Researchers at CU Anschutz have developed an experimental drug called Nezavist that works through an unexpected pathway: instead of acting directly on the brain, it activates communication between the gut and brain to reduce the urge to drink after withdrawal. The drug is currently undergoing Phase 1 human safety trials after showing significant promise in animal studies, where it prevented the dramatic increase in alcohol consumption that typically occurs when alcohol becomes available again after a period of abstinence.

How Does Nezavist Work Differently From Current Alcohol Treatments?

Current medications for alcohol use disorder (AUD), such as naltrexone and acamprosate, work by reducing cravings and helping people maintain abstinence. However, only a small percentage of people with AUD actually receive treatment with these drugs. Disulfiram (Antabuse) creates unpleasant reactions when alcohol is consumed, but requires close supervision to be effective.

Nezavist takes a fundamentally different approach. Rather than entering the brain and acting on reward systems, the drug works entirely in the gut and activates the vagus nerve, a major communication highway between the digestive system and the brain. This activation appears to reduce inflammation in the brain, which research suggests plays a key role in driving excessive drinking and relapse.

"What surprised us in our animal studies is that the drug does not appear to enter the brain. We barely see it in circulation because it is metabolized very rapidly. These findings suggest that Nezavist could produce its effects through actions in the gut," explained Paula Hoffman, PhD, professor emerita in the Department of Pharmacology at the CU Anschutz School of Medicine.

Paula Hoffman, PhD, Professor Emerita, Department of Pharmacology, CU Anschutz School of Medicine

Why Does Brain Inflammation Matter in Addiction?

Recent research has shown that chronic alcohol use and withdrawal trigger immune responses in the brain, creating inflammation that's associated with anxiety, depression, and post-traumatic stress disorder. This neuroinflammation appears to be a major driver of excessive drinking and vulnerability to relapse. By reducing this inflammation through gut-brain signaling, Nezavist may help break the cycle of escalating alcohol consumption that follows withdrawal.

In animal studies, when alcohol was removed and then made available again, consumption typically skyrocketed. Nezavist prevented that escalation, bringing drinking back to baseline levels rather than allowing it to spiral upward. Importantly, the drug doesn't produce complete abstinence; instead, it appears to normalize drinking patterns after withdrawal.

How to Understand the Key Differences in Addiction Treatment Approaches

• Brain-Targeting Drugs: Medications like GLP-1 drugs enter the brain directly and suppress reward pathways, which can reduce alcohol consumption but may carry risks of depression or anxiety as side effects.
• Gut-Based Approach: Nezavist activates the body's natural vagus nerve signaling to reduce brain inflammation without directly suppressing reward systems, potentially avoiding some neurological side effects.
• Traditional Medications: Naltrexone and acamprosate help maintain abstinence, while disulfiram creates negative reactions to alcohol, but all require consistent adherence and supervision.

The gut-brain approach is particularly appealing because it uses the body's existing communication systems rather than forcing new chemical pathways. By working through the vagus nerve, Nezavist essentially leverages mechanisms your body already relies on to regulate inflammation and other brain processes.

What Stage of Development Is Nezavist Currently In?

Nezavist is currently in Phase 1 clinical trials, which focus on establishing safety in healthy volunteers. The drug has completed animal safety and toxicology studies, and researchers have not identified significant safety concerns at the doses expected to be used therapeutically. The only issue observed in preclinical studies was potential gastric irritation at much higher doses, similar to what can occur with aspirin or other nonsteroidal anti-inflammatory drugs.

After Phase 1 safety studies are complete, the next steps will include multiple-dose safety studies, followed by Phase 2 trials in people with alcohol use disorder to compare the drug with a placebo and evaluate its effectiveness. If those results are positive, larger Phase 3 studies would follow.

Researchers are also exploring whether Nezavist might help with other addictions beyond alcohol. Early animal studies suggest the drug may have similar effects on nicotine, preventing the escalation of consumption that occurs when nicotine becomes available again after withdrawal. The team hopes to eventually investigate whether this approach could help with opioid addiction as well.

"We would like to know whether this approach could help with other addictions, including opioid addiction. We are still at the beginning of understanding exactly how the drug works," noted Hoffman.

Paula Hoffman, PhD, Professor Emerita, Department of Pharmacology, CU Anschutz School of Medicine

The development of Nezavist represents a shift in how researchers think about addiction treatment. Rather than viewing the brain in isolation, scientists are increasingly recognizing that the gut and the brain communicate constantly, and that this communication plays a crucial role in behavior and mental health. By harnessing this natural communication pathway, Nezavist offers a potentially safer and more targeted way to help people recover from alcohol use disorder and prevent the relapse that so often derails recovery efforts.