How Modafinil Strikes the Perfect Balance With Dopamine

How does Modafinil affect dopaminethe neurotransmitter that underpins reward?

This is actually a controversial question, partly because Modafinil’s mechanism has been shrouded in mystery until the last decade.

First, a little background info. Increasing dopamine tends to improve working memory. The caveat here is that enhanced dopamine function isn’t going to do much for you if your memory is already optimized. Also, whether or not you realize benefits from enhanced dopamine function is largely genetic.

Returning to the question of how Modafinil affects dopamine:

What’s at stake in this discussion?

If Modafinil works by increasing dopamine, than it behaves more similarly to drugs like Adderall than we first thought.

But if Modafinil’s effect on dopamine isn’t clinically significant and other targets in the brain are more important, in that case Modafinil can truly be said to be a novel cognitive enhancer.

The evidence right now favors a hybrid few. Namely, that Modafinil does augment dopaminergic signaling, but to a lesser extent than primary dopamine reuptake inhibitors like Ritalin.

But in addition to this dopaminergic effect, Modafinil works on a number of neural circuits. It’s this blend of biological activity in the brain that makes Modafinil such a perfect candidate for a cognitive enhancer.

Ultimately, evidence favors the notion that Modafinil hits the sweet spot in terms of dopamine.

Modafinil vs Other Wakefulness Enhancers

If you’re unfamiliar, Modafinil is a wakefulness enhancer that’s used clinically to treat disorders that make you sleepy during the day. Conditions like narcolepsy or sleep apnea. 

The idea is that sleepiness can be counteracted with a wakefulness enhancer like Modafinil, even if Modafinil isn’t really addressing the underlying disease process.

Modafinil is the first drug of its kind. There’s some promising evidence that it enhances cognitive function, even in healthy volunteers.

One point of contention is whether this effect is restricted to individuals with low baseline performance. More research is needed to definitively answer these questions.

It’s also likely that how Modafinil affects performance depends on the type of tasks used in the study.

On the whole, it’s much harder to boost performance for highly complex tasks that require a great deal of connectivity between disparate brain regions.

Modafinil’s Safety Profile

Modafinil also has a safer side effect profile compared with drugs like Adderall.

Adderall is a catecholamine releasing agent that crudely promotes dopamine release into the synaptic cleft. (This space is the just a gap that neurotransmitters must diffuse across to propagate a signal from a dendrite to a different neuronal cell body).

Adderall has harsh cardiovascular side effects, like increased blood pressure, heart rate, and peripheral vasoconstriction. (Peripheral vasoconstriction is what makes your hands feel cold on Adderall).

By contrast, Modafinil lacks the side effects that arise from overstimulating the sympathetic, fight-or-flight arm of the nervous system.

What Exactly Is Modafinil Doing in Your Brain?

Study drugs like Adderall, Ritalin, and Strattera are extremely well characterized compared with Modafinil.

There’s over fifty years of research that’s been conducted on amphetamines and amphetamine-derivatives. So these drugs are thoroughly understood.

Here’s a quick anecdote: both John F. Kennedy and Hitler were both medicated with amphetamine (actually, methamphetamine) during their political career.

Modafinil’s mechanism is less well understood. The beneficial effects of Modafinil on cognitive performance aren’t as cut and drug as other drugs.

It’s easy to describe the pharmacology of so many other drugs. Strattera is a selective norepinephrine reuptake inhibitor. Nicotine is nicotinic acetylcholine receptor agonist.

But Modafinil is pleiotropic. Meaning, it modulates a bunch of different neural circuits and neurotransmitter systems.

Here’s a laundry list of Modafinil’s neuronal targets:

  • Histamine – you know how antihistamines like Benedryl make you drowsy? Modafinil may have the opposite net effect on these receptors, which makes you feel alert
  • Orexin/hypocretin – This is a neuropeptide that’s deficient in narcolepsy (manifesting as excessive sleepiness). Modafinil tends to increase orexin release, promoting wakefulness
  • Catecholamines: dopamine and norepinephrine. Augmenting both of these neurotransmitters tends to improve working memory in humans and animals alike.
  • GABA and Glutamate – Modafinil increases glutamate and decreases GABA, in a brain-region specific manner. Crazy right?
  • Gap junctions – these connect the inside (cytoplasm) of one cell to another. This allows electrical impulses to pass from cell to cell, without a chemical synapse. Chemical synapses are extremely slow – it takes a while for a neurotransmitter to diffuse across the synaptic cleft. But electrical synapses are crazy fast.

Modafinil and Dopamine

Dopamine is that neurotransmitter that makes life itself rewarding.

That feeling of accomplishment you get from completing a project or even doing something small like turning the page of a book your reading? That hinges on dopamine release.

It’s no wonder that amphetamines (which are extremely potent dopamine-releasing agents) make it easier to complete mundane tasks. More dopamine is released and so you experience these boring chores as more rewarding. This phenomenon is called “task salience.”

There’s a dark side to dopamine, too. In addition to being the “happiness molecule”, it also underpins addiction.  Dopamine is the common thread underlying everything from pornography addiction to gambling to drugs of abuse like cocaine.

Even the addictive potential of opioids (like oxycontin), which are considered relatively selective for the opioid receptors in the brain, arises In part from eliciting dopamine release downstream.

Dopamine can also be neurotoxin in some circumstances.

What circumstances?

Well dopamine can autoxidize to form 6-hydroxydopamine (6-OHDA) in vivo (in your body). 6-OHDA is a toxin that damages dopaminergic neurons – these are the brain cells that do all the hard work of synthesizing dopamine from L-DOPA and packaging it into vesicles, primed for release.

Since amphetamines increase dopamine release, more dopamine hangs around and is available for conversion to the neurotoxin 6-OHDA.

Spoiler: Modafinil’s Effect on Dopamine Isn’t Negligible

Modafinil does have a weak affinity for the dopamine transporter (DAT). DAT pumps dopamine from outside the cell back into the cytoplasm. Inhibiting this process will cause dopamine to accumulate in the synapse, and continue to stimulate dopamine receptors.

There are some pretty bright researchers who maintain that Modafinil has such a weak affinity for the dopamine transporter that it’s not really contributing to Modafinil’s effects in humans.

Here’s an excerpt from one prominent review of Modafinil:

It was found that Modafinil was weakly selective for the dopamine transporter, binding to this cell-membrane protein and not at all to any other receptors tested. They were skeptical that Modafinil might act by blocking this transporter, and they pointed out that Modafinil has more potent behavioral effects than some molecules that bind with a much greater affinity to the dopamine reuptake transporter.

Here’s another remark, in the same paper:

A final in vitro study of dopaminergic synaptosomes showed that while amphetamine caused spontaneous dopamine release, Modafinil had no such effect.

But on the other hand, Wisor and Eriksson (2005) reported that a dopamine autoreceptor agonist (quinpirole) reduced the effect of Modafinil. This result suggests that dopamine plays a role in Modafinil’s wakefulness promoting effects.

Our reviewer commented: “As such, the authors suggested that Modafinil worked through an increase in dopamine tone and dopamine’s stimulation of the α1 adrenergic receptor.”

The answer lies somewhere in the middle: Modafinil is a much less robust dopaminergic drug than amphetamine, but has a high enough affinity for the dopamine transporter that this effect is relevant in humans.

Consider a study that investigated the affinity of Modafinil for the dopamine transporter in rats (Gert Lubec’s group, 2015). They reported the following affinities: