So what are the key differences between modafinil vs Adderall?
Adderall is comprised of mixed amphetamine salts. Amphetamines are an old-school drug with a well-characterized mechanism used by both Adolf Hitler and JFK. Amphetamines were repurposed for the treatment of ADHD in the 1990’s, when Adderall was approved by the FDA.
By contrast, modafinil is a relatively new drug with a novel mechanism. Modafinil banishes fatigue without the edginess associated with psychostimulants. Modafinil is safer than amphetamines, but less effective at controlling the core inattentive symptoms of ADHD.
Both drugs are increasingly being used in the workplace and in school to enhance productivity.
ADHD diagnosis rates have increased as the workforce shifts away from blue-collar work toward white-collar desk jobs. A recent article entitled Gin and juice: modafinil tightens up the drinker’s brain at rest describes how modafinil improves the functional connectivity of the default mode network in former alcoholics. The default mode network is just the pattern of neural activity at rest – when your brain isn’t engaged with anything in particular.
It's recent research like the finding that modafinil improves how neurons in the brain talk to one another that has led to the view of modafinil as a nootropic (cognitive enhancer).
Modafinil and Adderall are used for different purposes and don’t fall within the same class of medications. In a sense, the modafinil vs amphetamines comparison is like comparing apples to oranges. Provigil (modafinil) is an anti-fatigue agent, whereas amphetamines acts directly on the dopaminergic reward centers to increase executive function.
The worst-case adverse effect for modafinil is the development of Stevens-Johnson syndrome (SJS), which can be lethal if left untreated. Adderall may rarely precipitate psychosis, adversely affects cardiovascular health, may promote strokes and hypertension.
A number of studies have directly compared modafinil and classic catecholaminergic psychostimulant agents. This table was originally published by Minzenberg et. al.[^10]
Adderall is a prescription psychostimulant that promotes the release of catecholamines (dopamine, norepinephrine) and to a lesser extent serotonin in the brain.
Individuals with attention-deficit hyperactivity (ADHD) are classically calmed down by Adderall, whereas Adderall is experienced as more stimulating and mood-elevating in healthy subjects.
The subjective effects of Adderall include enhanced motivation, concentration, executive function, goal-oriented behavior and organization. Two studies published this year indicate that Adderall may be a nootropic (neuro-enhancer) even in healthy subjects [^1][^2]. One of these studies [^2] was a meta-analysis conducted with over 1400 participants, and demonstrated modest improvement in cognitive measures in subjects without ADHD:
Forty-eight studies (total of 1,409 participants) were included in the analyses. We found evidence for small but significant stimulant enhancement effects on inhibitory control and short-term episodic memory. Small effects on working memory reached significance, based on one of our two analytical approaches.
Effects on delayed episodic memory were medium in size. However, because the effects on long-term and working memory were qualified by evidence for publication bias, we conclude that the effect of amphetamine and methylphenidate on the examined facets of healthy cognition is probably modest overall. In some situations, a small advantage may be valuable, although it is also possible that healthy users resort to stimulants to enhance their energy and motivation more than their cognition.
Adderall use carries significant risks, however. It's associated with adverse events, such as the precipitation of psychosis. Other side effects including insomnia, dependence, personality changes, hypertension, and Reynaud’s syndrome (impaired circulation to the extremities).
Modafinil is a wakefulness-promoting agent that enhances arousal. Tentative evidence suggests that modafinil improves:
Modafinil has been reported to enhance cognitive performance in schizophrenic patients as an adjunct to antipsychotic medication [^3], in healthy sleep-deprived [^4] and non-deprived subjects alike [^5], and improves executive function in alcohol-dependent patients by modulating the functional connectivity of the default mode network [^6].
Quick aside: the default mode network (DMN) is comprised by the brain structures maximally active at rest, and the functional connectivity of this network is classically disrupted in chronic alcoholism.[^7]
Studies using healthy volunteers [^8][^9] suggests that modafinil enhances:
But the degree of improvement is likely related to baseline intelligence. This means that negligible benefits are appreciated by people at the highest end of the IQ bellcurve.
One study [^8], published in Psychopharmacology, concluded the following:
Modafinil significantly enhanced performance on tests of digit span, visual pattern recognition memory, spatial planning and stop-signal reaction time. These performance improvements were complemented by a slowing in latency on three tests: delayed matching to sample, a decision-making task and the spatial planning task. Subjects reported feeling more alert, attentive and energetic on drug. The effects were not clearly dose dependent, except for those seen with the stop-signal paradigm. In contrast to previous findings with methylphenidate, there were no significant effects of drug on spatial memory span, spatial working memory, rapid visual information processing or attentional set-shifting. Additionally, no effects on paired associates learning were identified.
Let's compare modafinil verses Adderall in terms of their nootropic effects. Both drugs clearly enhance cognition in a subset of the population.
Modafinil is most likely to confer cognitive benefits to individuals impaired by sleep deprivation or by a neuropsychiatric disorder associated with cognitive deficits like schizophrenia, depression or bipolar disorder.
Adderall is most likely to improve cognitive function in patients with ADHD or in healthy individuals that have a polymorphism. For example, a genetic variant that affects dopamine metabolism or the sensitivity and density of dopamine receptors.
|Parameter||Adderall (amphetamine)||Provigil (modafinil)|
|Mechanism||Catecholamine releasing agent, weak reuptake inhibitor of dopamine (Ki = 100nM), norepinephrine (Ki = 40-50 nM), and to a lesser extent serotonin (Ki = 1.4-3.8 uM), vesicular monoamine transporter 2 (VMAT2) inhibitor, weak Monoamine Oxidase (MAO) inhibitor||Weakly inhibits the dopamine transporter (DAT), norepinephrine transporter (NET), enhances histamine and orexin release, increases the glutamate/GABA ratio in hypothalamic regions and other brain regions.|
|Indications||ADHD, narcolepsy, obesity, depression||Excessive daytime sleepiness caused by narcolepsy, shift work sleep disorder, or obstructive sleep apnea; ADHD (off-label), disorders of fatigue (e.g., fibromyalgia)|
|Subjective Effects||Enhances arousal, motivation, goal-oriented behavior, focus, task salience, and mood||Promotes wakefulness, mood elevation, arousal and concentration|
|Evidence of cognitive enhancement||A meta-analysis with 1409 participants demonstrated cognitive enhancing effects [^1][^2]||Modafinil enhances vigilance, working memory, impulse control, sustained attention and other cognitive parameters in healthy controls [^8][^9]|
|Safety and Risks||Moderate risk of dopamine-related neurotoxicity||Low risk of glutamate-related neurotoxicity|
|Risk reduction||See this post for more information about amphetamine harm reduction||Magnesium and other NMDA-antagonists can mitigate neurotoxicity risks|
|Common side effects||Headache, weakness, dizziness, blurred vision, feeling restless, irritable, or agitated, insomnia, dry mouth, diarrhea, constipation, stomach pain, nausea, vomiting, fever, hair loss, loss of appetite||Headache, dizziness, nervousness or agitation, nausea, diarrhea, insomnia, or dry mouth|
|Standard dose||5-20 mg||100-200 mg|
|Half-life||10 hours||15 hours|
|References||[^1] Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis (2015), [^2] The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex (2015)||[^8] Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers (2013), [^9] Cognitive enhancing effects of modafinil in healthy volunteers (2003)|
[^1]: Spencer RC, Devilbiss DM, Berridge CW. The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex. Biol Psychiatry. 2015;77(11):940-950.
[^2]: Ilieva IP, Hook CJ, Farah MJ. Prescription Stimulants’ Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis. J Cogn Neurosci. 2015;:1-21. Rosenthal MH, Bryant SL. Benefits of adjunct modafinil in an open-label, pilot study in patients with schizophrenia. Clin Neuropharmacol. 2004;27:38–43
[^4]: Waters KA, Burnham KE, O’Connor D, Dawson GR, Dias R. Assessment of modafinil on attentional processes in a five-choice serial reaction time test in the rat. J Psychopharmacol.2005;19:149–58
[^5]: Makris AP, Rush CR, Frederich RC, Taylor AC, Kelly TH. Behavioral and subjective effects of d-amphetamine and modafinil in healthy adults. Exp Clin Psychopharmacol. 2007;15:123–33.
[^6]: Schmaal L, Goudriaan AE, Joos L, et al. Modafinil modulates resting-state functional network connectivity and cognitive control in alcohol-dependent patients. Biol Psychiatry. 2013;73(8):789-95.
[^7]: Chanraud S, Pitel AL, Pfefferbaum A, Sullivan EV. Disruption of functional connectivity of the default-mode network in alcoholism. Cereb Cortex. 2011;21(10):2272-81. Baranski JV, Pigeau R, Dinich P, Jacobs I. Effects of modafinil on cognitive and meta-cognitive performance. Hum Psychopharmacol. 2004;19:323–32.
[^8]: Muller U, Rowe JB, Rittman T, Lewis C, Robbins TW, Sahakian BJ. Effects of modafinil on non-verbal cognition, task enjoyment and creative thinking in healthy volunteers. Neuropharmacology.2013;64:490–5
[^9]: Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ. Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology (Berl) 2003;165:260–9. [^10]: Minzenberg MJ, Carter CS. Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology. 2008;33(7):1477-502.