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):
MDMA (Source):
Another one of MDMA (Source):
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?