Psychostimulant Adrafinil: is it safe as a dietary supplement? AJP explores the scientific background

Adrafinil is a psychostimulant prodrug of modafinil marketed as a dietary supplement with purported effects on concentration, productivity, cognition, and wakefulness, leading many individuals to take adrafinil without physician supervision. But what is the background medical evidence for this drug? Is it safe yet for over-the counter use?

A recent review article from the American Journal of Psychiatry has reviewed the scientific evidence about this "cognition-enhancing" supplement and has cautioned against its use as a dietary supplement.

Around 54.8% of adults in the United States take at least one dietary supplement according to the National Health and Nutrition Examination Survey. Dietary supplements that are available over the counter in one country could require prescriptions in another or even be classified as controlled substances, based on the classification assigned.

Adrafinil which is a prodrug, is metabolized to the active compound, modafinil, in vivo via liver metabolism. Although modafinil is regulated by the U.S. Food and Drug Administration (FDA), adrafinil is sold as an unregulated supplement and can be purchased without the need for a prescription.

Modafinil is FDA-approved for the treatment of excessive sleepiness associated with medical conditions such as narcolepsy, sleep apnea, and shift work sleep disorder. Unlike other stimulant medications, it does not appear to exert its effects by increasing the release of monoamines. Instead, it may act at the dopamine transporter (DAT) to reduce dopamine reuptake. Other proposed mechanisms include modulation of glutamate and g-aminobutyric acid (GABA) transmission, increases in serotonin release, and activation of orexin neurotransmission.

Few studies have shown that adrafinil:

(i) Increases focus, productivity, or motivation (59%) and wakefulness (35%).

(ii) Adrafinil was also often used as a substitute for another drug, due to the comparator drug being difficult to obtain, costing more, or having more side-effects (such as methylphenidate, lisdexamfetamine, modafinil, or dextroamphetamine-amphetamine).

(iii)In some cases, adrafinil usage has been described as an alternative to caffeine intake.

Adverse effects:

The most common spontaneously reported undesired effect was malodorous urine (20% of reports), followed by headache (16%), disturbed sleep (14%), anxiety or feeling "jittery" (12%), and feeling unpleasantly stimulated (10%). (Figure 1)

One individual using adrafinil for athletic performance enhancement suffered severe dehydration with significant cramping and increased body temperature. Although withdrawal effects are variable, they included fatigue, hypersomnia, poor focus, irritability, mental exhaustion, headache, nausea, vomiting, and worsened mood.

In conclusion, Despite unclear evidence of efficacy, adrafinil has attracted many individuals seeking to utilize its proposed benefits. Based on the evidence reported, we would not recommend adrafinil as a dietary supplement. Moreover, in a patient reporting adrafinil use or misuse, clinicians should evaluate for adverse effects similar to those associated with modafinil.

Despite unclear evidence of efficacy, adrafinil has attracted many individuals seeking to utilize its proposed benefits. There is a clear risk associated with adrafinil usage, owing to the side effects that are reportedly associated with comorbidities, overuse, and cross-reactivity with other medications. These factors are exacerbated by lack of physician oversight.

In this review article Lowe et al have discussed the limited scientific evidence for adrafinil administration in the elderly, while also highlighting the personal experiences reported by individuals who used adrafinil outside of a medical or research setting. "In conclusion, based on the evidence reported, we would not recommend adrafinil as a dietary supplement", conclude authors.

Source: American Journal of Psychiatry:

https://doi.org/10.1176/appi.ajp-rj.2021.170105