How Does Modafinil Work?

Modafinil is a widely prescribed smart drug designed to do one thing: keep you awake.

By now you’ve probably heard that everyone from Tim Ferriss to Dave Asprey to President Obama has taken Modafinil at some point.

They’re not alone.

Entrepreneurs, doctors, programmers and just about everyone I know has heard about Modafinil or used it themselves.

Yet despite its growing appeal, few people know how Modafinil actually works.

That’s a minor issue, given that 1) most of Modafinil use is off-label, meaning it’s made in random labs in India, and 2) it’s only going to get more popular with time.

As such, it’s worth stepping back for a minute and learning about this little white pill we take for work.

How does Modafinil compare to other stimulants?

Modafinil binds to the cell-membrane dopamine transporter (“DAT” for short) and is dependent on catecholaminergic (dopaminergic and adrenergic) signaling for its wakefulness-promoting effects.

Relative to other commonly used nootropics that act through catecholaminergic mechanisms, Modafinil has a relatively low abuse potential and helps you stay awake without “crashing” afterword.

Anyone who’s taken Modafinil recognizes the difference in effects compared to other substances like amphetamines (eg, Adderall) and cocaine.

Yet despite different effects, Modafinil still uses similar signaling pathways as Adderall and cocaine.

For example, both Modafinil and Adderall inhibit dopamine transport. However, Modafinil is much weaker, but far more selective than Adderall.

Furthermore, Modafinil’s effects last longer than stimulants Adderall (and of course, longer than cocaine).

To better understand Modafinil’s unique mechanism of action we need to take a quick look at drug’s history.

How Modafinil came to be

Modafinil was first approved by the US Food and Drug Administration (FDA) in 1998 and marketed as the racemic mixture of R- and S-enantiomers and later as a formulation containing only the R-enantiomer, which is pharmacokinetically distinct from the S-enantiomer in humans.

It has been viewed throughout its history as a unique wake-promoting therapeutic, and apparently is still viewed in the same manner to this day.

The fact that Modafinil seems distinct or “different” from other stimulants probably stems from the fact that the effects are noticeably different.

In this article i’m going to explain what actually makes Modafinil different, and why those difference lead to different effects.

In doing so, I’ll expose common myths about Modafinil and explain how the drug opens the door for an entire new wave of cognitive enhancers.

Modafinil’s mechanism of action can be broken up into seven parts:

1. Dopamine Signaling
2. Non-Dopamine Signaling
3. Recovery time
4. Sleep 
5. Anxiety
6. Addictive Potential
7. Latency time (how long it takes to kick in)

Now let’s take a closer look at each part…

(Warning: I’m about to science the shit out of this).

1. Modafinil -> dopamine

Like many compounds, Modafinil was found to be clinically useful long before its pharmacological target was known.

Still, as with any new wake-promoting agent, a number of potential targets came to mind in the search for its mechanism of action.

Among the potential targets for Modafinil were the cell-membrane monoamine transporters. These monoamine-selective transporters clear monoamines (ie, neurotransmitters) dopamine (DA), noradrenaline (NE), and serotonin (5-HT) from the extracellular space surrounding the neurons that release them.

The transporters are named for the neurochemical identity of the cells that express them at the highest levels – the dopamine transporter (DAT), the noradrenaline transporter (NET), and the serotonin transporter (SERT). Despite this nomenclature, they are not truly selective for their namesake neuromodulators.

For instance, the noradrenaline transporter has a higher affinity for dopamine than the dopamine transporter (Gee, thanks scientists). Further, all receptors have affinity for both dopamine and noradrenaline, leading to some confusion with regard to Modafinil’s mechanism of action.

At the time when Modafinil was discovered, other stimulants such as cocaine and amphetamines were known to also promote wakefulness. Thus, scientists assumed that Modafinil might act through monoamine transporter inhibition to produce wakefulness.

A series of studies in the early 1990s found that Modafinil primarily targeted the DAT receptor, leading to increased dopamine levels in brain cells. Researchers found that the elevated levels of dopamine directly contributed to Modafinil’s wakefulness effects in dogs and rats.

Collectively, the studies made a strong case for the argument that the wake-promoting effects of Modafinil are mediated by its interaction with the dopamine r and elevation of dopaminergic tone.

2. It’s not all about dopamine

Recent research found that Modafinil affects more than just dopamine signaling pathways.

Case in point: Modafinil triggers the a1 adrenergic signaling pathway, a critical regulator of sleep-week cycles.

However, it’s unclear whether this directly promotes wakefulness, or whether it’s a downstream effect of elevated dopamine.

Additional research found other neurotransmitter responses to Modafinil: GABA and glutamate. Modafinil leads to decreases in GABA concentrations and increases glutamate concentrations.

So yes, Modafinil has effects on adrenergic, GABAergic, and glutamatergic transmission, but all of these effects can be explained by its primarily role: a dopamine receptor blocker.

Still with me? Good.

Now we get to the fun stuff…

The elephant in the room:

3. Why it’s easier to recover after taking Modafinil (compared to Adderall and other stimulants)

Both Modafinil and Adderall promote wakefulness through the dopamine signaling pathway.

Yet, Modafinil has fewer side effects.

Why?

A lot of smart people are trying to answer that question.

What they’ve found is good news (for anyone who takes Modafinil).

The biggest differences between Modafinil and Adderall

The biggest differences between the side effects of Modafinil and Adderall can be summed up into the following two categories:

• Sleep. The effects of Modafinil on sleep and sleep disorders are distinct from those of methamphetamines.
• Anxiety. Amphetamine medications used to treat ADHD, such as Adderall, frequently cause anxiety in regular users. Modafinil has no such effect.

4. Modafinil, Adderall and Sleep

It’s an established fact that, when we don’t sleep, we build what’s called sleep debt. With each consecutive night of poor sleep, the debt accumulates. When you finally decide to get some quality shut eye, you will need to catch up by sleeping longer and deeper. Essentially, the body’s way of “paying the debt” (called “hypersomnolence”; hyper = lots, somnolence = sleep).

In this context, the effects of Modafinil on sleep differ from those of methamphetamine (re: Adderall). After taking methamphetamines to stay awake, you need to “pay the debt” at some point by having an extra night or two of deep, uninterrupted sleep. However, this is not the case with Modafinil.

One interpretation for this difference in side effects is that Adderall and Modafinil have distinct effects on the parts the cells that regulate sleep.

Specifically, this could be explained in one of two ways:

• Modafinil might decelerate the rate at which sleep need accumulates during wakefulness.
• Adderall might accelerate the rate at which sleep need accumulates during wakefulness.

Explanation #1: Modafinil decreases our need for sleep

Regarding the first of these two possibilities, a head-to-head comparison of the severity of hypersomnolence after a Modafinil-induced wakefulness and sleep deprivation-induced wakefulness found no difference.

In other words, the deciding factor is how long you’re awake, regardless of whether or not you take Modafinil.

ILikewise, taking Modafinil to stay awake through the night doesn’t change the body’s need for deep sleep. If you pull an all-nighter on Modafinil, your recovery sleep the following night will be the same as if you hadn’t used Modafinil to stay awake.

Therefore, Modafinil does not decelerate the rate at which sleep need accumulates during wakefulness. Explanation #1 = false.

Explanation #2: Adderall increases our need for sleep

It’s also possible that amphetamines like Adderall accelerate the accumulation of sleep debt.

Research shows that Adderall disrupts key NET and SERT signalling pathways, both of which are important regulators of sleep homeostasis.

The direct perturbation of noradrenergic and serotonergic receptors by amphetamines may contribute to the hypersomnolence that they cause.

As someone who used to take Adderall but made the switch to Modafinil, this is welcome information.

It means that Modafinil isn’t affecting the quality or quantity of my sleep (at least, not nearly as much as Adderall had been).

However, this still doesn’t explain why Adderall causes so much anxiety, but Modafinil does not. To answer this, we need to look again at Modafinil’s mechanism of action.

5. Why Modafinil doesn’t cause anxiety

Measures of gross locomotor behavior have long been applied to measure the psychostimulant effects of cocaine, amphetamines, and other DAT-binding agents.

In one study, rats were given Modafinil or d-methamphetamine. Researchers monitored their behavior to see how “restless” the rats became after taking the drugs.

The result?

In contrast to d-methamphetamine, which elevated the amount of activity per hour of wakefulness, the rats’ activity at home was not increased by Modafinil.

Further, videos revealed that the Modafinil group spent increased time spent in quiet wakefulness (“arousal without ambulation, head up, eyes open”), but not awake and constantly moving around.

This isn’t to say that Modafinil does cause any anxiety. There are plenty of Modafinil users who report feelings of anxiety. Perhaps this is through downregulation of GABA, or perhaps some other mechanism.

Whatever the cause, it’s clear that Modafinil’s anxiety side effects are much, much less than that of stimulants like Adderall.

6. Why isn’t Modafinil addictive?

Thanks to a relatively low toxicity and lack of unpleasant side effects, one would think that Modafinil would be abused by every student, banker and politician in the world.

And though its use is growing, Modafinil has not been abused the same way people abuse Adderall and cocaine.

The concept that Modafinil acts via DAT inhibition might be regarded as controversial because of inconsistencies in the preclinical and clinical literature on the potential for abuse and addiction.

There is even some evidence that Modafinil has rewarding properties. For example, Modafinil reinforces cocaine-seeking behavior in animals and humans.

Data from human subjects discriminate Modafinil from cocaine in terms of abuse potential. Cocaine users do not report a high when exposed to Modafinil; rather, they report that Modafinil blunts the subjective effect of cocaine when the two drugs are administered simultaneously. In other words, they have a greater sense of self control.

Research is ongoing as to Modafinil’s abuse potential. Current data suggest that Modafinil is pharmacologically distinct from both cocaine and amphetamines in the context of abuse and addiction.

Thus, ambiguities in the literature on drug abuse and sleep contribute to the concept that Modafinil is somehow novel and distinct from amphetamines and cocaine. Notwithstanding the fact that Modafinil, cocaine, and amphetamines all interact with DAT, the pharmacology of Modafinil is distinct from that of cocaine and amphetamines.

Whereas cocaine and amphetamines bind tightly to the dopamine transporter, Modafinil binds to the dopamine uptake carrier site with low affinity. This low affinity may explain why it triggers dopamine slowly, over time. And why the effects of a Modafinil dose can last upwards of 12 hours.

Modafinil is further distinguished from amphetamines and cocaine by virtue of the physical nature of its interactions with DAT. As a neurotransmitter sodium symporter, DAT undergoes a sequence of conformational changes in the process of transporting its ligand into the cell.

Therefore, the relatively low abuse potential attributed to Modafinil may reflect the nature of its interaction with DAT, not the absence of an interaction with DAT. The relationship between DAT conformation and abuse potential is admittedly a relatively new concept.

This work offers a potential explanation for the relatively low abuse potential associated with Modafinil without requiring some putative unknown mechanism.

7. Why does Modafinil take so long to kick in?

Buying nootropics from websites with names like “Duckdose” is an… interesting experience, to say the least.

Silly animal names aside, you’re essentially buying off-label drugs from India using Bitcoin (they now accept credit cards – luddites!).

Perhaps it’s a sign of the times… but the first time I bought Modafinil, I was a little wary.

Not only that, but when I popped the first pill, it took nearly an hour and a half to start working. I wasn’t sure what I’d just put in my body, or whether it would even work.

Anyone who’s taken Modafinil or Armodafinil can probably relate to this first time experience. It’s no wonder that people always ask me, how long does it take before I start to feel the effects of Modafinil?

Do a line of coke and you’ll feel it in minutes. Pop 100mg of Modafinil and you may be waiting an hour or two before you feel anything.

Again this boils down to Modafinil’s slow mechanism of action at the dopamine transporter site.

Drugs like Modafinil that bind the DAT with low affinity cause a slow, sustained release of dopamine from the system, thus having less addictive potential than sites that bind tightly to the receptor and cause a quick rush of dopamine (eg, cocaine and Adderall XR).

Give it a try

Modafinil works by slowly binding to the dopamine receptor and triggering the release of dopamine into the cell. In doing so, it keeps you awake.

Although Modafinil works in other ways, the dopamine signalling pathway is the main contributor of its wakefulness-promoting and focus-enhancing effects.

Modafinil’s effects last longer and have fewer downsides than other dopamine-boosting drugs like cocaine and Adderall. The primary reason for this is that it binds less tightly to the dopamine transporter, causing a relatively slow release of dopamine into the cell.

With more people turning to Modafinil to stay awake, focused and productive, knowing exactly how it works will give you a leg up.

Rather than aimlessly reading blog posts online that claim to have the answer, pay attention to new Modafinil research and you’ll know the answer yourself.