A team of scientists has found promising drug candidates that can treat depression and addiction. The new drugs are based on ibogaine, a psychedelic substance found in the native African plant Tabernanthe iboga (the iboga plant).

Scientists in the US and Europe were prominently studying ibogaine in the period between the 1950s and late 1990s. However, later it was discovered that ibogaine could trigger heart ailments in humans, so it failed to emerge as a mainstream medication. Moreover, it was declared illegal in many countries including the US. 

Now, new research conducted by scientists from Yale, UCSF (University of California San Francisco), and Duke University reveals that ibogaine blocks a protein called serotonin transporter (SERT) in the human body. What’s interesting is that conventional antidepressant drugs like Prozac also treat depression by targeting the same protein. Moreover, some previous studies hint that ibogaine could also be helpful in treating addiction. 

Based on these findings, the researchers recognized that the SERT-blocking action of ibogaine could lead to the rise of novel therapeutic treatments for both addiction and depression. They wanted to harness these beneficial properties, but they knew they couldn’t use the substance directly because of its detrimental effects on the human heart. 

So they tested millions of molecules to find chemicals that could block SERT in humans like ibogaine without causing any dangerous side effects. Brian Shoichet, co-senior study author and a professor at UCSF School of Pharmacy, said:

“Some people swear by ibogaine for treating addiction, but it isn’t a very good drug. It has bad side effects, and it’s not approved for use in the US. Our compounds mimic just one of ibogaine’s many pharmacological effects, and still replicate its most desirable effects on behavior, at least in mice.”  

The creation of ibogaine-inspired drugs

The two drug candidates discovered by the researchers are referred to as 8090 and 8219 in the study. Interestingly, these two SERT inhibitors were identified out of 200 million molecules without performing testing or chemical synthesis experiments for each molecule. So how did the researchers do it? 

Well, they employed a virtual chemical testing method known as docking. This technique enabled scientists to find their desired chemical structure by running their experiments on a computer. 

During this virtual chemical testing process, the researchers were also able to study the effect of each molecule on brain receptors associated with SERT activity. After the first docking round, they were able to shortlist 49 candidates, lab tests showed only 13 were effective in blocking SERT. The researchers then ran the 13 molecules again through the docking process to find the most efficient SERT blockers.

They were left with five desirable molecules that were further tested in animal models and went through a series of other lab tests that checked their stability. Finally, the researchers settled on just two drug candidates (8090 and 8219) that inhibited SERT action like ibogaine, and were effective in treating depression and addiction in mouse models. 

The study authors note, “The drugs inhibited SERT in a similar way to ibogaine, but unlike the psychedelic, their effect was potent and selective, with no spillover impacts on a panel of hundreds of other receptors and transporters.” They further added, “In mouse behavioral assays, both compounds had anxiolytic- and antidepressant-like activity, with potencies up to 200-fold better than fluoxetine (Prozac), and one substantially reversed morphine withdrawal effects.”

New depression and addiction drugs are on the way

Over the last 25 years, drug overdosing has caused the deaths of over 932,000 people in the US alone. Depression on the other hand is the leading cause of suicide around the globe. More than 700,000 people take their own lives every year. This is where the new drugs could make a big difference.

Although the drugs 8090 and 8219 have shown their potential in treating animals, there is a lot that needs to be done before these chemicals could be safely tested on humans. Professor Soichet and his team have sent the drugs to Sigma Aldrich (a biotech company in the US) where the molecules will be further tested by other experts. 

If these tests turn out to be a success, this will give a new ray of hope to millions of people suffering from addiction and depression, and hopefully, we’ll have treatments that will make these conditions curable and less painful.

The study is published in the journal Cell.