Repurposed Medications Show Promise for Stimulant-Related Disorders

Stimulant-related disorders (SRDs) continue to affect society on many levels. The economic temptation of producing or bringing stimulants or their precursors (methamphetamine and cocaine) across the U.S. border to sell is continuing as certain South American countries now allow full-fledged coca plant cultivation. Containing the flow of illicit drugs within state lines and across U.S. borders is an insurmountable task for any agency, and efforts aimed at reducing SRDs are desperately needed.

Neuroimaging studies have been essential to understanding central deficits and altered neurotransmission linked to SRDs. For example, recent evidence has dispelled the widely held misconception that individuals with SRDs are more sensitive to these drugs than the average person, and this is why they develop a use disorder. In fact, the opposite is true: they are less sensitive to the positive euphoric effects of stimulants. This also extends to natural rewards such as food.

In contrast, these same individuals are often hypersensitive to stress and overly influenced by environmental cues associated with drug taking that can trigger relapse. Environmental cues that control behavior are influenced by usurped memory circuits. SRDs are often accompanied by comorbid negative mood states that may also contribute to continued drug use through self-medication.

Neuroimaging studies have also revealed that abnormally low dopaminergic neurotransmission is associated with orbitofrontal hypoactivation in individuals with SRDs and limits impulse control, executive functioning, and working memory. Medications that modulate dopamine, glutamate, and norepinephrine neurotransmission that show promise for impulse control and enhance cognition may offer options for treating stimulant dependence.

Doxazosin is a repurposed norepinephrine blocker used for hypertension that has been found to block cocaine’s positive subjective effects and the feeling “likely to use cocaine” in cocaine-dependent volunteers after a cocaine infusion. An outpatient clinical trial is examining this medication for decreasing cocaine use.

Another repurposed medication, the angiotensin-converting enzyme inhibitor and antihypertensive perindopril blocks the cardiovascular and positive subjective effects of methamphetamine. The commonly prescribed antidepressant bupropion has also shown some efficacy in decreasing methamphetamine use in moderate users. Rivastigmine, used in the treatment of dementia, has been found to significantly decrease “likely to use methamphetamine” in individuals with methamphetamine use disorder. Finally, the atypical stimulant modafinil, used to treat narcolepsy, blocks cocaine’s positive subjective effects and has decreased cocaine use in a select subpopulation.

Psychiatric research on SRDs has benefited from repurposing a wide range of medications. The science behind using these medications is based on the understanding from neuroimaging of damaged and reinforcing human neural circuits due to stimulants. For the most part, the development of effective treatments for this pernicious disorder appears promising. ■