GLP-1s, Mounjaro & “Anhedonia” What We Know So Far
Graham Phillips
FRPharmS • Founder
Anhedonia
(a loss of pleasure or interest in things that used to feel good)
I wanted to unpack what we know (and don’t yet know) about GLP-1s, mood and anhedonia, and what practical steps you might take.
Anhedonia isn’t just “a bit low”. It’s a core symptom of major depression and is strongly linked with suicidal risk. People often describe:
- Feeling emotionally numb or flat
- No longer enjoying hobbies, food, sex or time with friends
- Going through the motions, but life feels grey or pointless
So what do the big studies say about GLP-1s and mood/suicidality?
This is where it all gets a bit confusing, because different types of evidence point in somewhat different directions.
Randomised Trials And Big Cohort Studies
Post-publication analyses of the STEP obesity trials found that people on semaglutide 2.4 mg did not have higher rates of depression or suicidal thoughts than those on placebo; mood scores actually tended to improve slightly as weight and metabolic health improved.
Large population studies (Sweden, France, etc.) similarly found no increased risk of suicide or suicide attempts in GLP-1 users overall compared with other diabetes/weight-loss medicines.
So at the population level, GLP-1s do not look like they dramatically increase suicide risk for most people. In fact, better metabolic health may improve mood on average.
Pharmacovigilance And Case Reports:
Analysis of the EMA’s EudraVigilance database found 372 reports with 481 psychiatric adverse events linked to semaglutide, liraglutide and tirzepatide between 2021–2023, including depression, anxiety and suicidal ideation/attempts.
A JAMA Network Open study of WHO safety data found a disproportionate signal for suicidal ideation with semaglutide compared with many other drugs – not proof of causation, but enough to flag concern.
Another pharmacovigilance analysis specifically noted a possible association between liraglutide, semaglutide and tirzepatide and suicidal thoughts/self-harm in the real-world weight-loss setting.
Multiple case reports now describe people developing new or recurrent depression, emotional blunting or anhedonia soon after starting semaglutide, with improvement after stopping or reducing the dose.
So: for the vast majority, GLP-1s don’t seem to cause psychiatric problems, but there is a small subset in whom clinically important mood changes appear temporally related to treatment.
What Are Regulators Currently Saying?
The MHRA in the UK recently completed a review and concluded that the available data do not support a causal association between GLP-1s and depression or suicidal thoughts, but they will keep monitoring and update advice if needed.
The EMA (Europe) looked at large EHR datasets and similarly reported no causal link between semaglutide and suicidal ideation, while keeping an open review.
The FDA in the US has acknowledged reports of suicidal ideation in GLP-1 users and is “evaluating regulatory action”.
Most recently, the Australian TGA has added class-wide warnings for Ozempic, Wegovy, Saxenda, Trulicity and Mounjaro about possible depression and suicidal thoughts, and is updating product information accordingly.
So How Could The GLP-1s Cause Anhedonia?
There are three big, plausible pathways and they can overlap.
Direct effects on the brain’s reward circuits.
GLP-1 receptors aren’t just in the gut and pancreas…they’re scattered through brain regions involved in motivation and reward.
Animal and human studies show GLP-1R agonists reduce dopamine signalling in these reward pathways and blunt the rewarding effects of alcohol and highly palatable food.
A recent rodent study found tirzepatide specifically dampened alcohol-induced dopamine release in the nucleus accumbens and reduced relapse-like drinking behaviour.
This “anti-consumption” effect is brilliant when we’re talking about cravings for junk food or alcohol, but for a small minority it may generalise into a broader “I don’t get much pleasure from anything” feeling – i.e. anhedonia.
Nutrition, Lean Mass And Biological Depression
These drugs can produce very large calorie reductions. Recent work shows:
GLP-1-assisted weight loss can involve substantial lean mass loss (20–40% of total weight lost) if protein intake and resistance training aren’t optimised.
Several reviews now warn about nutritional deficiencies and malnutrition (low protein, B-vitamins, iron, vitamin D, etc.) in people on GLP-1s who are just “picking” at food.
Deficiencies in B12, folate, iron and vitamin D are all independently associated with higher rates of depression and fatigue, and improving those deficiencies can modestly improve mood in some trials.
So if someone on Mounjaro is:
- Eating very little
- Losing muscle
- Running low on key micronutrients
…they may start to feel physically and mentally depleted, quite apart from any direct drug effect.
Psychological Adjustment
For many of us, food has been our main coping strategy and source of pleasure for years. (People talk about “eating their feelings” So taking that away overnight without simultaneously building new sources of joy (movement, hobbies, relationships, purpose) can unmask underlying depression or leave life feeling strangely empty.
Will Switching From Mounjaro To Wegovy “Fix” Anhedonia?
Short answer: we don’t have good comparative data.
There are anecdotal reports and a few case descriptions where mood issues improved after stopping or switching GLP-1s, but no robust, head-to-head evidence that “Wegovy is safer for mood than Mounjaro” or vice versa.
Different people clearly tolerate different molecules and doses differently, so an individual trial of a lower dose or an alternative agent with proper medical supervision can be reasonable if symptoms are clearly drug-linked.
What Should You Do If You’re On A GLP-1 And Feeling Emotionally Flat?
NB: This is general education, not personal medical advice but here’s a sensible framework to discuss with your prescriber:
Safety first: Any suicidal thoughts, thoughts of self-harm or total inability to function day-to-day. Treat as an emergency. Contact your GP urgently, NHS 111, crisis team or go to A&E. Don’t wait.
Medicines review: With your prescriber, go through
When exactly did symptoms start relative to starting or increasing the dose?
Are there other drugs on board that can worsen mood (e.g. some beta-blockers, steroids, hormonal changes, alcohol, recreational drugs)?
Options to consider:
Holding at the current dose and not escalating further
Reducing the dose or lengthening the interval between injections
In some cases, trial of a switch to a different GLP-1, or coming off the drug entirely, with a proper lifestyle plan in place
Basic Physical & Nutritional Work-Up
Ask whether it’s appropriate to check:
- Full blood count, ferritin/iron studies
- B12 and folate
- Vitamin D
- Thyroid function
…plus a reality-check on how much and what you’re actually eating and your rate of weight loss.
Often we find people are unintentionally on what is effectively a semi-starvation diet with inadequate protein.
Support The Brain While We Sort Things Out
Regardless of the cause, the following have decent evidence for helping mood:
Protein & nutrient-dense food: aim for around 2g protein per kg ideal body weight per day from real food (meat, fish, eggs, dairy, etc.), plus colourful veg and appropriate supplements if deficiencies are found.
Movement: even 10–20 minutes of brisk walking most days has a measurable antidepressant effect.
Daylight & sleep: morning light exposure and consistent sleep times support circadian rhythm and mood.
Connection: schedule regular contact with people who are safe and supportive, even if you “don’t feel like it”.
A Balanced Closing Thought
GLP-1s and tirzepatide are powerful tools. For many people, they improve not only weight and blood sugars but also energy, self-esteem and mood. There’s even early evidence they might help some patients with depression linked to metabolic dysfunction.
But powerful tools always come with trade-offs. A small minority seem to experience significant emotional blunting or depression, and we now have enough case reports and safety-signals that these experiences should be believed, monitored and acted on, not dismissed.
If you recognise yourself in this description:
- Please talk to your prescriber.
- Please don’t suffer in silence because “the scales are moving”.
And most of all please remember: your mental health is every bit as important as your weight and blood sugar.
Clinical References
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Fothergill E, et al. (2016). Persistent metabolic adaptation 6 years after “The Biggest Loser” competition. Obesity.
About Graham Phillips
Graham Phillips is a registered pharmacist (FRPharmS) with over 35 years of experience. Frustrated by “pill for every ill” medicine, he founded ProLongevity to help people reverse chronic disease and lose weight through precision lifestyle medicine.
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