How do stimulants (like Adderall) work?

The terms stimulant and psychostimulant aren’t well defined. Cocaine, amphetamine, methylphenidate, modafinil, armodafinil, caffeine, and nicotine belong to a class of drugs called psychostimulants for the marked sensorimotor (sensory and motor) activation that occurs in response to drug administration. Stimulants are characterized by their ability to increase alertness, heighten arousal, and cause behavioral excitement.

Stimulants have a rich history which is beyond the scope of this post. 

Today, psychostimulants are prescribed for the treatment of attention-deficit hyperactivity disorder (ADHD), narcolepsy, chronic fatigue, depression, and cancer-related fatigue to name a few. Stimulants are also drugs of abuse (such as cocaine, illicit methamphetamine, nicotine, and caffeine).

Let’s take a closer look at psychostimulants and how they work. 

Table of Psychostimulants

Dopamine and Norepinephrine

Dopamine (DA) and norepinephrine (NE) are monoamine neurotransmitters in the central nervous system that play very important roles in altering (or modulating) the communication between neurons. DA and NE are released from vesicles (called synaptic vesicles) into the synaptic cleft (i.e., area between neurons). DA and NE are recycled via reuptake into the neuron by transporter proteins called dopamine and norepinephrine transporters (see diagram below).

After being pumped back into the neuron by the transporters, dopamine (DA) and norepinephrine (NE) are taken up into small vesicles (little bubbles) called synaptic vesicles. They get pumped in by more transporter proteins called vesicular monoamine transporter 2 (VMAT2). Now they are ready to be released again!

After being released from the neuron, DA and NE bind to their receptors on the postsynaptic neuron (the next neuron).

See the figure below.

Both amphetamine (AMPH) and methylphenidate (MPH) target the dopamine and norepinephrine systems by increasing the concentration of these neurotransmitters in the synapse. AMPH has additional properties of promoting release by reversing the dopamine and norepinephrine transporters.

Amphetamine, AMPH (Vyvanse, Dexedrine, Adderall)

Amphetamine (AMPH) has numerous mechanisms.

First, it can be taken up into neurons via the dopamine transporter or norepinephrine transporter and then cause the transporters to reverse their actions, which means dopamine is pumped OUT instead of IN to the neuron.

Second, AMPH enters vesicles through VMAT2 and displaces dopamine by “forcing” dopamine out of the vesicle and into the cytoplasm which increases the dopamine concentration in the neuron and creates a gradient so that dopamine can “leak” out of the neuron through the dopamine reuptake pumps. This increases the dopamine concentration in the synaptic cleft.

Methylphenidate, MPH (Ritalin, Concerta, Focalin)

Methylphenidate (MPH) acts by inhibiting the dopamine and norepinephrine transporters only which increases the concentrations of dopamine and norepinephrine in the synapse. In this way, methylphenidate acts similar to cocaine. See the figure below.


Confused yet? Just keep reading…

Psychostimulants Reduce Noise and Enhance Signals

In individuals with attention and/or concentration problems, there may be a problem with how the brain is processing sensory input. Our brains spend an enormous amount of energy (up to 20-30% of all energy used by your body) processing information below our level of awareness. In fact, only a very small percentage of brain activity contributes to our conscious awareness (roughly 15%). The rest of the activity is all the unconscious processing, integrating, and analyzing of information that ultimately results in complex behavior. Much of the brain’s energy is spent “deciding” which signals are relevant and need to be brought to conscious awareness.

Think of all the activities we do that we aren’t even aware of.

While walking down the street talking with someone, do you actively feel your left big toe? Well, no, not unless you have pain or stub your toe. We aren’t aware of our left big toe because it’s irrelevant to what we are doing. But this doesn’t mean those signals are physiologically absent.

Dopamine and norepinephrine are neurotransmitters in the brain that act like the tuners of a piano. The strings of the piano that create the sounds represent the glutamate and GABA neurons that are the primary excitatory and inhibitory neurotransmitters in the mammalian brain, respectively. Dopamine and norepinephrine are there to tighten the strings so the music sounds good. No one likes a song that’s out of tune. That is, dopamine and norepinephrine are those “tuners” of the brain–they modulate communication between neurons. They help our brain decide what to ignore and what to focus on.

In fact, norepinephrine in the prefrontal cortex (PFC) plays a role in enhancing relevant and important signals so that we focus on relevant and important things.

Low-to-moderate concentrations of norepinephrine (NE) mediate these actions by acting preferentially on postsynaptic 𝛼2A-adrenoceptors.

However, as the concentration of norepinephrine increases, norepinephrine begins stimulating 𝛼1 and 𝛽-adrenoceptors.

Stimulation of 𝛼1-adrenoceptors and 𝛽-adrenoceptors (which occurs in high stress states) impairs our ability to focus.

This makes sense as there is no reason to focus on minutiae when a lion is chasing you…

So…when the NE concentration is too low, the signal strength (i.e., our ability to focus on things) is low. But as the NE concentration increases so does the signal strength (i.e., our ability to focus on things) until it reaches a peak. After that, any additional increase in NE impairs our ability to focus.

This explains the inverted U shaped curves depicted below.

Dopamine in the prefrontal cortex (PFC) plays a role in filtering out the irrelevant stimuli. That is, dopamine D1 receptors in the prefrontal cortex reduce the “noise” or irrelevant stimuli so that we can focus on relevant and important things without being distracted.

When DA levels are too low, all incoming signals, whether they are relevant or not, are treated in the same way. Therefore, it becomes difficult to focus on a single task as there are too many distracting stimuli. However, as the concentration of DA increases to moderate levels, it will decrease ‘noise’ by stimulating D1 receptors. This results in decreased firing of neurons to irrelevant inputs in PFC networks.

When DA levels are too high, D1 receptors in the prefrontal cortex are overstimulated and the brain’s ability to filter out the noise declines. Stressful situations and illicit drug use can cause dopamine levels to be too high.

Therefore, medications like amphetamines (Vyvanse, Adderall), methylphenidates (Ritalin, Concerta, Focalin), bupropion (Wellbutrin), and atomoxetine (Strattera) alter norepinephrine and/or dopamine levels to “enhance the signal” while “reducing the noise,” respectively. 

Medications (or illicit drugs) that enhance dopamine too much in certain regions of the brain may cause us to “hyper focus” or “fixate” our attention on unproductive tasks. In addition, the euphoria and motivational reinforcement that results from overstimulation of dopamine receptors in the nucleus accumbens increases the risk for addiction and drug abuse.

In summary, we don’t want too much stimulation of dopamine (D1) receptors because this is associated with euphoria, hyper focus (like scrubbing the floor with a toothbrush), impaired attention, and drug addiction. We don’t want too little stimulation of dopamine (D1) receptors because this is associated with anhedonia, depression, lack of motivation, and apathy.

The same goes for norepinephrine. We don’t want too much norepinephrine because then we will feel symptoms associated with the fight or flight response such as anxiety, hypervigilance, racing heart, sweating, and shortness of breath. We don’t want too little norepinephrine because then we will feel symptoms like fatigue, depression, drowsiness, and weakness.

Therefore, we want our DA and NE to be not too hot and not too cold, but just right (yes, like Goldilocks). This is why controlled doses of stimulants can be very beneficial for some people. 



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