FDA is reviewing reports of suicidal ideation possibly associated with GLP-1 RAs

Following additional worrisome reports of these drugs and their possible side effects.

Following behind European regulators it appears the FDA is looking into reports of several adverse events related to individuals taking GLP-1 RA medications, with the most notable adverse event being suicidal ideation.

This comes from a quarterly report from the months of July-September 2023 based upon reports to the FDA’s adverse event reporting system (FAERS):

Included in the quarterly report are case reports of alopecia and aspiration related to GLP-1s as well, and adds to a growing list of concerning adverse events associated with these medications.

This report also comes months after European regulators have reported that they were investigating possible suicidal ideations as well based on some of their own data:

So far the range of FAERS reports associated with these medications appears to range around the low hundreds, with some articles suggesting that Semaglutide reports of suicidal ideation near 200 case reports alone. When checking the FAERS dashboard for “Semaglutide” and narrowing down the Reactions to “Suicidal Ideation”, there appears to be 159 serious cases and 2 deaths associated with Semaglutide specifically.

It’s important to remember that FAERS reports can’t tell of any causative relationship between these drugs and the reports of suicidal ideation, but it’s interesting that these reports have begun to raise serious concerns, and adds to the growing list of other adverse events. And although these reports may be minimal so far, as more people begin to take these medications we may begin to see even more adverse events being reported of all different types and numbers.

This also follows as Eli Lilly, the makers of GLP-1 RAs Tirzepatide (Brand name Mounjaro and Zepbound) have come out stating that they will now help their Tirzepatide users with direct access to telehealth services, which can provide these medications directly to patients’ homes, becoming one of the first pharmaceutical companies to promote a direct-to-consumer approach in drug accessibility. This follows after companies such as Weight Watchers just released their own telehealth services.

From CNN

So as there appears to be a growing number of concerning adverse events it doesn’t appear that these drugs are seeing any reservation in their prescriptions, and instead it seems like the approach is to make these drugs more accessible while long-term effects continue to be unknown.

Bear in mind it’s quite possible that these reports are not related to GLP-1 RAs in particular, however why is it that precautions are not taken to warn people of possible side effects to look out for, or why they should show some degree of hesitation before immediately jumping into taking these drugs?

Rather, the narrative around these drugs have pushed a “safe and effective” ideation, and in fact are now considered the norm for weight-loss in many circles.

This doesn’t help that a retrospective study released just today¹ seems to suggest that there doesn’t appear to be elevated risk of suicidal ideation associated with Semaglutide when compared to other medications used for obesity or diabetes, although many outlets seem to hide the fact that this retrospective study was a comparative study to other medications. Instead, headlines like the ones below may make it appear that Semaglutide may actually reduce suicidal ideation when compared to the overall population, leading to a narrative that these drugs may help to treat depression:

From CNN

From the New York Times

More importantly, these articles obfuscate possible associations between incretin hormones such as GLP-1 and their relationship to other signaling systems. For instance, there appears to be some evidence that GLP-1 expression is inverse that of cannabinoid responses. In some individuals in which cannabis was administered there appeared to be reduced expression of insulin and GLP-1.² This also follows from the fact that many obesity medications in use and in development appear to target cannabinoid receptor type-1 (CB1) by acting as antagonists/blockers or inverse agonists.

One example from the Wang, et al. study notes the drug Rimonabant, which was pulled from trials after high reports of suicidal ideation. Rimonabant acts as a CB1 inverse agonist, although the drug was later found to be a nonselective binder to other receptors.

In contrast, the active ingredient in cannabis is THC which acts as a CB1 agonist and induces the feelings of hunger (aka “the munchies”) after administering cannabis. This points to further possibility of some cross-talk between these agents in dictating feelings of hunger and satiety. As of now some animal studies have come out pairing CB1 antagonists with GLP-1 agonists to see their effects on obesity, with evidence noting greater loss of weight with dual therapies as compared to monotherapies.³

All this suggests that there may be some intimate relationship between GLP-1 and neuropsychology that have yet to be elucidated. Thus, it may be early and rather ignorant to assume that these drugs may not have some relationship with depression and other mental health diseases. As I mentioned in my previous article “And now suicidal ideation?” GLP-1 appears to be related to release of neurotransmitters and therefore may provide some insights into the suicidal ideation that can be seen with some SSRIs.

And so maybe all of these concerns may be a nothingburger, but with how common these medications have become there needs to be some degree of caution taken rather than alleging that these drugs are purely safe. It requires that these reports be taken seriously and investigated in order to see if there is some relationship between these GLP-1 RAs and possible suicidal ideation.

More restraint and better information can help the public make informed decisions without being influenced by influencers and pharmaceutical representatives.

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1. Wang, W., Volkow, N.D., Berger, N.A. et al. Association of semaglutide with risk of suicidal ideation in a real-world cohort. Nat Med (2024). https://doi.org/10.1038/s41591-023-02672-2

2. Farokhnia, M., McDiarmid, G.R., Newmeyer, M.N. et al. Effects of oral, smoked, and vaporized cannabis on endocrine pathways related to appetite and metabolism: a randomized, double-blind, placebo-controlled, human laboratory study. Transl Psychiatry 10, 71 (2020). https://doi.org/10.1038/s41398-020-0756-3

3. Philippe Zizzari, Rongjun He, Sarah Falk, Luigi Bellocchio, Camille Allard, Samantha Clark, Thierry Lesté-Lasserre, Giovanni Marsicano, Christoffer Clemmensen, Diego Perez-Tilve, Brian Finan, Daniela Cota, Carmelo Quarta; CB1 and GLP-1 Receptors Cross Talk Provides New Therapies for Obesity. Diabetes 1 February 2021; 70 (2): 415–422.