Adderall, Stimulants & Modafinil for ADHD: Short- & Long-Term Effects

ADHD is characterized by hyperconnected brain networks where the prefrontal cortex fails to properly suppress or enhance activity of other networks like the default mode network, salience network, and dorsal attention network, not by deficient dopamine or norepinephrine levels.

“the brains of children and adults with ADHD have all of these networks functioning but those networks are actually hyper connected that is they tend to be co-active at times when ordinarily meaning kids and adults without ADHD they would not be co-active”

Dopamine acts to reduce neural noise by suppressing background signals and irrelevant external stimuli and internal distractions, while norepinephrine increases signal amplitude and frequency at specific synapses, together producing the noise reduction and signal amplification needed for focused attention.

“dopamine while it does many different things in the brain many many different things one of its main functions in the context of all this prefrontal cortex and attention stuff is to quiet the amount of noise that is it helps the prefrontal cortex suppress the signals that would otherwise distract us into thinking about oh yeah I'm kind of thirsty right now or I need to use the restroom or I really want to make this caller I really really want to pick up my phone”

Chronic elevation of sympathetic nervous system activity through sustained stimulant use increases cortisol levels throughout the day and evening, which can suppress testosterone and other steroid hormones through competitive use of cholesterol precursors, potentially reducing libido and affecting sexual function.

“first of all when you increase the activity of the sympathetic nervous system for long periods of time you are very likely increasing levels of cortisol cortisol is a quote unquote stress hormone but cortisol also plays some really important positive roles in your body”

Proper assessment of ADHD requires careful clinical evaluation by qualified psychiatrists using multiple diagnostic criteria (over nine criteria for each of the hyperactivity, impulsivity, and inattention categories), not just symptom report.

“diagnostic criteria include many things in children there are multiple there are more than nine diagnostic criteria for each of the categories relating to impulsivity hyperactivity and so on so a well-qualified psychiatrist will do several things they will first of all do a careful diagnostic evaluation of a child”

The locus ceruleus is a small nucleus of neurons in the back of the brain that releases norepinephrine throughout the brain via an extensive axonal projection system similar to a sprinkler system, capable of releasing norepinephrine either widely or at focal locations, and can modulate both the amplitude and frequency of neural communication.

“within the brain there's one major site of neurons that manufacture norepinephrine and the name of that site is Locus ceruleus it sits in the back of the brain it's actually a relatively small collection of neurons but they are very very powerful they extend their little axons their wires to multiple locations in the brain and they release norepinephrine at those locations so think of them sort of as a sprinkler system that originates from one very focal location but that can sprinkle norepinephrine at multiple locations in the brain”

ADHD is not an inability to focus but rather extreme difficulty in focusing on things required for life advancement (sustained attention tasks, conversations not of particular interest, etc.), while many people with ADHD can demonstrate intense focus on activities they find highly engaging.

“as in the general population children and adults with ADHD are capable of very concentrated periods of focus the pattern however tends to be that children and adults with ADHD have a harder time getting into that state of focus and perhaps most importantly they have a very hard time getting into a forced state of focus for things that they don't enjoy doing”

Most long-term studies on ADHD medication effects have focused on methylphenidate (Ritalin) rather than Adderall or Vyvanse because Ritalin was one of the first drugs used to treat ADHD; children who received Ritalin early are now adults and can be studied, whereas Adderall/Vyvanse-treated cohorts haven't yet reached adulthood to assess long-term outcomes

“most of the literature on the long-term effects of taking drugs to treat ADHD has focus on methylphenidate on Ritalin there are studies on Vyvanse and adderall... the reason why so many of the Studies have focused on methylphenidate on Ritalin is largely because that was one of the first drugs used to treat ADHD so in terms of addressing long-term effects so kids treated with ADHD meds those kids are now adults”

Adderall is a combination of D-amphetamine (75%) and L-amphetamine (25%) where D-amphetamine acts mainly on brain receptors for dopamine effects while L-amphetamine increases peripheral sympathetic effects like heart rate and blood pressure.

“Adderall is a three to one ratio of D amphetamine to L amphetamine you should know that L amphetamine tends to be less potent in increasing certain neurochemicals in the brain I'll talk about which neurochemicals they are in a moment then is D amphetamine so D amphetamine is potent stuff not as potent as methamphetamine but very potent stuff l-amphetamine a little bit less potent L amphetamine tends to be the amphetamine that increases blood pressure and heart rate what we call peripheral effects because it happens in the periphery outside the central nervous system peripheral effects like increased heart rate increased blood pressure sweating Etc are mostly activated by L amphetamine whereas D amphetamine tends to work mainly on receptors in the brain”

Vyvanse is D-amphetamine covalently bonded to the amino acid lysine, making it a pro-drug that is slowly cleaved in the bloodstream to release D-amphetamine over 12-18 hours, functionally creating a time-released dexedrine rather than extended-release Adderall.

“Vivant is a drug in which the pharmaceutical industry has taken one component of Adderall just the D amphetamine component and attached to it an amino acid called lysine now the amino acid lysine is a big amino acid and the attaching of Lysine to D amphetamine what we call vivance makes it what's called a pro drug it actually can't have any effect on its own but when one takes Vyvanse and it's broken down in the gut but to a greater extent actually in the bloodstream the lysines are cleaved off slowly over time”

Methylphenidate (Ritalin) increases dopamine primarily by inhibiting the dopamine transporter, with minimal effects on norepinephrine, using only one mechanism of action compared to Adderall's three mechanisms, making it less potent at increasing dopamine and norepinephrine overall.

“Ritalin methylphenidate does increase dopamine transmission at synapses and it does so also by inhibiting the function of that presynaptic dopamine transporter that would otherwise suck more dopamine back up into the presynaptic cell methylphenidate Ritalin also disrupts the activity of the noradrenergic transporter leading to net increases in the amount of norepinephrine at the synapse but it is not as much a potent inhibitor of the noradrenergic transporter and therefore most of the effect of methylphenidate is to increase dopamine at synapses”

Repeated daily ADHD medication use leads to smaller dopamine peaks over time through homeostatic plasticity rather than desensitization, allowing systems to equilibrate such that synaptic connections strengthen without requiring persistently elevated dopamine.

“it is the repeated taking of that drug by the child with ADHD or by the adult with ADHD that actually leads to lesser and lesser peaks in dopamine each time which is not to say that the person becomes entirely desensitized to the effects of the drug but rather that the system equilibrates through what's called homeostatic plasticity sometimes referred to broadly as habituation to a drug but there are systems in the brain and body that regulate the connections between neurons so that if dopamine and norepinephrine are elevated above Baseline levels for a while the system normalizes so that instead the connections between neurons become stronger”

The sympathetic nervous system is not the fight-or-flight system alone, but mediates alertness, focus, sexual arousal, excitement about learning, and readiness states generally, while the parasympathetic system does more than rest-and-digest, also mediating some forms of sexual arousal and other functions.

“the sympathetic arm of the autonomic nervous system has nothing to do with sympathy has everything to do with ramping up our level of attention and arousal it is the so-called fight or flight aspect of our nervous system or rather it mediates fight or flight but immediates a bunch of other things too including sexual arousal including excitement and focus about something that we want to learn”

It is extremely difficult to predict individual responses to ADHD medication based on weight, genetics, or other observable factors, with some individuals requiring as little as 2.5mg of Adderall for therapeutic effect while others require 180-240mg daily, making individualized dosing under psychiatrist supervision essential.

“it is extremely extremely difficult to predict how a child or adult will react to a given dosage of any of these drugs so much so in fact that he anecdotally reported to me that one of his patients is a male 3 100 pounds diagnosed with ADHD and who achieves tremendous relief from just 2.5 milligrams of Adderall per day and at the same time he has two patients both of whom are sisters so they're genetically related who are in the 120 to 140 pound range who did not respond well at all for the treatment of their ADHD until their dosages were very very high”

Children with true ADHD who are treated with appropriate doses of prescription sympathomimetics show far better performance in school, general focus, and long-term life outcomes compared to untreated children, with treated children also having lower likelihood of developing addictive behaviors in adulthood.

“children with ADHD true ADHD who are diagnosed with ADHD and are treated with appropriate doses of drugs like Adderall ritalin or Vyvanse they're far better both in childhood and later in life when it comes to Performance in school performance in terms of focusing on anything and in terms of General outcomes”

Individuals with family history of psychosis or schizophrenia have increased predisposition to psychotic episodes from ADHD medications, with amphetamine-type stimulants (Adderall) creating greater risk than methylphenidate (Ritalin), and Vyvanse's extended release creating lower risk than immediate-release formulations.

“having a first relative with schizophrenia or with bipolar depression or sometimes called bipolar disorder sometimes it's also just called bipolar these days is going to be a strong predisposition for psychotic episodes made much greater anytime one takes a sympathomimetic drug such as amphetamine but also methylphenidate Ritalin is going to increase that likelihood of psychotic episodes”

As many as 80% of college-age young adults report having used prescription ADHD medications without a prescription at some point, obtaining them from people with prescriptions or black market sources, exposing them to fentanyl contamination present in 75% of black market drugs.

“some surveys reveal that as high as 80 percent of college-age young adults have used one or several of prescription drugs such as adderall Ritalin Vyvanse or similar at some point and are doing so without a prescription so they are either obtaining those drugs from those that do have prescriptions for them for ADHD or they are obtaining them through Black Market sources which of course carries an additional and very serious risk related to the so-called fentanyl crisis that is as high as 75 percent of black market drugs nowadays”

Guanfacine is sometimes prescribed in combination with other ADHD medications (e.g., Adderall + guanfacine or Vyvanse + guanfacine) to offset side effects, though this polypharmacy approach raises concerns about cumulative effects

“yes there are kids out there and adults out there who are taking Adderall and guanfacine where they're taking Vyvanse and guanfacine and this is where it starts to get into drug cocktails and a bunch of other things that gets everybody a little bit uncomfortable”

Methamphetamine is responsible for neurotoxic damage to serotonergic and dopaminergic neurons and increases dopamine levels 5 times more than Adderall, with extremely rapid onset and offset that creates severe peaks followed by crashes below baseline dopamine, driving both addiction potential and psychosis risk across all populations regardless of genetic predisposition.

“methamphetamine is considered an illicit drug a drug of abuse it is responsible for a lot of The Misfortune and tragedy... it is neurotoxic to serotonergic neuron so it kills serotonin neurons that is absolutely clear it kills dopaminergic neurons that is absolutely clear”

Guanfacine profoundly reduces tolerance for alcohol such that even small amounts can cause serious problems and potentially death, making it a very serious warning for off-label use.

“one note about guanfacine in no way shape or form am I encouraging anyone who's not prescribed guanfacine to take it but should you know someone who's taking guanfacine off label in order to improve their focus or enhance any aspect of their biology or psychology please let them know that it has a profound effect on lowering the tolerance for alcohol such that even small amounts of alcohol can lead to really serious problems and even potentially death”

The prefrontal cortex serves as an orchestra conductor orchestrating which neural circuits should be active or inactive through top-down inhibition, enhancing relevant circuits while suppressing irrelevant ones to enable focus, task-switching, and adaptive behavior.

“the prefrontal cortex has this amazing ability through what's called top-down inhibition to quiet other brain areas... your prefrontal cortex that is controlling that active suppression”

There are no published peer-reviewed studies supporting the common belief that generic versions of ADHD medications (particularly generic Adderall) are less potent or effective than brand-name versions, despite tens of thousands of people reporting this; the belief may reflect a 'belief effect' or real but undocumented differences in pill binders.

“I went into the literature to try and find any real concrete support for the idea that generic adderall is less potent or less effective than brand name Adderall and despite the tens of thousands of people who will say to the contrary I could not find any peer-reviewed published data about that so who knows maybe it's a belief effect as it's called maybe there's a real difference there”

Modafinil and armodafinil can cause side effects including decreased appetite, runny nose, and headache, and in rare cases Stevens-Johnson syndrome with severe skin blistering that can be fatal, which is one reason these drugs are not more widely prescribed for ADHD.

“both modafinil and armodafinil are associated with a good number of side effects if they don't agree with you or if the dosage is too high things like decreased appetite people get a run nose headache there's this instance of skin rashes in fact one of the reasons why modafinil and arm modafinil aren't more broadly prescribed is that there's a very rare skin condition in which people who have taken certain drugs not just modafin or arm modafinil have developed these very severe burn type blisters and in some cases this can be fatal this is again very rare and it was observed in at least one patient who took modafinil”

Guanfacine is an alpha-2A agonist that was developed as a blood pressure-lowering medication and works as a non-stimulant ADHD treatment by increasing norepinephrine through the alpha-2A receptor system without affecting dopamine.

“guanfacine is an interesting compound it's a compound that was developed to lower blood pressure and indeed it does lower blood pressure and it is an alpha 2A Agonist Alpha 2A being a receptor for norepinephrine so guanfacine is a non-stimulant medication to treat ADHD and it's also used to treat some other conditions as well that is only working on the noradrenergic system it is not tapping into the dopamine system”

Combining alcohol with sympathomimetic ADHD medications is more detrimental to the brain and body than taking the medications alone, despite alcohol and sympathomimetics having opposite effects on the nervous system, and alcohol should be avoided when taking ADHD medications.

“combining alcohol with sympathomimetics even though they reside in very different Pathways within the brain in fact the sympathomimetics are driving up sympathetic nervous system activity whereas alcohol is actually doing the opposite it's depressing it and yet all the data points to the fact that combining alcohol with sympathomimetics such as Vyvanse Adderall ritalin or any kind of amphetamine is going to be more detrimental to the brain and body than simply taking those drugs on their own put differently and more directly if you are taking any of the drugs that we've been talking about to treat ADHD or if you just happen to be taking them for whatever reason you are going to want to avoid drinking alcohol at any time”

Tapering off ADHD medications should be done under close psychiatrist supervision rather than abrupt cessation, as sudden discontinuation produces withdrawal symptoms including lethargy, depressed mood, and focus difficulties.

“there is a withdrawal potential of Simply stopping these drugs very quickly because they do ramp up dopamine and norepinephrine... if one very abruptly ceases taking any of these drugs it does not feel good that drop in dopamine that one inevitably experiences is almost always associated with lethargy with depressed mood with feeling not good in a number of ways and of course challenges in Focus so anytime one is going to go off one of these drugs or sample what it is to even reduce dosage that has to be done in close communication with a board-certified psychiatrist”