Could Ozempic and similar medications be used to treat substance use disorders?

One of the most notable medical developments in recent years has been the emergence of a class of drugs called glucagon-like peptide-1 receptor agonists (GLP-1 RAs). The best known of these drugs is Ozempic, a diabetes drug that is often prescribed for off-label use as a weight loss aid. A new study published in the journal addiction on October 16 investigates whether GLP-1 ARs could prove to be effective treatments for substance use disorders (SUDs).

The researchers examined 100 million anonymized medical records from Oracle Cerner Real-World Data, a large database of de-identified medical data. The records covered the period from January 2014, which, as the study notes, “coincided with the initial approval by the US Food and Drug Administration of many GLP-1 RA drugs” — through September 2022. Researchers identified records of people with diagnosed SUDs, specifically. opioid use disorder (OUD) and alcohol use disorder (AUD), who also took a GLP-1 RA for diabetes or weight loss. They then compared rates of “severe outcomes” (opioid overdoses and acute alcohol intoxication events, respectively) with rates among people in the data set who had OUD or AUD but were no taking a GLP-1 RA. The results look promising: Opioid overdose rates were 40% lower in those taking a GLP-1 AR than in those not taking either medication, while rates of acute alcohol poisoning they were 50% lower.

Dr. Fares Qeadan, the paper’s lead author, explains Popular Science that opioids and alcohol were chosen for the study because “both … interact with reward pathways in the brain that are known to be influenced by GLP-1 receptor agonists (RAs), which aligns with the hypothesized mechanism of action of these drugs.”

This hypothesized method of action involves the brain’s reward pathways, which provide a feeling of pleasure and gratification when activated, encouraging a person to repeat the behavior that elicited those feelings. “Preliminary research suggests that GLP-1 RAs modulate dopamine in reward pathways,” explains Qeadan. In other words, these drugs appear to work by suppressing the activation of these pathways. This reduces both the desire to perform the behavior in question (ie, cravings) and the feelings of gratification that come from fulfilling that drive.

The quid pro quo is that in some patients, it’s not just certain behaviors that are modulated by Ozempic, but some patients report what Qeadan calls “a generalized reduction in pleasure.” In some people, this can worsen the symptoms of conditions such as depression, of which anhedonia, a general inability to find joy or pleasure in life, is already a symptom.

There is significant comorbidity between SUDs and mental health problems, and as a result, Qaedan says, “monitoring mental health outcomes and considering adjunctive psychological support is critical if GLP-1 ARs are to be used for SUDs, especially in populations at risk for mood-related side effects.” He also suggests that it will be “especially (important) to understand whether medications can selectively decrease drug-related reward without affecting other positive experiences.”

More generally, one of the perennial questions with SUDs is how to strike a balance between treating the addiction itself and treating the underlying causes of drug use. Existing treatments for OUD, in particular, involve transitioning patients from dangerous short-acting opiates such as diamorphine (heroin) and fentanyl to methadone or buprenorphine, allowing users to slowly taper off opiates while receiving counseling and psychotherapy.

“Many people with SUD are dealing with underlying mental or systemic health issues,” agrees Qeadan. “Medications such as GLP-1 ARs can reduce the compulsion to use substances by decreasing reward signals, but they do not address these underlying problems directly. (I) unlike traditional medication-assisted treatments (MATs) such as methadone or buprenorphine, which offer a stepwise approach and support harm reduction, GLP-1 ARs would likely be used more to reduce cravings and addictive behaviors rapidly.

This raises the question of what kind of psychological support would be required for people experiencing relatively rapid transitions from the substance to which they are addicted, and whether the existing rehabilitation infrastructure could provide such support. Qeadan says this is a crucial area for future research: “Going forward, research into the integration of GLP-1 AR with psychological support would be invaluable in helping to create a balanced and effective treatment model for SUDs, which address both the behavioral and systemic challenges underlying addiction.”

The paper by Qeadan and colleagues has also raised other key questions for future research. Because the study only looked at the frequency of serious events, it is not clear exactly how GLP-1 ARs lead to the reduction of these events; researchers don’t know whether patients taking these medications used alcohol or opioids less often, or less intensely, or both.

It is also unclear how the transition to GLP-1 RAs would affect people who use them to treat SUDs. Although some studies have found that most people prescribed RA GLP-1 for off-label weight loss use were able to maintain a lower weight when they stopped the drug, other studies have found the opposite. One of the latter studies noted that their findings “confirm the chronicity of obesity and suggest that ongoing treatment is required to maintain improvements in weight and health.” Since SUDs are also chronic conditions, it seems important to investigate whether disabling a GLP-1 may contribute to relapse rates.

“Our study followed the participants for several years,” says Qeadan. “The protective effects of GLP-1 RAs appeared to be consistent over this time period. However, we do not yet have data on whether patients may require increased doses over time or how outcomes may change if they switch from GLP-1 RAs. Long-term studies would be valuable to understand whether tolerance develops or whether benefits are maintained without increasing doses.”

This last point might be the most exciting of all. Although drug treatments are already available for OUD and AUD, this is not the case with all medications. In fact, there are no FDA-approved treatments for several of the most commonly used illegal drugs, cocaine and methamphetamine being the most prominent examples. Could GLP-1 RAs also be effective for addictions to these drugs?

Qeadan is cautiously optimistic: “The mechanism of GLP-1 ARs to modulate reward and craving behaviors could have potential in a range of addictions, potentially expanding the therapeutic applications of these drugs to other substances (such as cocaine). However , cautions that “further research is needed to explore whether GLP-1 RAs affect the reward circuits involved in stimulant addiction.”

Ultimately, this study is a new first step toward diversifying the treatment options available for SUD. Qeadan says the next step will be clinical trials: “To advance our understanding, randomized controlled trials specifically focused on SUDs are a top priority. These trials could confirm whether GLP-1 RAs directly reduce substance use, help determine optimal dosing regimens and establish long-term safety profiles.”

He also suggests several other areas for future research: “Neuroimaging studies would also be valuable to observe changes in reward circuits in real time, allowing us to see how GLP-1 RAs affect brain activity related to Craving and Addiction Furthermore, studying the effects of GLP-1 RAs on other types of addiction, such as stimulant or nicotine dependence, could clarify the broader applicability of these drugs and help guide tailor-made interventions”.