The good and the bad of nootropics

Let’s talk about modafinil

Modafinil (MOD)

A widely cited definition characterises “enhancement” as biological, behavioural and physical interventions in humans that aim to improve mental functioning beyond what is necessary to sustain or restore good health (Hacking the Brain: Dimensions of Cognitive Enhancement).

Diet, natural remedies, recreational drugs, body derivatives and pharmaceutical drugs are all biological cognitive enhancement interventions or nootropics or smart drugs or cognitive enhancers.

Among these smart drugs, modafinil (MOD) — a non-amphetamine central nervous system stimulant with wakefulness-promoting properties, sold under the brand name Provigil among others — is considered the prototypical cognitive enhancement intervention. 

MOD is a medication used to treat sleepiness due to narcolepsy, shift work sleep disorder or obstructive sleep apnea. Additionally, MOD has reported efficacy for the following “off-label” indications:

• attention-deficit hyperactivity disorder,

• acute unipolar and bipolar depressive episodes,

• cocaine dependence,

• cancer-related fatigue and

• multiple sclerosis-related fatigue.

MOD's serious side effects may include:

• allergic reactions such as anaphylaxis,

• Stevens–Johnson syndrome (a painful rash that spreads and blisters), and

• hallucinations.

Moreover, the amount of MOD used may need to be adjusted in those with kidney or liver problems and it is not recommended in those with an arrhythmia, significant hypertension, or left ventricular hypertrophy. 

How it works is not entirely clear, but one possibility is that it may affect the areas of the brain involved with the sleep cycle. As of today, the research on its effectiveness for this use as cognitive enhancer is not conclusive (for more information you can visit Drugs.com).

Knowing that MOD has so many side effects would you try it as a smart drug?

Well, the answer depends on whether you have taken before the “red pill” that reveals an unpleasant truth or the “blue pill” that gives you a “blissful ignorance”.

“If ignorance is bliss, why isn’t the world happier?” 

Mark Twain

Mechanism of Action of MOD

MOD is known to be a weak inhibitor of dopamine (DA) re-uptake — which may be its primary clinically important role — since it has a low micromolar affinity for the dopamine transporter (DAT).

Inhibition of DA re-uptake via the DAT explains the enhancement of DA levels in several brain areas (enhanced dopaminergic signalling by suppressing transmitter re-uptake), that is consistent with its beneficial effects on cognitive performance processes such as attention, learning and memory.

DAT’s effect is shared with other psycho-stimulants like cocaine, methylphenidate and amphetamines, yet animal studies suggest it has a lower risk of dependence compared to other psycho-stimulants. In fact, its neurochemical effects and anatomical pattern of brain area activation differ from typical psycho-stimulants.

Just a brief reminder: DA (an hormone and a neurotransmitter) is the main chemical that confers motivational salience (i.e., the desirability or aversiveness) of an outcome, which in turn propels the organism’s behaviour towards achieving an outcome.

So, let’s see now how MOD works?

A preclinical study showed that a low dose of MOD (0.75 mg/kg) in mice enhanced memory of contextual fear conditioning (tested off-drug one week later), while a high dose (75 mg/kg) disrupted memory. In fact, MOD’s effects can vary greatly in accordance with the dose taken.

However, in humans the findings regarding working memory tasks and MOD were more mixed, with some studies finding improvements in working memory with reduced errors or reduced reaction time and others reporting no effect. The reason for these mixed findings might be influenced by baseline effects (reduced effect in high-performing participants).

Moreover, in a study in healthy volunteers, MOD significantly enhanced performance on tests of digit span, visual pattern recognition memory, spatial planning and stop-signal reaction time. Subjects reported also feeling more alert, attentive and energetic when taking MOD. But the effects were not clearly dose dependent.

These data indicated that MOD selectively improved neuropsychological task performance, and this improvement may be attributable to an enhanced ability to inhibit pre-potent response (a response for which immediate reinforcement — positive or negative — is available or is associated with that response). This effect appears to reduce impulsive responding, suggesting that MOD may be of benefit in the treatment of attention deficit hyperactivity disorder.

Other executive functions such as planning and fluency have also been investigated, with planning performance found to be improved by MOD. All these effects were investigated with single doses.

MOD also improved working memory, planning, decision making and flexibility in sleep-deprived doctors without showing the typical side effects of caffeine, such as tremor and anxiety. Finally, clinical studies based on PET scans suggested that doses of 400mg on humans had effects in brain areas known to be involved in substance abuse and dependence.

In general, cognitive-enhancement drugs like MOD, tend to show stronger and more robust effects when they are used to mitigate negative effects such as sleep deprivation or when they are used to maintain performance for longer than normal duration in suboptimal circumstances.

Furthermore, MOD has little to no in vivo affinity for the serotonin (the happy chemical that contributes to wellbeing and happiness) or norepinephrine (the stress hormone) transporters, although elevated concentrations of both in the prefrontal cortex and hypothalamus have been observed following MOD administration, possibly as an indirect effect of increased extracellular dopamine.

To summarise, MOD

• directly increases cortical catecholamine levels (dopamine, norepinephrine and epinephrine),

• indirectly up-regulates cerebral serotonin, glutamate, orexin, and histamine levels, and

• indirectly decreases cerebral gamma-amino-butrytic acid levels.

But let’s talk about orexin now, being indirectly up-regulated by MOD.

Orexin

Orexin is a neuropeptide that regulates arousal and wakefulness, connected with time and our circadian clock genes (Sleep the shutting of the eye: sleep duration and genes). As a matter of fact, the most common form of narcolepsy (cataplexy) is caused by a lack of orexin.

Orexin (from orexis meaning “appetite” in Greek) also known as hypocretin—because it is produced in the hypothalamus and bears a weak resemblance to peptide secretin—is a neuropeptide that has a very famous transcriptional repressor: the “Thatcher gene” (named after the U.K. Prime Minister Margaret Thatcher who famously lived on four hours of sleep per night )  or simply named DEC2.

More specifically, people who inherit a particular mutation in the gene DEC2  average only 6.25 hours of sleep per night, while participants lacking the mutation averaged 8.06 hours. Furthermore, preclinical studies in mice have shown that a mutant form of DEC2 results in increased orexin production and a decrease in the total duration of daily sleep (a natural short sleep behavioural trait).

So, when a drug like MOD — designed to treat sleepiness due to narcolepsy — up-regulates orexin mimicking a natural short sleep behavioural trait, and has also as a positive side effect the cognitive enhancement of the brain (the anti-aging of brain), that confirms that aging (intended as becoming less efficient) is also somehow correlated with how we perceive time.

But what is time?

Time according to many physicists is an illusion, where past, present and future coexist (Albert Einstein, Carlo Rovelli). Moreover, Einstein believed that the time “now” (present) was a human concept which was not meaningful in the mathematical description of the universe and he said that the “now” worried him seriously (Time will explain (while the longevity industry is making money)).

He explained that the experience of the “now” means something special for people, something essentially different from the past and future, but that this important difference does not and cannot occur within physics. And since this experience couldn’t be grasped by science this seemed to him a matter of painful but inevitable resignation. 

He wrote:…“there is something essential about the “now” which is outside the realm of science”. 

In fact if you think about it, we can’t really measure “now” with a clock, since by the time we have finished measuring the “now”, is already future.

But how MOD hacks time?

“We must welcome the future, remembering that soon it will be the past; and we must respect the past, remembering that it was once all that was humanly possible.”

George Santayana

A study published in 2003 indicated that the alertness-promoting effect of MOD preferentially disrupts the homeostatic down-regulation of a waking drive. In other words, MOD probably disrupts a mechanism and as a result our cells “sense” time differently (Circadian Clock Genes).

In particular, MOD is a wake-promoting agent that affects hypothalamic structures involved in the homeostatic and circadian regulation of vigilance.

Administered during sleep deprivation, it reduces the need for prolonged recovery sleep and decreases the rebound in electroencephalogram slow-wave activity. These effects suggest an action of MOD on a homeostatic sleep regulatory process.

This homeostatic sleep regulatory process (actually an internal time machine), is genetically specified, and the proteins encoded by the “time genes” are components of a self sustaining negative feedback loop, which is now thought to form the driving oscillation of the timing system (an auto-regulatory interlocked transcriptional–translational feedback loop of clock genes).

This internal time loop (our inner world) is synchronised to the outer world by light. In fact, in this study (only twelve unmedicated patients with obstructive sleep apnea) MOD reduced the light reflex amplitude, suggesting an increase in the inhibitory input at the pupilloconstrictor Edinger-Westphal nucleus.

The Edinger-Westphal nucleus supplies preganglionic parasympathetic fibers to the eye

• for constricting the pupil,

• for accommodating the lens and convergence of the eyes, and

• is also implicated in the mirroring of pupil size in sad facial expressions.

To make a long story short, the Edinger–Westphal nucleus is important in the functioning of the pupillary light and accommodation reflexes. 

So, this is how MOD affects the homeostatic sleep regulatory process, by increasing the inhibitory input at the pupilloconstrictor Edinger-Westphal nucleus. And always remember, time is a brain construction.

But let's leave behind us MOD and hacking time, and let’s talk now about histamine being indirectly up-regulated by MOD.

Histamine

MOD is known also to indirectly increase your histamine levels.

For example, in this preclinical study MOD (150 mg/kg, i.p.) increased histamine release by 150% of the basal release. This observation suggested that MOD might also promote waking via the activation of the histaminergic system, although it does not appear to be a direct pharmacological target of MOD.

Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological function in the gut and acting as a neurotransmitter for the brain, spinal cord and uterus. Histamine is involved in the inflammatory response and has a central role as a mediator of itching (you’ve probably heard of antihistamines).

But if you are someone with histamine intolerance due to the overproduction of histamine in the body (gastrointestinal disorders, bacterial overgrowth) or the inability to break it down (medications that block diamine oxidase for breaking down histamine), I guess taking MOD isn’t a smart idea.

The symptoms of histamine intolerance include:

• headaches or migraines,

• nasal congestion or sinus issues,

• fatigue,

• hives,

• digestive issues,

• irregular menstrual cycle,

• nausea, and

• vomiting.

Following a low histamine diet should be solution to this problem, but you have to avoid all the following:

• canned foods and ready meals,

• ripened and fermented foods (older cheeses, alcoholic drinks, products containing yeast, stale fish),

• alcohol, eggplant, smoked meat products — salami, ham, sausages, shellfish

• beans and pulses — chickpeas, soy flour

• long-stored nuts — e.g peanuts, cashew nuts, almonds, pistachio

• chocolates and other cocoa based products

• seitan

• rice vinegar

• salty snacks, sweets with preservatives and artificial colourings

and the list goes on… be prepared to change your lifestyle for good.

Going back now to the initial question: "would you try MOD as a smart drug?" 

I guess is up to you, but bear in mind that:

• If you decide to take the “red pill” that reveals an unpleasant truth, then natural supplements for cognitive enhancement such as fish oils, resveratrol, caffeine, phosphatidylserine, acetyl-L-carnitine, ginkgo blob, creatine, bacon monnieri, rhodiola rosea and S-Adenosyl methionine are advised for you.

• But you are free also to take the “blue pill” that gives you a “blissful ignorance”. In this case prepare yourself for a long journey of MOD side effects and intense studying trying to hack a natural decentralised system billions years old. And probably by studying a lot in order to hack this system, you might actually become smarter. After all no one has ever become smarter by just taking a pill.

“We are free to choose our actions, . . . but we are not free to choose the consequences of these actions.”

Stephen R. Covey, First Things First

Until next time,

*Disclaimer: This information is for educational purposes only.