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).

how does modafinil work in the brain

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 prom