GLP-1 drugs and anhedonia: what the evidence actually shows

What did @kelly_keelan actually say?

Kelly's core argument is that semaglutide causes more anhedonia than tirzepatide or retatrutide because it's a "straight GLP" agonist, and that the added GIP (and glucagon, in retatrutide's case) dilutes the GLP-1 component's effect on the brain's reward centers. Her conclusion: if you're struggling with anhedonia on semaglutide, switching to a dual or triple agonist might help.

That's a more nuanced claim than most GLP-1 TikTok content, and it's worth taking seriously. But nuance doesn't equal accuracy, and there are real problems with how she frames the mechanism and the evidence behind it.

Does the science back this up?

Partially, but the evidentiary foundation is thinner than she implies. GLP-1 receptors are expressed in dopaminergic brain regions, including the ventral tegmental area and nucleus accumbens. Animal studies have documented reduced reward-seeking behavior with GLP-1 receptor agonism. That part is real.

What's missing is direct human clinical evidence that semaglutide causes clinically meaningful anhedonia at higher rates than tirzepatide. The SURMOUNT and STEP trials weren't designed to measure anhedonia or hedonic tone. A 2023 analysis by Rubino et al. in Diabetes, Obesity and Metabolism flagged mood-related adverse events across GLP-1 therapies, but the FDA's own pharmacovigilance review (2024) found no confirmed causal link between semaglutide and depression or anhedonia. Kelly is drawing a mechanistic inference that sounds logical but isn't yet supported by head-to-head clinical data.

What did they get wrong (or right)?

Kelly gets the basic receptor pharmacology directionally right. Tirzepatide is a dual GIP/GLP-1 agonist and retatrutide adds glucagon agonism on top of that. The idea that GLP-1 receptor activity modulates reward processing is supported by preclinical neuroscience.

But her "ratio" framing is where things go sideways. She argues there's "less of a ratio of the actual GLP" in tirzepatide or retatrutide, implying the GLP-1 signal is weaker and therefore less likely to blunt reward. That's not how receptor pharmacology works cleanly. Tirzepatide's GLP-1 receptor affinity is lower than semaglutide's on a molar basis, but GIP receptors are also expressed in the brain, and GIP agonism has its own CNS effects that aren't well characterized in humans yet. Framing this as simply "less GLP equals less anhedonia" oversimplifies a system we genuinely don't fully understand.

Her drug names are also mangled throughout: "Simicluetide," "trizepitide," and "rhodotrutide" are clearly semaglutide, tirzepatide, and retatrutide. That's a credibility issue when you're giving clinical guidance to 280,000 viewers.

What should you actually know?

Anhedonia and blunted reward responses are real, documented patient experiences on GLP-1 medications. This isn't just a fringe complaint. A 2023 paper by De Silva et al. in eClinicalMedicine documented reduced food reward and hedonic eating, which some patients experience as welcome, and others find distressing.

What we don't have yet is a clean clinical trial showing that switching from semaglutide to tirzepatide resolves anhedonia. Kelly's recommendation, "you may want to consider switching," is based on plausible mechanism, not proven outcome data. That distinction matters enormously when someone is already dealing with mood symptoms.

If you're experiencing anhedonia or depressive symptoms on any GLP-1 medication, that's a conversation for a licensed prescriber, not a TikTok comment section. Mood changes on these medications should be documented and evaluated, not self-managed by switching drugs based on a mechanistic hypothesis shared on social media.

• GLP-1 receptor activity in dopamine pathways is real neuroscience, but human anhedonia data remain limited.
• No head-to-head trials compare anhedonia rates between semaglutide and tirzepatide.
• GIP receptors also exist in the brain; their role in mood is understudied, not simply neutral.
• Retatrutide is still in clinical trials and is not currently FDA-approved for any indication.