Modafinil for Depression - Does it work?

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Modafinil is a wakefulness-promoting drug lately popularized as a cognition-enhancing Smart Pill. The popularity of modafinil has also paved the way for several useful effects of the medication on the body, one of which includes the treatment of depression. Before you order modafinil online, it is important that you know all the functions of this drug in detail. In this blog, let us discuss if modafinil is really capable of treating depression.

What is Modafinil?

Modafinil is a eugeroic and nootropic drug initially created in France in the 1970s as a potential cure for sleeping problems including narcolepsy. As a therapy for several sleeping disorders, such as narcolepsy, shift-work disorder (SWD), and obstructive sleep apnea, the drug became widely used in the 1990s (OSA). The FDA authorized Modafinil for regular use in 2004. In the USA, it is classified to be a Schedule IV medication with minimal to no dependence and addiction hazards.

How does Modafinil work in your body?

As a CNS stimulant, modafinil activates our CNS's primary organ, the brain. You may well ask modafinil stimulates the brain in what way? Well, as a CNS stimulant, modafinil affects the body's dopaminergic pathway, to put it simply. A neurotransmitter called dopamine is in charge of facilitating the movement of nerve sensations to the rest of the system. Dopamine specifically aids in the dissemination of inputs related to attention, motivation, enjoyment, and alertness. Dopamine reuptake inhibitor, or DRI, is how modafinil works. The body has a built-in mechanism for eliminating dopamine from the nervous system whenever it effectively conveys a message via active dopamine reuptake. Dopamine reuptake is slowed down by modafinil because it binds to the receptors involved in the process.

Depression - How does it occur?

Depression is a clinical brain disorder whose mechanism has not yet been well elucidated by experts. The cause of depression is thought to be for two reasons, one, lack of serotonin in the body, and two, lack of dopamine. Yes, depression is a clinical condition that can occur due to hereditary or clinical causes although it is more than often triggered by environmental factors.

Modafinil for Depression - A study

Nearly 300 million individuals worldwide suffer from depression, and almost half of them do not recover with conventional first-line treatments. For some people, augmentation techniques frequently serve to lessen the intensity of depression. Even though there are numerous possible supplementary pharmaceutical treatments, psychostimulants are one of the most debatable choices.
A study to describe the relative effectiveness and safety of several stimulant-like drugs used to treat depression was conducted by BahjI, A, Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada, and Mesbah-Oskui, L, Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada in 2021 in response to the growing use of nootropics and their alleged effectiveness against depression.
To treat adult depression, the researchers performed a systematic review with a network contextual analysis of randomly selected, controlled trials (RCTs) that included psychostimulant drugs. Rate Ratios (RRs) were used for binary outcomes (e.g., reaction, adverse outcomes) and standardised mean differences (SMDs) were used for continuous products when pooling the results.

What did the researchers do?

Nearly 300 million individuals, or 5–10% of the population, are affected by depression, which is a major contributor to disability worldwide. Up to 60% of people have treatment-resistant depression (TRD), which is characterized by a poor response (defined as a 50% decrease in basal depression severity) or remission (defined as the resolution of depressive symptoms) to two antidepressant trials of an appropriate dose and duration.
The researchers adhered to the extension statement for including NMAs, and PRISMA, that is, Preferred Reporting Items for Systematic Reviews and Meta-analyses rules. They did not pre-register for the procedure because this was an exploratory review. However, they did not need to have an ethical committee assess our secondary study of published data.
1425 citations were produced overall by the systematic search. A total of studies conducted from 70 reports were chosen from these. From 1958 through 2016, 37 controlled trials were conducted. The length of the studies varied from 2 days to 16 weeks. In investigations, methylphenidate, dextroamphetamine, and modafinil were the most commonly used stimulants.

What did the Researchers find?

The researchers located 37 studies that qualified, between 1958 to 2016 on the probable effect of Modafinil on depression. Methylphenidate, dextroamphetamine, modafinil, lisdexamfetamine, methylamphetamine, pemoline, atomoxetine, desipramine, and imipramine were the nine psychostimulants that we evaluated. Overall, psychostimulants showed promise for treating depression, decreased tiredness and drowsiness, and seemed well-tolerated. However, the data varied among different psychostimulants. For instance, methylphenidate was the only psychostimulant that showed effectiveness for depression in terms of both symptom intensity and response rates.
Although the evaluation indicates that some psychostimulants, particularly methylphenidate, seem to be well-tolerated and show some effectiveness for depression, fatigue, and drowsiness, the amount of evidence included in their projections was low to very low for the majority of agents due to the small sample sizes, lack of RCTs, and inaccuracies in most estimates. A clear hierarchy of therapies cannot be established due to inconsistent data, which highlights the need for further high-quality RCTs.

Modafinil for Psychiatric Treatment

Modafinil was initially developed as a treatment drug for ADHD. However, it's effect on the dopaminergic pathway was soon found to be therapeutic for several other psychological disorders. In this section, let us discuss some of the psychiatric disorders Modafinil has been found to be useful against.


Stimulants are frequently used to supplement antidepressant medication in individuals who have only had a mild reaction to first-line therapy, despite the relative paucity of controlled research. The psychostimulant called modafinil has been launched for the treatment of excessive daytime drowsiness brought on by narcolepsy but has positive effects against major depressive disorder, according to a study from 2000. Modafinil's exact mode of action is based on increasing dopamine reaction time in the body, but unlike other stimulants, it has a much-reduced potential for addiction and is relatively specific to the CNS. It also has little impact on the striatal dopaminergic system. Modafinil appears to be a medicine that could enhance antidepressant medications, especially for individuals who still feel weary or fatigued after taking them. Its limited potential for misuse makes it an especially alluring substitute for other stimulants.

Bipolar Depression

A study in 2003 showed how modafinil may be used to treat hypersomnia in people with bipolar illness when their mood symptoms are under control. When severe, hypersomnia, which usually happens during depressive episodes, can be incapacitating. Antidepressants and mood stabilizers had the best effects on the patient's moods, but their extreme daytime drowsiness persisted. Because of their potential to produce mania, standard drugs were not taken into consideration. With the administration of the specific psychostimulant modafinil, the hypersomnia significantly improved, and functionality also improved. There were no negative side effects or mood swings.


Modafinil (Provigil) has been demonstrated to be more effective than a placebo for treating attention-deficit hyperactivity disorder (ADHD) in both children and adults in a study in 2006. In particular, three sizable, drug-company-sponsored studies on children and teenagers with ADHD who took a film-coated version of modafinil showed continual improvement in ADHD symptoms compared to placebo. The ADHD-Rating Scale-IV range version questionnaire revealed mean decreases in symptom ratings, which ranged from 15.0 to 19.7. Insomnia, headaches, and reduced appetite were the most frequent side reactions. The majority of adverse effects associated with modafinil were graded as low to mild in intensity.


Clinicians often anticipate pharmacokinetic interactions appearing a few days to a few weeks after introducing a new medicine. Because many schizophrenia patients do not relapse for several months after stopping their antipsychotics, it is expected to take an individual patient several months of reduced antipsychotic levels for psychological decompensation to happen; the likelihood of such hypotension and the timeline for its onset would fluctuate with amounts of stress, coping, and social and family support. Therefore, a pharmacological action involving modafinil (or armodafinil) and an antipsychotic medication like quetiapine or clozapine may take place over a long time before it is identified as the outcome of a pharmacological interaction, as found in a study in 2012.

The Verdict - Does Modafinil help with Depression?

Although developed to treat ADHD, it has turned out that Modafinil can be quite useful in the treatment of major depressive disorder, as we discussed in this blog. Depression, chronic or acute, has been lately found to be dependent on the brain chemistry based on two neurotransmitters, serotonin, and dopamine. However, only the mechanism of serotonin and its effect on depression has been properly elucidated at the moment. As a result, most of the treatment of depression is targeted towards manipulating the serotonin levels of the body. Not much has been known about controlling the dopaminergic pathway in the body. However, since Modafinil naturally effects the dopaminergic pathway, it poses a rather opportunistic path in the treatment of depression.

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