Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of medications originally developed for type 2 diabetes and, more recently, obesity treatment. These drugs mimic the natural GLP-1 hormone, stimulating insulin release and slowing digestion, which improves blood sugar control and promotes a feeling of fullness (FDA description). By helping regulate appetite and glucose levels, GLP-1 RAs can lead to significant weight loss in people with obesity or overweight.
Examples of GLP-1–based medications include:
Other GLP-1 RAs like liraglutide (Saxenda®) and dulaglutide (Trulicity®) also exist, but semaglutide and tirzepatide have garnered the most attention due to their potency in weight reduction. Retatrutide is an even newer experimental drug showing striking weight-loss results in trials. Given the widespread use of these medications for metabolic diseases, clinicians and researchers are now examining how they impact the brain – particularly regarding mood, depression, and addictive behaviors.
Originally, GLP-1 drugs were valued for their effects on the pancreas and gut, but we now know GLP-1 receptors are also found in the brain. In fact, GLP-1 receptors are present in key brain regions that regulate reward, motivation, and emotion – including the ventral tegmental area (VTA) and nucleus accumbens (NAc), which are central to the brain’s reward circuitry for food, alcohol, and drugs (Scientific Reports 2023). Activation of these brain GLP-1 receptors can reduce dopamine-driven reward signals, meaning that stimulating GLP-1 pathways may blunt the pleasurable reinforcement from eating or substance use. Consistent with this, animal studies have shown that GLP-1 agonists dampen dopamine release in reward circuits and reduce drug-seeking behaviors in models of addiction (MDPI 2025 review). Beyond reward effects, GLP-1 activation in the brain may also influence mood regulation. Preclinical research suggests GLP-1 RAs can have neuroprotective and anti-inflammatory effects in the brain, potentially enhancing neuroplasticity and modulating neurotransmitters involved in mood (eClinicalMedicine 2025). This raises the exciting possibility that GLP-1-targeting drugs might not only curb appetite, but also improve certain aspects of brain health – or conversely, cause unexpected psychiatric side effects. Below, we delve into what emerging evidence says about GLP-1 agonists’ impact on mood, depression and substance use disorders.
Some early evidence hinted that GLP-1 RAs could positively affect mood, especially in patients with metabolic conditions. Improved blood sugar control and weight loss often lead to better energy and self-esteem, which can translate into improved mood. Moreover, given the presence of GLP-1 receptors in mood-regulating brain regions, scientists theorized these drugs might have direct antidepressant properties. Indeed, recent clinical reviews have found signals of antidepressant effects. For example, a 2024 systematic review and meta-analysis of clinical trials concluded that GLP-1 agonist treatment led to significantly greater improvements on depression rating scale scores compared to control treatments (placebo or other drugs) in adults (Chen et al., 2024). In other words, in trials where mood was measured, patients on GLP-1 RAs tended to report lower depression scores than those not on GLP-1 therapy. Some individual trials and reports have similarly noted improved mood or reduced depressive symptoms in diabetic patients treated with GLP-1 RAs, potentially as a result of better overall health and possible direct neurochemical effects.
There are also intriguing real-world anecdotes: Patients on semaglutide for weight loss sometimes report not only eating less, but also feeling less anxious or “freed” from constant food thoughts – which could alleviate stress and improve mental well-being. However, such anecdotal reports need to be viewed with caution, as many factors (like lifestyle changes while losing weight) could influence mood.
Despite the hopeful signs, more recent data have raised concerns about depression and even suicidal ideation in some patients taking GLP-1 RAs. In mid-2023, the European Medicines Agency (EMA) announced it was reviewing safety data on GLP-1 drugs after receiving post-marketing reports of depression and self-harm in patients on these medications. Around the same time, the U.S. FDA also began investigating reports of suicidal thoughts in patients using GLP-1 agonists for obesity or diabetes.
So far, findings are mixed. On one hand, a large 2024 cohort study (over 160,000 patients with obesity) reported a significantly higher incidence of new psychiatric diagnoses among GLP-1 RA users: an ~98% increase in risk of any psychiatric disorder compared to matched non-users, including a 195% higher risk of major depression and ~106% higher risk of suicidal behavior (Scientific Reports 2024). This observational study (using real-world data from 2015–2023) suggests there may be a concerning association between GLP-1 therapy and the emergence of depression or anxiety in some individuals. Additionally, several case reports have emerged describing patients who developed depression while on semaglutide. For instance, a 2023 report detailed two cases of adults who experienced severe depressive symptoms about one month after starting weekly semaglutide injections – one had no prior history of depression, and the other had a history of well-controlled depression that relapsed after starting semaglutide. Notably, in both cases the depression markedly improved after discontinuing semaglutide (Frontiers in Psychiatry, 2023). Such reports suggest a possible causal link in susceptible individuals, although it remains unclear why this occurs.
On the other hand, regulatory analyses have not yet confirmed a direct causal relationship. In a January 2024 update, the FDA stated that its preliminary evaluation “has not found evidence” that GLP-1 RAs cause suicidal thoughts or actions, based on available clinical trial data and adverse event reports (FDA Drug Safety Communication, 2024). Specifically, the FDA’s review of large trials and health records did not show an imbalance in suicide-related events between those on GLP-1 drugs and those on placebo (FDA update). However, the agency cautioned that the number of such events was very small in both groups, so a rare risk can’t be definitively ruled out. As a precaution, current prescribing information for weight-management GLP-1 RAs (like Wegovy) already carries warnings about possible depression or suicidal ideation (a class warning shared by other weight-loss drugs). Both FDA and EMA have advised healthcare providers to monitor patients for mood changes and advised patients to report any new or worsening depression or suicidal thoughts while on these medications.
Population differences: Clinical trials for obesity and diabetes often excluded patients with a history of major depression or other serious psychiatric issues. This means the initial safety data may not reflect what happens when those drugs are used in a broader population (including people predisposed to depression). In the real world, GLP-1 RAs are now prescribed to many individuals, including those with past or current mental health challenges – a group in which mood shifts could be more likely to occur.
Weight loss and biology: Rapid weight loss itself can have psychological effects. Some people experience an emotional letdown or hormonal changes during fast weight loss that might affect mood. Additionally, GLP-1 RAs commonly cause gastrointestinal side effects (nausea, reduced appetite) which, if severe or chronic, could indirectly lower mood or energy. (Notably, the observational analysis found no increase in depression reports with tirzepatide, even though tirzepatide causes similar GI side effects and often even greater weight loss than semaglutide (eClinicalMedicine 2025). This suggests factors beyond just weight change or nausea might be at play.)
Neurochemical effects: GLP-1 receptors in the brain might have dual effects – they could improve certain mood pathways (through neuroprotective or anti-inflammatory actions), but they might also blunt the reward system in a way that could lead to apathy or anhedonia in some individuals.
Reporting bias and media attention: As media coverage grew around “Ozempic and mood,” patients and doctors may have become more vigilant in reporting any psychological symptoms on these drugs. This heightened awareness can inflate reported cases without the drug truly increasing the underlying incidence.
Bottom line: At this point, there is no clear evidence that GLP-1 agonists cause depression or suicidal behavior in the average patient, but there are signals that merit caution. Patients on semaglutide, tirzepatide, or similar drugs should be mindful of their mood and communicate changes to their clinicians.
One of the most fascinating discoveries about GLP-1 receptor agonists is their potential to reduce addictive behaviors such as alcohol use, nicotine use, and possibly other substance addictions. This was not an originally intended effect, but it emerged from a combination of animal research and clinical observations.
Tirzepatide (GLP-1/GIP agonist): In pharmacovigilance analyses, semaglutide showed a stronger signal for depression reports, whereas tirzepatide did not – despite tirzepatide’s potent metabolic effects (eClinicalMedicine 2025). On addiction-related outcomes, tirzepatide appears similar to semaglutide, likely via GLP-1 pathway effects (Scientific Reports 2023).
Retatrutide (GLP-1/GIP/Glucagon agonist): Still investigational; no clinical data yet on psychiatric or addiction effects. Given its GLP-1 activity, similar reward-modulating effects are plausible, but unproven.
GLP-1 receptor agonists like semaglutide and tirzepatide, and investigational agents like retatrutide, are transforming metabolic care. Beyond weight and glucose, they intersect with mental health: they can modulate mood and reward circuitry. Evidence to date suggests potential benefits (improved mood in some, reduced alcohol/nicotine cravings) alongside cautionary signals (rare reports of depression or suicidality, especially in vulnerable individuals). Patients and clinicians should weigh whole-person outcomes, monitor mood, and adjust therapy as needed while research continues to clarify these brain–body connections.
