Adderall and Modafinil are stimulants commonly prescribed for ADHD, sleep disorders, and fatigue. Their off-label use to enhance cognitive and athletic performance is growing in popularity as people try to meet the demands of our society’s fast-paced lifestyle. Read on to find out how these drugs work, what shared uses they have, and what potential negative effects you should be aware of.
Disclaimer: By writing this post, we are not recommending these drugs. Some of our readers who were already taking one of these drugs requested that we commission a post on it, and we are simply providing information that is available in the scientific and clinical literature. Please discuss your medications with your doctor.
What are Adderall and Modafinil?
Adderall and Modafinil are both stimulants. Because they have different chemical structures and mechanisms of action, Adderall and modafinil differ in their clinical applications and potential side effects [1, 2].
Adderall is used mainly for ADHD and narcolepsy. Modafinil is approved for excessive daytime sleepiness caused by narcolepsy, shift-work sleep disorder, and obstructive sleep breathing cessation and to relieve the fatigue caused by depression and cancer. Modafinil is commercially sold under the brand names Provigil, Modavigil, and Alertec [3, 4, 5].
Adderall is classified as a schedule II controlled substance by the FDA due to its high potential for abuse and physical and psychological dependence. Because modafinil’s potential for abuse is considered to be lower, it is classified as a schedule IV drug [6, 5].
Components
Modafinil is a mixture of both structural variants of 2-[(diphenylmethyl)sulfinyl] acetamide in equal proportions. The two versions of the molecule are mirror images of each other and have different properties. The variants are named with either an “L” for “levo or left” or a “D” for “dextro or right” [7, 8].
Adderall is composed of equal proportions of the following amphetamine salts [1]:
- Dextroamphetamine (d-amphetamine) saccharate
- D-amphetamine sulfate
- Levoamphetamine (l-amphetamine) sulfate
- L-amphetamine aspartate
As in the case of the molecules present in modafinil, d- and l-amphetamine have different properties, are processed differently by the body, and are more effective when used together [9, 10, 11].
Mechanisms of Action
How Modafinil Works
Modafinil partially blocks the dopamine transporter, which prevents dopamine uptake and thus increases its availability in the brain. Modafinil also increases dopamine levels in the brain by partially activating the dopamine D1 and D2 receptors. This promotes wakefulness and might be responsible for increasing motivation, confidence, creative thinking, and task enjoyment [12, 13, 14, 15, 16, 17, 18].
Although modafinil also increases norepinephrine availability by blocking the norepinephrine transporter, this does not appear to be its main mode of action [19, 20].
How Adderall Works
Adderall works by triggering the release of neurotransmitters such as dopamine, norepinephrine, and adrenaline [1, 21].
In addition to stimulating their release, Adderall prevents neurotransmitters from being taken up, broken down, and stored inside nerve cells. This is achieved by blocking the proteins that bring neurotransmitters into the cell, the dopamine and noradrenaline reuptake transporters [1, 22].
It also prevents the storage of dopamine into cell compartments (vesicles) and blocks the proteins that break it down (monoamine oxidases A and B), which increases the dopamine availability in the brain. Higher dopamine levels may be responsible for improving the “perceived intelligence” on Adderall, especially in people with low to average levels of dopamine [23, 24, 25].
Additionally, Adderall stimulates α- and β-adrenaline receptor sites. Stimulating the β-adrenaline receptor site activates the brain by increasing heart rate, blood flow to the muscles, and output of blood from the heart [21, 3].
Adderall is approved by the FDA to treat ADHD and narcolepsy. While these other applications are not approved by the FDA, doctors may prescribe Adderall for its off-label use in people with depression, anxiety, and bipolar disorder. Additionally, some people misuse Adderall for cognitive performance and weight loss.
In turn, modafinil is approved for daytime sleepiness caused by narcolepsy, obstructive sleep apnea, and shift work sleep disorder. It’s sometimes used off-label for ADHD, depression, anxiety, weight loss, and fatigue due to multiple sclerosis.
Whether you are taking modafinil or Adderall, follow your doctor’s instructions carefully. Take these drugs as recommended and do not change their dose and frequency or stop taking them without your doctor’s approval. Your healthcare provider may recommend you to combine them with other medications depending on your condition and symptoms. Talk to your doctor if your condition doesn’t improve or if it worsens.
Approved Uses
1) Narcolepsy
Narcolepsy is a condition characterized by abnormal excessive daytime sleepiness. Both modafinil and Adderall can be used in people with narcolepsy, although a case study on a 60-year-old man showed that Adderall is more effective for late-stage narcolepsy [26, 27].
The capacity of modafinil to reduce narcolepsy symptoms has been proven in a meta-analysis and 8 studies of over 800 people [28, 29, 30, 31, 32, 33, 34, 35, 36].
A form of Adderall, Adderall XR, is preferred for narcolepsy since it works for longer periods and has a lower potential for abuse [37].
Although both drugs promoted wakefulness, Adderall and modafinil acted differently on the circadian rhythm in a clinical trial on 33 people [38].
Two additional trials on 47 people showed that d-amphetamine reduced total sleep time and sleep efficiency compared to modafinil [39, 40].
In an animal study, only amphetamine prevented muscle weakness, a symptom of narcolepsy. In two animal studies, d-amphetamine, but not modafinil, changed the sleeping pattern and increased the need for subsequent sleep [41, 42, 43].
2) ADHD
ADHD is a condition characterized by a frequent lack of attention, excess activity, and impulsive behavior [44].
Adderall is one of the most commonly prescribed stimulants for ADHD in children. A clinical trial on over 150 children found that Adderall was effective for ADHD in 89% of them. The drug mainly increases attention and concentration while reducing distraction and excess activity levels [45].
The beneficial effects of Adderall for ADHD in children and teens are supported by findings of 5 clinical trials on over 300 people [46, 47, 48, 45, 49].
Adderall is also widely prescribed to adults for the short-term management of ADHD, where it is estimated to work in 70% of people. However, its long-term use for ADHD has not proven to be helpful [50, 51].
Similarly, modafinil improved ADHD symptoms in a meta-analysis of studies involving over 900 people and a clinical trial on almost 250 people [52, 53].
In a small trial on 22 people, both modafinil and d-amphetamine improved ADHD symptoms and were well tolerated [54].
However, modafinil was the only drug not showing any beneficial effects for ADHD over placebo in a meta-analysis of 20 studies comparing modafinil, Adderall, Vyvanse, and Ritalin [55].
Off-Label Uses
1) Fatigue
Either alone or in combination with other medications, modafinil reduced fatigue from depression, multiple sclerosis, cancer, or sedative use in multiple studies on over 600 people [56, 57, 58, 59, 60, 61, 62].
In two studies, d-amphetamine increased perceived energy levels [63, 64].
In a clinical trial on 41 people, both modafinil and d-amphetamine were equally effective at improving mood, tiredness, and cognitive performance. Because it had fewer side effects, the study concluded that modafinil was a safer alternative to amphetamines, including Adderall. Interestingly, people on modafinil tended to be excessively confident when evaluating their cognitive performance in the tests [65, 66].
20 mg of d-amphetamine and 400 mg of modafinil were similarly effective in restoring psychomotor performance in three clinical trials on over 150 sleep-deprived people. One study showed that d-amphetamine had the longest effect but modafinil did not disturb the subsequent recovery sleep and had fewer side effects [67, 68, 69].
2) Cognitive Function
Because modafinil and Adderall improve several cognitive traits, both drugs are considered “smart drugs”.
Adderall improves a kind of focus called sustained attention or vigilance, which is the ability to stay attentive on a task for prolonged periods of time [70].
Adderall also improved the performance in different types of tests in two small trials on 46 people [71, 72].
In two trials on 70 people, d-amphetamine improved long-term recall but had no effect on word acquisition [73, 74].
In another trial on 10 people, d-amphetamine improved the performance in a working memory task in people with a low baseline capacity but worsened it in those with a higher capacity [75].
However, the effect of Adderall on cognitive functions can be sometimes difficult to distinguish from that of placebo. Those who thought they were taking the drug improved their cognitive performance regardless of whether they received the treatment or the placebo in a trial on 32 people [76].
Modafinil has also been found to improve several cognitive traits such as:
- Attention and executive functions [77]
- Processing speed [78]
- Memory [77, 79, 80]
- Non-verbal cognitive function [18]
- Task enjoyment [18]
- Creative thinking [18]
In a review of 14 studies, modafinil improved reaction time, logical reasoning, and problem-solving, while amphetamine enhanced consolidation of information [81].
Since it also maintained alertness, feelings of well-being, cognitive function, judgment, risk perception, and situation awareness, modafinil was suggested as a replacement for d-amphetamine in a small trial on 18 people [82].
Both d-amphetamine and modafinil improved planning skills but only modafinil reduced repetitive errors in executive functions in a trial on 54 people [83].
3) Weight Loss
In a clinical trial on 56 people taking amphetamines for ADHD, the most common side effect is weight loss, which was more prominent at higher doses. Weight loss may be due to the fact that amphetamines help control impulsivity, which prevents users from binge eating or snacking [84].
Reduced food intake as a side effect of modafinil was observed in 2 small trials on 33 people [85, 54].
Because modafinil has fewer side effects and a much lower risk of addiction than Adderall, this drug may be a promising medication for obesity. As opposed to amphetamines, modafinil could be used to help weight loss at a dose that does not increase heart rate based on a small clinical trial on 11 people [86].
Side Effects
The long-term use of modafinil at the prescribed dosage can cause [87, 88]:
- Infection
- Headache
- Nervousness
- Nausea
- Anxiety
- Insomnia
- Low back pain
- Indigestion
- Inflammation of the nose lining
- Vertigo
Although rare, modafinil can cause Stevens-Johnson syndrome, a potentially life-threatening skin disease [89].
The most common side effects of Adderall are:
- Dizziness
- Dry mouth
- Headache
- Loss of appetite
- Sleeping difficulties
- Stomach pain
- Weight loss
More serious but less common side effects that should be immediately reported include [90]:
- Agitation
- Allergic reactions (itching or hives, swelling of hands or face, tingling mouth or throat, chest tightness, trouble breathing)
- Anxiety
- Blurred vision
- Confusion
- Diarrhea
- Fainting
- Fever or sweating
- Hallucinations
- Irregular heart rate
- Muscle spasms and twitching
- Nausea and vomiting
- Numb, cold, pale, or painful fingers or toes
- Restlessness
- Seizures
- Unusual mood or behavior
In a small trial on 16 people, d-amphetamine caused higher anxiety, vigor, and blood pressure than modafinil [91].
Abuse and Dependence
Modafinil
The non-medical use of modafinil is growing among students and people who work high-stress jobs with long hours to increase alertness and reduce the need for sleep [2].
Because modafinil does not increase blood pressure, heart rate, and body temperature, it has been used by athletes to reduce fatigue and train more intensely and for longer periods. However, its use is now banned in many sports competitions [92, 2].
Off-label modafinil use can also lead to an overdose, which has these symptoms [93]:
- High heart rate
- Insomnia
- Agitation
- Dizziness
- Anxiety
Modafinil has a low potential for addiction and is even prescribed for withdrawal symptoms in people with addiction to stimulants such as amphetamines and cocaine [94, 12, 95, 96].
However, in one case, an addict who took up to 2 g/day experienced withdrawal symptoms such as [97]:
- Cravings
- Weakness
- Irritability
- Difficulty to focus
Due to the heavy doses of modafinil taken, he had slurring of speech (dysarthria) and reduced attention and concentration [97].
Adderall
Despite its classification as a schedule II substance, Adderall off-label use is common among students. In a survey, 34% of students reported using non-prescribed Adderall to increase their performance. This may be partially due to the perception that Adderall is safe. Most illegal users of Adderall obtained it from peers with a prescription, who often sold, exchanged, or gave some of their medication [98, 99, 100].
Users taking non-prescribed Adderall were more likely to exceed the highest recommended dose. Adderall overdose can cause [21]:
- Enlarged pupils (mydriasis)
- High body temperature
- High saliva production
- Hyperactivity
- Increased blood pressure
- Increased heart rate
- Lack of voluntary muscle coordination (ataxia)
- Low blood sugar levels
- Rapid breathing
- Seizures
- Tremors
Similarly, they were more prone to take the drug for extended periods. Long-term use of Adderall and other amphetamines has been associated with brain damage and abnormalities in brain chemistry, which can lead to psychosis and other mental disorders [23, 101].
Since it increases blood pressure and accelerates heart rate, Adderall use has been associated with heart attacks and other heart conditions, especially in people with a family or personal history of heart problems [102, 103].
Due to its addictive potential, Adderall can cause withdrawal symptoms, which include [23, 104]:
- Aggression
- Anxiety
- Cravings
- Depression
- Fatigue
- Irritability
- Sadness
- Social issues
Drug Interactions
Modafinil
Modafinil blocks CYP2C19 and, to a lesser extent, CYP3A4, enzymes that break down drugs. Thus, it may increase the effect of several medications, including [105, 106, 107, 108]:
- Antidepressants (clomipramine)
- Antiepileptics (diazepam, phenytoin)
- Antifungals (ketoconazole)
- Antipsychotics (haloperidol)
- Benzodiazepines (triazolam)
- Calcium channel blockers (amlodipine)
- Chemotherapeutics (tamoxifen)
- Glucocorticoids (hydrocortisone)
- H1 receptor blockers (chlorphenamine)
- Hypnotics (zopiclone)
- Immunosuppressants (cyclosporine)
- Macrolides (erythromycin)
- Opioids (codeine)
- Protease blockers (ritonavir)
- Proton pump blockers (omeprazole)
- Sex hormones (ethinylestradiol)
- SSRIs (citalopram)
- Statins (verapamil)
Because modafinil itself is partially broken down by CYP3A4, its effect may be increased by drugs that also block this enzyme, such as [109]:
- Antibiotics (clarithromycin and erythromycin)
- Antifungals (ketoconazole and itraconazole)
- HIV antivirals (indinavir, ritonavir, and saquinavir)
- Medications for cardiovascular diseases (diltiazem and verapamil)
In contrast, modafinil levels may be reduced by those stimulating CYP3A4, such as [109]:
- Antibiotics (rifamycin)
- Anti-seizure medications (carbamazepine, phenobarbital, and phenytoin)
- HIV antivirals (efavirenz and nevirapine)
Adderall
Adderall may interfere with the effect of the following medications:
- Acetazolamide (medication for glaucoma, epilepsy, altitude sickness, and heart failure)
- Allergy medications
- Ammonium chloride (cough medicine)
- Antacids and other stomach medicines (cimetidine, esomeprazole, omeprazole, pantoprazole, sodium bicarbonate)
- Antidepressants (lithium, desipramine, fluoxetine, paroxetine, protriptyline)
- Antiepileptics (ethosuximide and phenobarbital)
- Antipsychotics (chlorpromazine and haloperidol)
- Blood pressure medications (guanethidine and reserpine)
- Buspirone (medication for anxiety)
- Fentanyl (sedative)
- Hydrochlorothiazide (diuretic)
- Methenamine (antibiotic)
- Pain medications (meperidine, propoxyphene, and tramadol)
- Phenytoin (stimulant)
- Quinidine (heart rate medication)
- Ritonavir (HIV antiviral)
- Triptan (medicine for migraine headache)
- Tryptophan supplements
Fruit juice and vitamin C can decrease the effect of Adderall by reducing its absorption.
Like all amphetamines, Adderall may enhance the effect of alcohol and cause [110, 111, 112, 113]:
- Blackouts
- Headaches
- Irregular heart rates
- High blood pressure
- Reduced coordination
- Heart attack
People taking monoamine oxidase inhibitors, a class of antidepressant, must wait at least 14 days before taking Adderall since the combination of these two drugs may cause [114]:
- Agitation
- Coma
- High fever
- Muscle spasms
- Seizures
Contraindications and Risk of Use
The modafinil dosage should be reduced in elderly people, as well as in those with liver damage or low levels of the CYP2D6 enzyme [115].
People with a personal or family history of heart conditions should not take Adderall, since it may increase the risk of heart attack or stroke [116, 117].
Other disorders in which the use of Adderall may be contraindicated include [118]:
- High blood pressure
- Liver damage
- Kidney disease
- Narrowing of intestines
- Severe anxiety
- Glaucoma
- Tourette syndrome (multiple muscle twitches)
- Mood disorders such as depression and bipolar disorder
- Frequent seizures
- History of drug or alcohol abuse
- Overactive thyroid
- Allergy to Adderall or amphetamines
Additionally, pregnant and breastfeeding women should consult their doctor before taking Adderall.
Dosage
Modafinil is available in 100-mg and 200-mg tablets. The official doses are [115]:
- 200 mg/day for people with narcolepsy and obstructive cessation of breathing
- 400-600 mg/day for people with narcolepsy who experience late evening sleepiness
- 200-300 mg/day before starting the night shift for people with shift work sleep disorder
Adderall is sold as 5-mg, 10-mg, 15-mg, 20-mg, and 30-mg tablets. The drug can be taken in two different forms [23]:
- Extended-release capsules (Adderall XR): The capsules must be taken 1x/day in the morning to prevent insomnia at night. Their effects peak at 4-7 hours after intake and last for 12 hours.
- Regular tablets (Adderall IR): The tablets must be taken 2x/day in the morning or early afternoon to prevent insomnia at night. Their effects start 45-60 minutes after intake and peak at 2-3 hours.
The highest recommended daily dose in children is 30 mg. Due to the lack of evidence supporting the need for higher doses, adults should not exceed 20 mg/day [23].
Limitations and Caveats
1) Study Outcomes
Although several studies found that modafinil improves ADHD, a meta-analysis could not find any benefits over placebo [55].
The cognitive enhancement effect of Adderall was also difficult to distinguish from that of placebo in one study [76].
2) Study Design
Most studies comparing the effects of Adderall and modafinil had small sample sizes [86, 54, 46, 65, 69, 83].
Many of the studies on their off-label effects were also small. This includes those testing:
- Cognitive enhancement by both drugs [74, 75, 72, 71, 80, 78]
- Weight loss as a side effect of both drugs [54, 85]
- Fatigue relief by modafinil [59, 60, 62, 61]
Few studies on the long-term effects, mechanisms of action, and the addictive potential of modafinil have been carried out. Therefore, it should be taken with caution [2, 5].
3) Study Funding and Conflicts of Interest
Some of the studies were totally or partially funded by companies selling Adderall (Shire Richwood, Inc.) and modafinil (Cephalon, Inc.) [119, 120, 45, 46, 45, 121, 58, 59, 80].
