GLP-1s: Potentially A New Direction in Addiction Care

GLP-1 medications have dominated headlines and medical conversations pertaining to weight loss for a while now, but a new frontier is emerging: treating addiction.

Following early trial data two years ago, a study published in JAMA Psychiatry last year formally demonstrated semaglutide’s ability to reduce alcohol consumption. This milestone prompted Manish Jha, M.D., Associate Professor of Psychiatry at UT Southwestern, to look beyond alcohol and investigate the drug’s broader capabilities in treating substance use disorders.

Finding a breakthrough

 A psychiatrist by training, Dr. Jha studies mood disorders and treatment-resistant depression. UT Southwestern’s O'Donnell Brain Institute has invested in his addiction expertise, earning him an endowed scholar position to develop treatments and clinical trials for three primary stimulant use disorders – methamphetamine, cocaine, and prescription stimulants.

"We were running several clinical trials for methamphetamine use disorder, and we just weren't seeing the breakthroughs we needed,” Dr. Jha said. “After attending the presentation by [Christian Hendershot, Ph.D., first author of the JAMA Psychiatry article] on semaglutide for alcohol use disorder, I wanted to research these medications as a potential option.”

Securing backing for a pilot study, Dr. Jha began by evaluating FDA-approved GLP-1 medications. One drug immediately stood out: tirzepatide. Unlike standard GLP-1 medications, tirzepatide is a dual agonist. This means it targets two metabolic pathways at once, binding to both the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptors, marking a potential breakthrough for addiction therapy.

“We went with tirzepatide because of its unique mechanism of action among currently FDA-approved GLP-1 receptor agonists, which we believed would offer a more therapeutic benefit,” Dr. Jha said.

Unexpected demand

Because individuals with substance use disorders often do not meet obesity thresholds, recruiting presented a unique challenge. The protocol required participants to have a moderate-to-severe addiction while concurrently meeting the FDA-labeled weight criteria.

Even with these stringent enrollment parameters, no advertising, and posting only on clinicaltrials.gov, participant response was unexpectedly high. The team raised its enrollment cap from 30 to 45. Ultimately, 42 people cleared the initial screening, and 35 successfully enrolled in the study.

“There is a lot of interest around GLP-1 medication, but the demand also reflects the pervasive nature of this illness and the lack of treatments available,” Dr. Jha said.

Strict adherence

To follow the prescription guidelines, each participant took 2.5 milligrams for four weeks before increasing to 5 milligrams, the lowest approved dose. If a participant could not tolerate the 5-milligram dose, they exited the trial because any lower dose is considered subtherapeutic.

From there the dose could then be titrated between 5 to 15 milligrams based on their tolerability and on their target weight loss. In addition, participants were required to complete weekly diet and physical activity counseling. There was no behavioral support provided because that was not on the FDA label.

Next came the question of timing: How long should the treatment last? The team settled on a 32-week study window. Because it takes 20 weeks of gradual step-up to reach tirzepatide’s maximum 15-milligram dose, this timeline gave the team an adequate window to observe the drug’s full effects at peak strength.

Early concerns

Paticipant compliance was an initial concern for investigators, given confounding socioeconomic variables – such as criminal justice involvement – that occasionally disrupted appointment attendance. Ultimately, however, adherence exceeded expectations. The team administered 923 of the projected 1,120 protocol injections, yielding an overall compliance rate of more than 80%.

As for side effects, GI symptom severity increased at first, but over time, less constipation and less indigestion was reported – possibly because of the changes in the kind of food participants were eating. Instead of fast food, they were cooking more, eating healthier, and incorporating more fiber in their diets.

Excessive weight loss is common with GLP-1 medications, and researchers monitored it closely since losing weight was not the primary goal of the study. Over 32 weeks, participants lost an average of 17.6% of their body weight, mirroring the 18% average seen in other tirzepatide clinical trials. Only three people dropped out because they could not tolerate the drug.

Reduced cravings

At 2.5 milligrams, there were not many changes in methamphetamine cravings, as self-reported each week. But at 5 milligrams, there were observed reductions.

Researchers measured craving in two ways: Participants completed a 10-question assessment that captured how strongly they craved methamphetamine at that moment, while also rating the most intense craving they had experienced during the previous week.

Although the two measures assessed slightly different aspects of craving and were minimally correlated, both showed meaningful declines over the course of the study, suggesting participants experienced fewer intense cravings overall as well as reduced day-to-day urges.

Positive themes

At the start of the study, participants used methamphetamine an average of 28 out of 30 days, putting the probability of use close to 100%. By the end of the study, that average dropped to about 70%. In fact, after five months of treatment, more than 50% of participants either no longer met the criteria for methamphetamine use disorder or qualified as having only had mild case.

Another key observation was that more than half of the participants met DSM-5 criteria for another substance abuse disorder – alcohol, opioid, cocaine or cannabis – and the reduction in craving was even greater for them. This is noteworthy because patients with comorbidities are traditionally much harder to treat, and medications often prove less effective as an illness gains complexity. In this study, however, the reverse occurred. The drug’s impact actually appeared stronger in the presence of more severe illness.

Another positive theme was reduced symptoms of depression. This stood out because 75% of people with similar methamphetamine use disorder have moderate or mild depression severity.

“Depression is not the only thing that got better,” Dr. Jha said. “Participants reported less irritability and less anxiety, and for those who had moderate-to-severe PTSD-related symptoms, there was a reduction in those symptoms as well.”

The missing pieces

Overall, participants showed a clear trend toward improved mental health symptoms. While the findings were preliminary, the signal of potential therapeutic benefit was strong enough to support a grant application to the National Institute on Drug Abuse (NIDA) for a randomized controlled trial. Recently funded by NIDA (UG3DA066252), the study will build on the findings where people with methamphetamine use disorder will be enrolled and treated for six months with either tirzepatide or placebo. UT Southwestern will be the lead site with other sites in Tulsa, Oklahoma, led by W. Kyle Simmons, Ph.D.; the University of Southern California in Los Angeles, led by Dr. Hendershot and the Center for Substance Use and Health in San Francisco, led by Phillip Coffin, M.D., M.I.A.

The team at UT Southwestern also plans to expand the research by doing neuroimaging studies with behavioral therapy and MRI scans with ongoing support from the O'Donnell Brain Institute.

“We want to know with even more clarity and across other substance use disorders if the benefit for prescribing GLP-1s for addiction is there,” Dr. Jha said. “And if so, how durable is that benefit? Does it stay, does it go away – and for how long?”

Going forward

This new research will help answer critical questions about who benefits the most, when those benefits begin, and whether GLP-1s can increase the likelihood of lasting remission. The answers will give psychiatrists the evidence and confidence they need to integrate this new class of medications into clinical practice.

As home to one of the nation's largest addiction psychiatry fellowships, led by Sidarth Wakhlu, M.D, and through multidisciplinary collaboration with endocrinology, weight management, and community partners, UT Southwestern is advancing the science behind the field of addiction with a long-standing NIDA Clinical Trials Network node led by Madhukar Trivedi, M.D. Each study brings researchers closer to determining whether GLP-1 therapies can become a new frontline option for treating stimulant use disorders.

"The question isn't just whether someone is using less methamphetamine or other substances, it's whether their life is improving,” Dr. Jha said. “Our focus on the diagnostic criteria and the real-world impact of GLP-1s is ultimately what defines meaningful clinical benefit."