Introduction

GLP-1 (glucagon-like peptide-1) is a hormone that is released by your stomach after eating food. This helps to regulate appetite and blood sugar. GLP-1 agonists, often referred to as GLP-1s, mimic the action of this natural hormone.¹ They were first introduced as a treatment for diabetes because of the various functions they have in reducing blood sugar, but were later approved as a weight-loss therapy for obesity because they can reduce your appetite. They will typically be taken as an injection as instructed by your doctor.¹ There are several physical side effects you may experience:

• Feeling sick 
• Stomach pain 
• Headaches 
• Low blood sugar 
• Constipation or diarrhea¹

It is important that you consult a healthcare professional before taking GLP-1s, and that you follow their advice and attend regular follow-ups while taking the medication. They are likely to advise that you also make some healthy changes to your lifestyle, such as:

• Eating fruits and vegetables every day 
• Eat high fiber foods like wholegrains 
• Eat less fatty meats¹

Liraglutide (brand name Saxenda) and semaglutide (brand names Ozempic or Wegovy) are examples of the GLP-1s available. Liraglutide was developed to be taken once daily, followed by semaglutide, which only has to be taken once weekly.²

Recently, there have been growing concerns around the impact of GLP1-1s on mental health. Some users even report suicidal thoughts.³

How GLP-1s Work in the Body and Brain

GLP-1 is produced in our intestines, pancreas, and brain. It interacts with and activates GLP-1 receptors (GLP-1R), which have several functions:

• Stimulates the release of insulin
• Prevents the release of glucagon from the liver, a hormone that acts to increase blood sugar
• Slows down digestion by slowing the emptying of the stomach, which:
  • Slows the absorption of sugar
  • Increases feelings of fullness 
• Suppresses appetite, therefore reducing consumption of food⁴

GLP-1 influences insulin and glucagon release by affecting signalling pathways involved in their synthesis, which produces the hormones and their release once made. It also reduces apoptosis (cell death) of the pancreatic cells that produce insulin, and promotes their proliferation (cell division). This protects the liver's ability to produce insulin in response to sugar.⁴

GLP-1 is crucial for controlling blood sugar levels and food consumption through these functions. GLP-1 agonists mimic the action of natural GLP-1, showing how they can be useful in both managing type 2 diabetes (T2DM) and as a weight loss treatment.

Mood and Emotional Well-being

Early research suggests that GLP-1s might improve anxiety and depressive symptoms, improving mood. One way they may do this is by regulating the release of neurotransmitters such as serotonin, which plays an important role in mood, preventing depression, and promoting happiness.⁵ Results also show that different GLP-1 agonists might have different effects on mood, and some may have a larger effect than others. Further research might allow doctors to choose the best medication for patients depending on their symptoms and histories.⁶ Findings are limited and can be mixed, especially in human studies, so more research is needed to determine the exact effects of GLP-1s on mood. In diabetic patients, the antidepressant effect may be due to an improvement in diabetes symptoms, so it might be difficult to label the GLP-1 agonist itself as the cause. Improvements in mood may also be due to weight loss, especially when people have struggled with weight loss previously.

Some patients using GLP-1s have reported thoughts of suicide and self-injury that they may not have felt before. In a study focusing on reports in social media, people taking GLP-1s were found to have a negatively impacted mood. One potential explanation for this is that over time, GLP-1s are not as effective, and if weight loss slows down, then people may experience some depressive symptoms.⁷ Somewhat conflicting research found that there was no significant increase in self-harm and suicide in users of GLP-1s.⁸ More thorough research is needed into the effects of these weight loss treatments to help people make decisions on using them, and to help doctors inform their patients better.

Motivation and Reward Processing

The reward system in our brain is where things like events, behaviours, and substances are associated with a positive outcome. These things are reinforced, encouraging us to repeat actions. Dopamine is the key hormone involved in this process. When something rewarding is encountered, the system is activated, and dopamine is released. This hormone gives feelings of enjoyment and, therefore, reward. While food is rewarding because it is necessary for survival, drugs such as alcohol, nicotine, and illegal substances can activate the parts of the brain that release dopamine, causing a large amount to be released, encouraging people to keep seeking out their addictions.⁹

Recent research has shown that GLP-1 is involved in reward-related behaviours. Early signs came when GLP-1 and its receptors were found in reward centres of the brain, including the hippocampus. GLP-1 was later found to increase activity of neurons in the reward system, which are essential for the release of dopamine, with similar effects found in injectable GLP-1 agonists. Studies in mice show that these injections lead to decreased food intake and decreased body weight. This is because the reward and therefore motivation to consume food for pleasure rather than hunger was reduced.¹⁰

There are, therefore, potential uses for GLP-1s in the treatment of addiction. In animal models, GLP-1 has been shown to reduce intake of drugs such as cocaine, alcohol, and nicotine, however, to apply these results to humans, we would need to perform studies on humans. However, the effect of opioid addiction, including morphine, is the opposite when studied in mice. This is why more thorough testing is necessary.¹¹ The effects are mostly seen in patients with T2DM, suggesting that as a therapy for addiction, it should be targeted at this group.¹²

Mental Health Side Effects

A common concern with GLP-1s is fatigue, particularly during the first months of taking the treatment. One reason for this is the reduced food consumption. When consuming fewer calories, you have less energy, and this fatigue can affect mental health if people struggle to complete daily tasks or to do things they enjoy. There are several ways to manage this, and it is typically temporary. It is important that you stay hydrated, and eat nutrient-rich meals consisting of protein and fruits, and vegetables to boost energy levels.⁷

Some users have reported apathy, which is a lack of interest, motivation, or emotion. However, these findings have not been seen in a large study [13]. Some researchers have suggested that instead of being due to the medication, this apathy might be because changing your lifestyle and diet is hard, and food can often be a social event, so changing your diet can impact your relationships.¹³ Regardless of the cause, if you are taking a GLP-1 agonist, you should monitor any side effects and negative feelings and communicate them to your doctor to make decisions on continuing treatment and to prevent anything from worsening.

What We Don’t Know Yet

Research so far into GLP-1s and their effect on mental health is limited and often conflicting. There is a lack of long-term studies looking at the effects on mental health following the use of these treatments, making it difficult to say for certain what the effects may be. More thorough research should focus specifically on mood and motivation, using randomised trials rather than what people have reported. There should also be a focus on the wider potential uses of GLP-1s to decide if there is any merit to using them in a clinical setting.

Summary and Future Directions

There is promise for GLP-1s beyond that of diabetes and weight loss, including a potential use for mood regulation in overweight and T2DM patients, in addiction, and in a range of health conditions:

• Studies in mice show decreased markers for Alzheimer’s disease following GLP-1 agonist treatment¹⁴
• GLP-1 appears to have a role in protecting dopamine-releasing neurons, making it a potential treatment for Parkinson's disease¹⁴
• GLP-1 agonists in mice have inhibited cancer development in pancreatic cells, likely due to the role they play in signalling pathways⁴

More thorough research is needed into the uses of GLP-1s outside of weight loss and T2DM. If it were found to be effective in humans with any of the above conditions, it would be revolutionary for healthcare and those suffering. 

It appears most likely that the effects of GLP-1s are complex and could be specific to each individual, especially when it comes to mental health. If they were to be offered for a wider range of uses, the best approach would be a personalised one in terms of whether it is an appropriate option, which agonist to use, and the dose. It would be important for patients to monitor any side effects and report them to their doctor, and to have regular follow-up appointments to decide if they should continue the treatment. 

It might be safe to assume that those with a history of eating disorders and body image issues could be at risk of harm when using GLP-1s for weight loss, and they may need extra consideration and precautions in place if they were to use this treatment. Before there is concrete evidence for the effect on mental health, whether positive or negative, it may also be beneficial to use extra caution when people have a history of mental illness.