely stopped.Before that I was dosing 3mg twice a day for 5 days.So my total experiment was 5 days 3mg twice (1st week), 5 days 4mg x3/day (2nd week) and 5 days 3mg twice (3rd and final week).


Wow and you can still function and have energy? Did you start anything else?

#19 stefdude

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Posted 14 June 2018 - 10:04 AM

Wow and you can still function and have energy? Did you start anything else?

 

I was never using amphetamines regularly, only as needed and only 1 dose in the morning.Yes, the difference is big so far, we'll see.



#20 theobromananda

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Posted 15 June 2018 - 01:35 PM

Are you trying to sensitize your d-systems? Have you read the post? A sensitized d-system is very undesireable.

 

BPC-157 can be used to reverse sensitization.



#21 stefdude

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Posted 15 June 2018 - 06:05 PM

Are you trying to sensitize your d-systems? Have you read the post? A sensitized d-system is very undesireable.

 

BPC-157 can be used to reverse sensitization.

 

I've read it yes, but in my case it worths the risk.Other than the sleep problems I have no other side effects, only positives.Isnt BPC-157 used if you have a down-regulated dopamine receptors?



#22 jack black

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Posted 15 June 2018 - 08:46 PM

first, the doses used in those studies that were referenced don't strike me as "low-dose" and certainly not "micro-dose." By saying "low dose" the authors probably mean "sub-neurotoxic dose."

2nd, looks like those "sensitization effects" elicited by amphetamine challenge are undesirable, basically psychosis:

 

 

extreme vigilance, tracking of nonapparent stimuli, constant checking, startle responses in the absence of visible/audible stimuli, grasping in midair, and hyper-responsiveness to sensory stimuli (Ridley et al. 1982). This behavioral repertoire is reminiscent of positive-like symptoms in schizophrenic patients.

 

3rd, in between of those "sensitization effects" elicited by amphetamine challenge the monkeys were depressed.

 

 

The monkeys in this study also displayed behavioral depression following withdrawal from chronic AMPH treatment.

 

I don't see anything here being beneficial. Did I miss anything?

 

 



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#23 stefdude

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Posted 15 June 2018 - 09:28 PM

I dont know the equivalent dosage that the monkeys were taking or for how long.I read some anecdotal reports on this and it drew my attention.The positives are many, it's like day and night.Much more energy, I get tired much less, more motivation, much less grogginess in the morning, I wake up and feel fresh like I woke up from afternoon sleep, more sex drive, basically more dopamine as far as I know.It totally worths it, nothing had worked so far except for 6 months last year when I was taking Wellbutrin.Then when I stopped I probably returned to base.

Except for sleep difficulties I didn't notice any other side effect, no paranoia, no motor tics, no aggression except maybe for the first days, no depression, no stimulant sensitivity (I took 2-3 times normal amphetamine dosage and I didn't notice increased effects).


Edited by stefdude, 15 June 2018 - 09:28 PM.





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