Approved Drug May be the Key to Cocaine Addiction

Drugs that have already been approved for the treatment of type 2 diabetes and obesity may help treat cocaine addiction. A recent study tested the drug Exendin- 4 which is commonly used for the treatment of type 2 diabetes and obesity. The study tested the drug’s ability to treat cocaine addiction by reducing the tendency of the patients to relapse.

The University of Pennsylvania in Philadelphia researchers discovered that the FDA approved drug decreased the cocaine-seeking behaviors of rats addicted to cocaine. The cocaine-seeking behaviors were attenuated during the normal withdrawal period.

The findings were reported in a paper that has been published in Neuropsychopharmacology in February 2018.

The National Survey on Drug Use and Health (NSDUH) from 2014 showed about 913,000 cocaine users now are considered dependent or are abusing cocaine in the US.

40 to 60% of Cocaine Users Relapse

In order to kick a cocaine addiction, users have to face immense pressure from relapse behaviors. About half of all those seeking to kick the habit are relapsing. This means that treatment space, financing and other resources are essentially being wasted on half of all rehab patients.

Aside from the new application of the obesity and diabetes drug exendin-4 there have not been any FDA approved effective treatments. Users have been left with psychological counselling and willpower as their only tools. It is easy enough to imagine why this fails 40 to 60% of the time.

The study authors have noted that cocaine relapse is considered to be a “significant public health concern.”

The senior study author Heath D. Schmidt is an assistant professor of psychiatry at the University of Pennsylvania. Schmidt explains that “Our goal as basic scientists is to use animal models of relapse to identify novel medications to treat cocaine addiction.”

The Repurposing of GLP-1 Receptor Agonists

When used as a treatment for type 2 diabetes and obesity Exendin 4 mimics an important hormone that reduces the blood sugar levels and ultimately food consumption. This is an FDA approved treatment for type 2 diabetes and obesity.  Since the drug has been approved for other purposes, the FDA approval process is significantly shortened, because it only needs to be proven effective, not proven safe. The previous approvals would have required proving the safety of the drug.

There are also pilot studies being conducted to see if Exendin 4 might be an effective treatment for Alzheimer’s disease. This suggests that scientists believe that the Exendin 4 actions on the brain may affect both cognitive impairment and cocaine-seeking behaviors.

Exendin 4 belongs to a drug class that is called a glucagon-like peptide 1 (GLP-1) agonist. The drugs in this class work by stimulating the GLP-1 receptors. These are the particular proteins that receive signals that are present both in the gut and in the brain.

The Discovery of the Role of GLP-1 Receptors

In 2015, a previous study was conducted by the same group of researchers. They used the rat model for cocaine-seeking relapse behaviours. It was during this study that they discovered the previously unidentified critical role that the GLP-1 receptors played in cocaine-seeking behaviours.

They specifically identified the doses that were required of the GLP-1 receptor agonist. They found the Exendin 4 was able to selectively reduce cocaine-seeking. Most importantly it did not produce any adverse side effects in the rats.

Anti- Relapse Medication with No Side Effects

The suggestion is that these findings will make a strong case to re-purpose exendin-4 to be prescribed, marketed and sold to be used as an anti-relapse medication.

The research team was specifically able to determine an exact low dosage level of the Exendin 4. This precise dosage delivered results making the drug effective, yet did not produce any side effects. This is especially important because the drug Exendin 4 has a high rate for side effects. Patients taking Exendin 4 for obesit and type 2 diabetes are prone to high rates of nausea and vomiting.

The scientists were able to narrow down the specific drug dose to be certain the cocaine-seeking behavior in the rats was not just as a result of the rats feeling too sick because of the side effects. Nausea and vomiting may be helpful in reducing cocaine-seeking behaviors, but human patients and doctors would not likely be willing to consider that as an option.

A Four Stage Study to Reduce Drug Seeking Behavior

The recent research study was completed in four stages. The team first tested the blood from the cocaine addicted rats. These rats were taking cocaine for the previous 21 days. These blood tests showed the rats’ blood had reduced levels of the GLP-1 hormone.

The main production of GLP-1 hormone is specific cells that are located in the small intestines. The secondary production in the body for the GLP-1 hormone nucleus tractus solitarius is in the brain stem.

The fact that the GLP-1 levels were low peaked the attention of the scientists. They then wondered if increasing these levels may influence the rats’ cocaine-seeking behaviour.

Secondly, the research team began testing the effect of the GLP-1 receptor agonists in what is called the “rat model of relapse.”

They allowed the rats to dose themselves freely through an intravenous line with cocaine for the 21 days.

The Withdrawal Period

Afterwards, a withdrawal period was induced by replacing the cocaine with just saline.

There were also behavioral cues. When the rats pressed levers to dose themselves with cocaine a light would come on. It does not take long for a rat to associate the light with the cocaine.

During this withdrawal time period, the cocaine-seeking behaviors were reduced significantly as compared to the 28 self-administered daily doses that occurred in the first phase.

Bringing Back the Drug Seeking Behaviors

In the third phase, the researchers returned the cocaine-seeking behavior in two different ways. They either reintroduced some cocaine, or they left saline in the IV dose but they switched on the cue light when the rats were pressing the levers to get a shot.

Both of these approaches worked. The rats returned to pressing the lever more frequently, which suggested they were “seeking the cocaine.” This is much like what happens to people who are addicted to drugs during a relapse period. They will seek or be triggered by familiar people, places, and things that they have associated with their drug habit.

The researchers then repeated phase 3 of the experiment. This time, the rats were dosed with Exendin-4. The rats’ drug-seeking behaviors did not increase when the procedure to reintroduce the cocaine was initiated during the withdrawal period. Neither the approach of giving the rats an acute dose of the cocaine, nor when they exposed to their paired trigger cues increased the cocaine-seeking behaviors.

In the fourth and final part of this study, the research team used a fluorescent marker. The marker was used to track exactly where the GLP-1 receptor agonist travelled into the brain. The marker was able to tag exactly which one of the molecular pathways was boosted by the GLP-1 signalling.

The research is clear. For the first time it has been determined that central GLP-1 signalling plays a significant role in cocaine-seeking.

Since the FDA approvals have been previously completed for Exendin 4, there is hope that this extraordinary option will be available soon. Cocaine addiction need not be the “significant public health concern” it has been in the past. Soon user can be treated as patients, with a high success rate. This should take pressure off of the medical rehab facilities, and hopefully reduce some of the stigma associated with cocaine addiction rehabilitation.

References

https://www.nature.com/articles/s41386-018-0010-3

https://www.drugabuse.gov/publications/research-reports/cocaine/what-scope-cocaine-use-in-united-states

http://orcid.org/0000-0002-0700-4042

https://clinicaltrials.gov/ct2/show/NCT01255163

https://www.nature.com/articles/npp2015362