Modafinil, known under the brand name Provigil, is a prescription medication primarily used to promote wakefulness and manage conditions characterized by excessive daytime sleepiness. While not approved by the FDA for weight loss, some research and anecdotal evidence suggest a potential link between modafinil and weight management. This article explores the possible effects of modafinil on weight loss, its mechanisms of action, side effects, and other considerations.
Primary Uses of Modafinil
Modafinil is approved for managing narcolepsy with or without cataplexy. Narcolepsy is a neurological disorder characterized by an overwhelming urge to sleep during the day and may include symptoms like cataplexy (sudden muscle weakness), sleep paralysis (inability to move or speak while falling asleep or waking up), and hallucinations. Narcolepsy is linked to a deficiency in the brain chemical hypocretin (orexin), mainly produced in the hypothalamus. Modafinil is not a cure for narcolepsy, but it can help manage its symptoms and may also reduce the frequency and severity of cataplexy attacks in some people.
Modafinil is also used for shift work sleep disorder and obstructive sleep apnea.
Off-Label Uses of Modafinil
Beyond its approved uses, modafinil is sometimes prescribed off-label for other conditions, including as an adjunctive treatment for the acute depressive phase in bipolar disorder, which may feature excessive sleepiness and fatigue. The depressive phase of bipolar disorder may feature excessive sleepiness and fatigue. Modafinil and armodafinil have been repurposed as adjunctive treatments to alleviate symptoms of acute depressive phase in people with bipolar disorder. Drug repurposing in psychiatry is a strategy for discovering new uses for drugs that have already been approved or tested in clinical trials for other illnesses.
Modafinil has also been used non-medically as a "smart drug" by various groups, including students, office workers, transhumanists, and professionals in various sectors. The effectiveness of modafinil as a cognitive enhancer is still debated.
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Appetite Suppression and Weight Loss
Weight loss wasn’t a reported side effect during 9-12 week clinical studies of Provigil (modafinil) submitted to the FDA for approval. However, nausea, indigestion, and poor appetite are common side effects of Provigil. As of March 2024, the FDA has received 168 reports of weight loss in patients taking Provigil. Provigil is not FDA approved to treat weight loss. If you are experiencing a loss of appetite or weight loss while taking Provigil, consult with your healthcare provider.
Studies on Food Intake
In a limited number of studies modafinil has been shown to decrease food intake by laboratory animals and humans. In one study, individuals taking modafinil consumed less food. Compared to amphetamine, which also increases wakefulness and decreases appetite, modafinil did not cause increased heart rate at high doses.
One study represents a secondary data analysis, in which the effects of modafinil on several measures of food intake were determined in humans living in a residential laboratory during simulated shift work. During this 23-day study, a wide selection of food items and beverages were freely available. During this double-blind, within-participant study, volunteers (N = 11) received oral modafinil dose (0, 200, or 400 mg) one hour after waking for three consecutive days under two shift conditions: day shift and night shift. Shifts alternated three times during the study, and shift conditions were separated by an "off" day. Modafinil (200, 400 mg) dose-dependently decreased total caloric intake by ~18% and ~38%, respectively, regardless of shift condition, without selectively altering the proportion of total calories derived from carbohydrate, fat and protein. Ratings of “Hungry” were also significantly decreased by both active doses, but only immediately before the lunch break period.
Neurochemical Actions
Although its exact neurobiological mechanisms are unknown, modafinil binds to both the dopamine and norepinephrine transporter at clinically relevant doses; a large database suggests that the ability of the drug to enhance catecholaminergic activity is crucial to its currently approved therapeutic actions. Modafinil has also been shown to increase serotonin (5-HT) turnover in several brain regions including the frontal cortex, the amygdala, and the dorsal raphe. These neurochemical actions are consistent with effects produced by many medications approved to treat obesity.
Comparison with Amphetamine
In a study comparing modafinil and amphetamine, researchers reported that modafinil produced food intake reductions comparable to those produced by d-amphetamine. However, modafinil-associated effects were not dose-dependent, as food intake was significantly decreased only by one dose (3.5 mg/kg or ~245 mg).
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Side Effects and Risks
Modafinil is generally well-tolerated but can have potential risks and side effects. Common side effects of modafinil include anxiety, insomnia, dizziness, and headache.
Serious Adverse Reactions
Rare but serious adverse effects include severe skin rashes and allergy-related symptoms. Between December 1998 and January 2007, the FDA received reports of six cases of severe cutaneous adverse reactions, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome. The FDA has issued alerts regarding these risks and also noted reports of angioedema and multi-organ hypersensitivity reactions in postmarketing surveillance. In 2007, the FDA required Cephalon to modify the Provigil leaflet to include warnings about these serious conditions.
Cardiovascular Risks
Modafinil is also contraindicated in certain cardiac conditions, including uncontrolled moderate to severe hypertension, arrhythmia, cor pulmonale, and in cases with signs of CNS stimulant-induced mitral valve prolapse or left ventricular hypertrophy. The package insert in the United States cautions about using modafinil in people with a documented medical history of left ventricular hypertrophy or those diagnosed with mitral valve prolapse who have previously exhibited symptoms associated with the mitral valve prolapse syndrome while undergoing treatment involving central nervous system stimulants. The reasons why modafinil is contraindicated in certain cardiac conditions are because modafinil affects the autonomic nervous system and, in particular, exerts significant effects on autonomic cardiovascular regulation, leading in some people to notable increases in heart rate and blood pressure. The increase in heart rate and blood pressure can worsen the symptoms of such pre-existing conditions as hypertension, arrhythmia, and cor pulmonale. These changes in the autonomic system induced by modafinil can increase the risk of heart attack, stroke, and heart failure. Modafinil can stimulate the release of norepinephrine and epinephrine, hormones that activate the sympathetic nervous system. This can cause vasoconstriction, which is the narrowing of blood vessels, and increase the heart's workload, which is not desired in people with pre-existing heart conditions. In particular, modafinil can worsen the consequences of mitral valve prolapse or left ventricular hypertrophy, which are structural abnormalities of the heart.
Tolerance and Dependence
Repeated administration of modafinil for off-label use, such as increased alertness and cognitive-enhancing effects in sleep deprivation, can lead to drug tolerance, which means that the effectiveness of the drug may decrease over time. Despite being a CNS stimulant, the addiction and dependence liabilities of modafinil are considered low. Although modafinil shares biochemical mechanisms with stimulant drugs, it is less likely to have mood-elevating properties. Unlike other stimulants, modafinil does not induce a strong subjective feeling of pleasure or reward, which is commonly associated with euphoria, an intense feeling of well-being. Euphoria may be an indicator of a drug's potential to be abused. Modafinil was not observed to promote overuse or misuse, even in people who have a history of cocaine addiction. Despite the initial belief that modafinil carried no abuse potential, emerging evidence suggests that it works at the same neurobiological mechanisms as other addictive stimulants.
Overdose
An overdose of modafinil can lead to a range of symptoms and complications. In animal studies, the median lethal dose (LD50) of modafinil varies among species and depends on the route of administration. The LD50 value for humans have not been established. Human clinical trials have involved total daily doses up to 1200 mg/d for 7-21 days. The management of modafinil overdose involves supportive care, monitoring of vital signs, and treatment of specific complications.
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Drug Interactions
Modafinil may result in a drop in opioid plasma concentrations because of faster clearance of opioids by CYP3A4. Modafinil may have an adverse effect on hormonal contraceptives (such as birth control pills, patches, etc.) for up to a month after discontinuation. Both modafinil and armodafinil in the United States and the United Kingdom come with package inserts that highlight the interaction between these medications and hormonal birth control. Modafinil may induce cytochrome P450 enzymes that are involved in the clearance of steroid hormones taken as hormonal contraceptives, reducing their effectiveness, which may lead to pregnancy despite taking the birth control medication. Besides steroid hormones, modafinil may affect pituitary gland hormones. Since modafinil induces the activity of the CYP3A4 enzyme involved in cortisol clearance, modafinil may reduce the bioavailability of hydrocortisone.
Pharmacokinetics
Cmax (peak levels) occurs approximately 2 to 3 hours after modafinil administration. Food slows the absorption of modafinil but does not affect the total area under the curve (AUC). In vitro measurements indicate that 60% of modafinil is bound to plasma proteins at clinical concentrations of the drug. Renal excretion of unchanged modafinil usually accounts for less than 10% of an oral dose. The two major circulating metabolites of modafinil are modafinil acid (CRL-40467) and modafinil sulfone (CRL-41056). Elimination half-life is in the range of 10 to 12 hours, subject to differences in sex, in cytochrome P450 genotypes, liver function and renal function. Modafinil is metabolized mainly in the liver, and its inactive metabolites are excreted in the urine. Modafinil exhibits sex-specific pharmacokinetic differences. It demonstrates higher bioavailability in women compared to men. The mean Cmax is higher in women than in men, 5.2 mg/L vs. 4.2 mg/L (p < 0.05), following a single 200 mg oral dose of modafinil. The clearance of modafinil is 30% higher in men than in women, and plasma concentrations after a single dose are significantly higher in women than in men.
Regulatory Status and Legal Considerations
Modafinil's use varies by region. In the United States, modafinil is classified as a schedule IV controlled substance under US federal law, meaning that the drug has a low potential for abuse and dependence compared to other controlled substances. In Australia, modafinil is considered to be a Schedule 4 prescription-only medicine.
In mainland China, modafinil is strictly controlled like other stimulants such as amphetamines and methylphenidate. It is classified as Class I psychotropic drug. This classification means that modafinil is considered to have a high potential for abuse and dependence, and is therefore subject to strict regulation and control. As a result, modafinil is only available by prescription and cannot be purchased over the counter. In order to obtain a prescription for modafinil, a patient must have a valid medical reason for using the drug, such as narcolepsy or obstructive sleep apnea. Additionally, the prescription must be written by a licensed physician and filled at a licensed pharmacy.
In Denmark and Finland, modafinil is a prescription drug but not listed as a controlled substance. In the Republic of Moldova, modafinil is classified as a psychotropic drug and is available by prescription. Importation of modafinil may be considered illegal and subject to severe penalties, even if you have a prescription. In the Transnistria region of Moldova, modafinil is completely prohibited. In Sweden, modafinil is classified as a schedule IV substance, which means that it is considered to have a low potential for abuse and a low risk of dependence. In Japan, modafinil is Schedule I psychotropic drug. In Russia, starting from May 18, 2012, modafinil is Schedule II controlled substance. Modafinil is not approved for medical use in Russia and cannot be bought even in pharmacies.
Other Potential Applications
Modafinil and armodafinil were studied as a complement to antipsychotic medications in the treatment of schizophrenia. Modafinil is being researched as a potential remedy for excessive daytime sleepiness in myotonic dystrophy (DM), an inherited condition characterized by progressive muscle loss, weakness, and myotonia. Studies suggest that modafinil may be a promising drug that can reduce both daytime sleepiness and myotonia itself, without significant cardiac conduction effects.