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.
