Studies Identifying Compounds That May Improve Treatment of Opioid Addiction

Since the 1960s, the psychedelic drug ibogaine has attracted interest as a potential treatment for opioid addiction due to limited evidence and anecdotal claims by people who claim that they no longer feel cravings for opioids after taking ibogaine. However, this drug comes with risks, including heart disease and death.

In a new study, Yale University researchers have identified two compounds that have been shown in experiments with mice to be more biologically targeted than ibogaine, but, like hallucinogens, It improved depression, anxiety, and opioid withdrawal symptoms.

The findings could inform future drug development and lead to more effective treatments for opioid addiction, the researchers said.

research published In the journal Cell on May 2.

Ibogaine, a natural psychotropic drug found in the iboga plant, is known to bind to all kinds of target proteins in the body. makes it difficult to determine how

One of its targets is the serotonin transporter, which is also where antidepressants such as Prozac, Celexa, and Paxil act. Serotonin transporters are proteins in the membranes of neurons in the brain. Its job is to return serotonin (a neurotransmitter linked to depression) to the neurons that released it, limiting its effects. Antidepressants block the transporters from doing this, allowing serotonin to continue working for a longer period of time.

Gary Rudnick, emeritus professor of pharmacology at Yale School of Medicine and co-lead author of the new paper, first became interested in ibogaine because of its effects on the serotonin transporter. It’s likened to a shipping lock. Like a ship passing through a canal, serotonin molecules first enter her one gate on the outside of the cell. Once inside the transporter, the first gate closes and he opens the second gate, allowing the serotonin molecule to re-enter the cell.

Most compounds that bind to the serotonin transporter, such as antidepressants and recreational drugs such as cocaine, deactivate the transporter by keeping the outward gate open. However, as Rudnick found in previous work, ibogaine blocks the transporter by keeping the inner gate open.

After making this discovery, Rudnick wondered whether other compounds that similarly act on transporters might have effects similar to ibogaine by stabilizing this internal gate. .

“The idea was that if we could find a compound that binds like ibogaine, we might be able to identify a compound that is more selective for the serotonin transporter and has no side effects like ibogaine.

Working with researchers at the University of California, San Francisco (UCSF), the University of North Carolina at Chapel Hill, Duke University, and the Medical University of Vienna, Rudnick and his colleagues identified two compounds that could fit that bill. Did.

Starting with a database of over 2 billion compounds, the research team selected about 200 million compounds with the desired properties, including the ability to penetrate the brain. From there, they used a computer program to see if the molecule binds with the inner gate of the serotonin transporter open. Thirty-six best candidates were synthesized and tested further, and the researchers selected the two that bind the serotonin transporter the most strongly.

“Ultimately, the two compounds did not affect the transporter in exactly the same way as ibogaine — they did not have the same effect on the shape of the transporter — yet worked differently than other known compounds. “They were also potent and highly selective for the serotonin transporter.”

In mouse models of anxiety and depression, the research team found that the two compounds performed as well or better than the antidepressant fluoxetine (known by its brand name Prozac).

They also tested the most potent compounds against opioid withdrawal symptoms in mice and compared their effects to the antidepressant drug paroxetine (also known as Paxil), which is used to treat withdrawal symptoms in humans. Looking at the various behaviors associated with , paroxetine inhibited two behaviors (jumping and standing), and the test compound inhibited three behaviors (jumping, paw tremor, and whole-body tremor).

“Some people swear by ibogaine for the treatment of addiction, but ibogaine is not a very good drug with severe side effects and is not approved for use in the United States,” said the study’s senior author. “Our compound mimics one of ibogaine’s many pharmacological effects and, at least in mice, reproduces the most desirable effects on behavior.”

Rudnick believes that these two compounds could be further investigated as treatments themselves or used as starting points for drug development. Additionally, the methods used in this study could potentially be used to identify compounds for other therapeutic targets, he said.

“For drug development, I think this approach is very promising,” said Rudnick. “We showed that we can take a well-known target and come up with new highly selective inhibitors in a relatively short period of time.”

Rudnick added that while there are already many options available for treating depression with these two compounds, opioid withdrawal deserves further investigation. “It’s a great idea to pursue in light of the opioid crisis.”