Repurposing Medications to Treat Addiction?

Human and animal studies have consistently shown that addiction is accompanied by blunted dopamine signaling in the striatum, and that the status of dopamine transmission predicts relapse or recovery from addiction. Therefore, there is a consensus that manipulating this neurotransmission system could be an efficient strategy to treat addiction. In particular, converging evidence suggests that targeting the dopamine type 2 (D2) receptor - i.e. enhancing its activity - would increase the response rate to treatment by giving patients the boost they need to shift their habits away from drug or alcohol use. Various pharmacological approaches have been tried, with limited success so far, but other novel, promising ways to increase signaling at the D2 receptor have not reached the stage of clinical trials.

Why is that? In previous articles we have described the neurobiology and behavioral effects of blunted striatal dopamine transmission. In this issue, we describe new medications that have been developed and tested in human clinical trials. These medications were developed for other disorders (Parkinson’s disease and depression), but the neuroscience supports their use in addiction. However, despite the scientific rationale for trying these for addiction, clinical trials with these new medications is unlikely.

Adenosine 2A antagonists

A promising way to increase signaling at the D2 receptor is by blocking the adenosine 2A (A2A) receptor. A2A receptors are closely linked to dopamine D2 receptors and are able to modulate their signaling (PMID: 26051403). Blocking the A2A receptor potentiates the effect of dopamine at the D2 receptor by facilitating the downstream cellular effects. Accordingly, studies in rodents have shown that A2A antagonists can enhance dopamine-mediated processes, such as reward-driven behaviors and motivation. More precisely, the administration of A2A antagonists in the setting of impaired dopamine transmission increases the animal's willingness to exert effort for more effortful but preferred outcomes over immediate, easily accessible, but less preferred rewards (PMID: 23583616). In the context of addiction, such a switch in behavior could help counteract the impulsive response towards the drug and therefore improve response to treatment. 

Based on these rodent studies, there has been a lot of interest in A2A antagonists for addiction research in humans, and one experiment using A2A antagonists for cocaine dependence with functional MR scanning showed that this medication increased activity in brain regions known to be hypoactive in cocaine addiction (PMID: 22654774). However, despite these promising data, there is, to our knowledge, no clinical trials testing A2A antagonists for addiction. This is likely to be related to the difficulty of obtaining the compounds that have been developed by pharmaceutical companies. 

For example, several A2A antagonists have been developed for Parkinson’s disease. The neurobiology of addiction has similarities to the neuroscience of Parkinson’s disease, where striatal dopamine signaling is also impaired. A2A antagonists are being tested for Parkinson’s disease specifically to increase dopamine signaling at the D2 receptor, and several compounds have been proven to be safe for use in humans. To date, three medications (istradefylline, preladenant, and tozadenant) have been used in human clinical trials. Istradefylline has been approved and is marketed in Japan for Parkinson’s disease. Tozadenant is being tested by a pharmaceutical company in Finland (Biotie). Preladenant was developed in the United States by Merck, but clinical trials in Parkinson’s disease were stopped in 2013 because it did not improve symptoms better than placebo. Getting access to these medications to try them as a new treatment for addiction is challenging, but not impossible. To conduct new tests the pharmaceutical company that owns the medication would need to provide the medication and share the human safety data. The data however is promising and should be tested: from animal models to human imaging, it appears that blocking the A2A receptor could constitute treatments for addiction.  

Kappa receptor antagonists

While dopamine plays an important role in addiction, we also know that the kappa receptor system in the brain modulates stress and anxiety in addiction, which we discussed in a previous article. Animal studies show that activating this receptor increases drug and alcohol seeking behavior, whereas blocking this receptor inhibits this in the context of stress – a behavioral feature known to be a vulnerability factor for relapse. 

Kappa receptor antagonists, like A2A receptor antagonists, have been developed for human use. The development of these medications has not been easy. The National Institute on Drug Addiction previously performed human safety studies so that a kappa antagonist could be available for publically funded research, but this medication did not pass safety testing (PMID: 25628006). However, Eli Lilly has developed a kappa antagonist that is safe for human use. Eli Lilly began testing this medication about 5 years ago and has been focused on using it for depression, but then sold the kappa antagonist to the pharmaceutical company Cerecor in early 2015. The human and animal data indicates that kappa receptor antagonists would be instrumental in treating addiction; with access to this medication, academic researchers could test this medication to see if it would be successful in addiction treatment.

While the cost of developing a new medication is high, it is important to recognize the role of publicly funded research in this process. Academic research has provided crucial data on the potential therapeutic effects of new medications, usually with animal models, and this data fuels new treatments for diseases, including Parkinson’s diseases, depression, and addiction. Thus, while there are clear and justifiable reasons why pharmaceuticals are reluctant to allow basic research to access compounds for which they often spent years and a huge amount of money to develop, these compounds are usually developed based on discoveries made by academics performing publicly funded research, and, if proven efficient, such drugs would eventually profit the companies. 

A bidirectional exchange between academia and private companies could prove profitable to everyone. After all, everybody has to keep in mind that the patient should be the priority.