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 [R, R].

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 [R, R, R].

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 [R, R].

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” [R, R].

Adderall is composed of equal proportions of the following amphetamine salts [R]:

  • 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 [R, R, R].

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 [R, R, R, R, R, R, R].

Although modafinil also increases norepinephrine availability by blocking the norepinephrine transporter, this does not appear to be its main mode of action [R, R].

How Adderall Works

Adderall works by triggering the release of neurotransmitters such as dopamine, norepinephrine, and adrenaline [R, R].

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 [R, R].

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 [R, R, R].

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 [R, R, R].

Shared Uses of Modafinil and Adderall

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 [R, R].

The capacity of modafinil to reduce narcolepsy symptoms has been proven in a meta-analysis and 8 studies of over 800 people [R, R, R, R, R, R, R, R, R].

A form of Adderall, Adderall XR, is preferred for narcolepsy since it works for longer periods and has a lower potential for abuse [R].

Although both drugs promoted wakefulness, Adderall and modafinil acted differently on the circadian rhythm in a double-blind randomized controlled trial on 33 people [R].

Two double-blind randomized controlled trials on 47 people showed that d-amphetamine reduced total sleep time and sleep efficiency compared to both modafinil [R, R].

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 [R, R, R].

2) ADHD

ADHD is a condition characterized by a frequent lack of attention, excess activity, and impulsive behavior [R].

Adderall is one of the most commonly prescribed stimulants for ADHD in children. A double-blind randomized controlled trial on 154 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 [R].

The beneficial effects of Adderall for ADHD in children and teens are supported by findings of five double-blind randomized controlled trials on 314 total people [R, R, R, R, R].

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 [R, R].

Similarly, modafinil improved ADHD symptoms in a meta-analysis of five double-blind randomized controlled trial studies involving 927 people and a double-blind randomized controlled trial on 248 people [R, R].

In a double-blind randomized controlled trial on 22 people, both modafinil and d-amphetamine improved ADHD symptoms and were well tolerated [R].

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 [R].

3) Fatigue

Either alone or in combination with other medications, modafinil reduced fatigue from depression, multiple sclerosis, cancer, or sedative use in multiple studies with over 600 people [R, R, R, R, R, R, R].

In two studies, d-amphetamine increased perceived energy levels [R, R].

In a randomized controlled trial of 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 [R, R].

20 mg of d-amphetamine and 400 mg of modafinil were similarly effective in restoring psychomotor performance in three double-blind randomized controlled trials on 153 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 [R, R, R].

4) 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 [R].

Adderall also improved the performance in different types of tests in two double-blind randomized controlled trials on 46 total people [R, R].

In two double-blind randomized controlled trials on 70 total people, d-amphetamine improved long-term recall but had no effect on word acquisition [R, R].

In a double-blind randomized controlled 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 [R].

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 double-blind randomized controlled trial on 32 people [R].

Modafinil also improved several cognitive traits such as:

  • Attention and executive functions [R]
  • Processing speed [R]
  • Memory [R, R, R]
  • Non-verbal cognitive function [R]
  • Task enjoyment [R]
  • Creative thinking [R]

In a review of 14 studies, modafinil improved reaction time, logical reasoning, and problem-solving, while amphetamine enhanced consolidation of information [R].

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 double-blind randomized controlled trial on 18 people [R].

Both d-amphetamine and modafinil improved planning skills but only modafinil reduced repetitive errors in executive functions in a double-blind randomized controlled trial on 54 people [R].

5) Weight Loss

In a double-blind randomized controlled trial of 56 people taking amphetamines for ADHD, the most common side effect was 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 [R].

Reduced food intake as a side effect of modafinil was observed in a double-blind randomized controlled trial and a randomized controlled trial on 33 total people [R, R].

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 (double-blind randomized controlled trial on 11 people) [R].

Side Effects

Long-term use of modafinil at the prescribed dosage can cause [R, R]:

  • 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 [R].

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 include [R]:

  • 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 double-blind randomized controlled trial on 16 people, d-amphetamine caused higher anxiety, vigor, and blood pressure than modafinil [R].

Abuse and Dependence

Modafinil

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 [R].

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 [R, R].

Off-label modafinil use can also lead to an overdose, which has these symptoms [R]:

  • 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 [R, R, R, R].

However, in one case, an addict who took up to 2 g/day experienced withdrawal symptoms such as [R]:

  • 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 [R].

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 sell, exchange, or give some of their medication [R, R, R].

Users taking non-prescribed Adderall were more likely to exceed the highest recommended dose. Adderall overdose can cause [R]:

  • 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. [R, R].

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 [R, R].

Due to its addictive potential, Adderall can cause withdrawal symptoms, which include [R, R]:

  • 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, modafinil may increase the effect of several medications, including [R, R, R, R]:

  • 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 will be increased by drugs that also block this enzyme, such as [R]:

  • Antibiotics (clarithromycin and erythromycin)
  • Antifungals (ketoconazole and itraconazole)
  • HIV antivirals (indinavir, ritonavir, and saquinavir)
  • Medications for cardiovascular diseases (diltiazem and verapamil)

In turn, modafinil levels will be reduced by those stimulating CYP3A4, such as [R]:

  • 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.

As all amphetamines, Adderall can enhance the effect of alcohol and cause [R, R, R, R]:

  • 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 can cause [R]:

  • 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 [R].

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 [R, R].

Other disorders in which the use of Adderall may be contraindicated include [R]:

  • 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 ask their doctor before taking Adderall.

Dosage

Modafinil is available in 100-mg and 200-mg tablets. The recommended doses are [R]:

  • 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 [R, R]:

  • 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 [R].

Limitations and Caveats

1) Study Outcomes

Although several studies found that modafinil improves ADHD, a meta-analysis could not find any benefits over placebo [R].

The cognitive enhancement effect of Adderall was also difficult to distinguish from that of placebo in one study [R].

2) Study Design

Most studies comparing the effects of Adderall and modafinil had small sample sizes [R, R, R, R, R, R].

Many of the studies on their off-label effects also were small:

  • Cognitive enhancement by both drugs [R, R, R, R, R, R]
  • Weight loss as a side effect of both drugs [R, R]
  • Fatigue relief by modafinil [R, R, R, R]

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 [R, R].

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.) [R, R, R, R, R, R, R, R, R].

About the Author

Carlos Tello, PhD (Molecular Biology)

PhD (Molecular Biology)

Carlos received his PhD and MS from the Universidad de Sevilla.

Carlos spent 9 years in the laboratory investigating mineral transport in plants. He then started working as a freelancer, mainly in science writing, editing, and consulting. Carlos is passionate about learning the mechanisms behind biological processes and communicating science to both academic and non-academic audiences. He strongly believes that scientific literacy is crucial to maintain a healthy lifestyle and avoid falling for scams.

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