Safer Stimulants

Two compounds have both recently emerged through clinical trials and been approved by the FDA as orphan drugs for the treatment of narcolepsy and few other sleep disorders that cause excessive daytime sleepiness.  These two drugs, modafinil and pitolisant, have both been stated to have a low abuse potential are marketed as wake-promoters instead of stimulants to avoid association with amphetamines and amphetamine-like compounds, such as methylphenidate. 

Researchers conducting this study compared modafinil and pitolisant in multiple animal models to analyze mechanisms of action and addictive liability of each drug.

They first compared the amount of dopamine (DA) activation following pitolisant or modafinil administration.  A single dose of modafinil produced a 96 percent increase in the amount of DA present in the nucleus accumbens.  Pitolisant did not create an increase in DA.  When this increase was measured through microdialysis for 2.5 hours after administration, modafinil resulted in an average 67 percent increase in DA, and still no change was seen with pitolisant.  

The locomotor activity of rats in an open field test was observed after receiving cocaine, pitolisant, or modafinil.  No significant increase in activity was seen with pitolisant.  Cocaine caused double the baseline activity. Modafinil activity depended on doses, but resulted in significant activity increases.  Higher locomotor activity levels with cocaine than pitolisant were also seen in mice.

The likelihood for rats to form conditioned place preference (CPP) after exposure to nicotine, cocaine, modafinil, or pitolisant was examined.  High CPPs developed for cocaine and nicotine.  No CPP was observed with pitolisant or low doses of modafinil.  CPP developed for the opposite side of the enclosure in higher doses of modafinil, likely a result of the formation of aversive affects. 

The frequency of self-administration in Rhesus monkeys for both cocaine and pitolisant was observed.  All tested monkeys administered more cocaine than saline, but no tested monkeys administers more pitolisant than saline.  Similar results were observed with mice

The final model compared the likelihood of rats to develop withdrawal symptoms after chronic administration of pitolisant or morphine.  No apparent withdrawal symptoms were observed with pitolisant, while a drop in body temperature and other symptoms of withdrawal were observed with cessation of morphine. 

The results of all models point to modafinil and pitolisant being much safer and less addictive options to be used in treating sleep disorders. 

However, this study only used animal models. While these are typically good indicators of how humans will respond, some differences may still exist. 

ABSTRACT

Uguen, M., Perrin, D., Belliard, S., Ligneau, X., Beardsley, P., Lecomte, J., & Schwartz, J. (2013).  Preclinical evaluation of the abuse potential of Pitolisant, a histamine H₃ receptor inverse agonist/antagonist compared with Modafinil. British Journal of Pharmacology, 169 (3). 632-644. Doi: 10.1111/bph.12149