Why some drugs are linked with increased suicidal ideation remains a major unsolved mystery. One 2009 study identified 800+ drugs spanning categories from analgesics to flu treatments to anti-cancer meds that were linked to more suicidal thoughts and suicide attempts. But the mechanism(s) by which a given drug might cause a user to contemplate suicide are almost completely unknown. This, and the equally unexplained rise in placebo responses in clinical trials, should prompt more investigations into how pharmacological molecules trigger biopsychosocial effects.
GABA = depression is a crude oversimplification. Consider benzodiazepins, which cause an increase in GABA signalling as they are allosteric modulators. They cause a significant relieve in someone who is depressed.
I've been watching a lot of "Ozempic experience" YT videos recently because a family member is considering it. It seems like by far the most common side effect is a few weeks of diarrhea. After that, some nausea. Overall, I get the impression that most people tolerate it well if they can accept the diarrhea, but a small portion aren't able to get past the side effects and discontinue.
The more interesting number is that the vast majority of people who discontinue, even after long term use, regain 100% or more of the weight they lost. Weight loss doctors talk about this drug as something like statins which you'll likely need to take for the rest of your life. I think that's the area that needs the most improvement.
Unfortunately "improving" a medication to have a permanent instead of temporary effect doesn't seem to be a thing. E.g. Aspirin temporarily helps against headache, but there is still no pill you can take that cures headache permanently.
My better half has been on Wegovy (same drug, but indicated for weight loss) for several months. No diarrhea, but definitely nausea that peaks on the injection day and then slowly recedes. Over time, the overall level has decreased.
The effect of the drug has been for her to not always be thinking about food, and the amount of food required to feel full is dramatically reduced. It also forces slower eating because passing the full point results in the same very uncomfortable "I ate too much" feeling that used to require much more food before.
The NY Times Daily podcast had a pretty good episode a few weeks ago about the experience of two women who took the drug. One had a good experience and the other did not - it was interesting that she ended up malnourished while still obese. As far as regaining weight, I would think that absent required lifestyle changes, you would expect that people would regain weight once the drug is discontinued.
"Lifestyle changes" (eating less calories) alone would be sufficient to lose weight, but people presumably take semaglutide because they are always too hungry and can't realistically make those changes. It doesn't seem like the drug makes behavioral changes and easier when it isn't used anymore.
> majority of people who discontinue, even after long term use, regain 100% or more of the weight
Is it known whether this is primarily psychological or physiological?
Or in other words, is the weight gain simply caused by people returning to their poor diets/routines or is increased hunger (or something) a withdrawal symptom of the drug?
> It seems like by far the most common side effect is a few weeks of diarrhea. After that, some nausea.
I took it for a month or so, and those symptoms only happened when you ate heavy/fatty food. With salads and other light food, I didn't get any symptoms.
Anecdotal: I have been on Liraglutide and Semaglutide and it has helped considerably with weight loss, but does have side effects that aren’t great but has not yet hit me with suicidal thoughts.
If you eat any heavy food, you get diarrhea/vomiting. I once ate a curry while on semaglutide and I spent the whole night on the toilet, but the worst was the burps. The diarrhea cleared up by morning, but I had these disgusting, revolting burps from the food basically rotting in my stomach. They stank up the whole room and smelled like decomposition.
Semaglutide doesn't make it so you don't want to eat, it makes it so you regret doing it. I quit it shortly after, since I only have a few extra kilos I want to lose (so it wasn't worth it), and because I didn't want to lose the weight by being punished for eating. I figure that if I'm going to have a list of foods I absolutely must avoid, why do I need the semaglutide?
Anecdotal: I used Saxenda (Liraglutide), for about 4 months, and whilst I did lose about 20lbs the side effects I had were awful - really bad bloating, almost gastroparesis, erectile dysfunction (which I'm sure was due to trying to push more when on the toilet).
Even with fibre supplements I had to take stool softeners daily, bisacodyl fortnightly, and I just had an awful time on them.
I had passive suicidal ideation before I started taking it, I'm not sure if it got worse though although I did once move to the more active side.
Still - on a positive note - I did for once know what it was like to not feel hungry and to not think about food 24/7 as someone who has suffered from binge eating thanks to dopamine chasing adhd.
> erectile dysfunction (which I'm sure was due to trying to push more when on the toilet)
I know pushing on the toilet is the most common cause of hemorrhoids, but I hadn’t seen it linked to ED before. Is this based on research you’ve seen, or just a suspicion you have? If the latter, curious to hear how you’ve connected those two things.
Ive been fat my whole life and when I lost weight I struggle to maintain it. and when the pandemic hit, Ive blown up to be severely obese and its becoming harder and harder to lose weight now that Im reaching 30, I recently discovered and got prescribe and on my 1st week of ozempic and I really hope this helps me loss and maintain the weight.
Ozempic looks quite impressive and I hope that it can help you, but as someone over 30 I have to say that the mindset that age is such a disability is very self-defeating, and you can trust me from experience on that one.
I've recently been getting back to the gym and getting my diet cleaned up (for mental health reasons above any other), and as a result I've lost about 30 pounds in 3 months and gained some muscle along the way - far better than I thought was possible at my age.
I also saw a post on Reddit of scans of the legs of 2 70-year-olds; one active and the other sedentary. The active one was almost all muscle while the sedentary one was riddled with fat.
There's no secret; it's diet and exercise, but obviously it isn't easy either. If ozempic can help with the one, then that's a big bonus.
I'm 48, and back in the gym after several years of first too much else to do, then laziness, then injury and the pandemic, and I'm now finally back up to a 4 year personal best. It's tougher than it used to be, but at the same time most people have never been anywhere near what they could achieve and have no idea how strong they could get if they were just consistent and trying.
I keep seeing people go in and lift the same weights every time while at an age they could easily increase the weight several times a week for months on end before starting to hit limits.
Having a great diet and exercise are easy when you’re not in the rat race. Super rats are able to do both but that requires fortitude, which a majority of the population lacks (lotta soft people these days).
My wife has recently lost quite a bit of weight; she's at probably her lowest adult weight in her life now in her 40's. Many people who see her ask what her routine is and how much she exercises.
As it turns out, the simple rule of "calories in, calories out" is true and possibly the easiest heuristic to follow to lose weight. She has hardly increased her metabolic activity (calories out), but primarily shifted her diet (calories in).
The mentality around weight management would do well to focus more on sustainable diet changes rather than on exercise (not that the latter isn't important, but that diet management seems to me more attainable and effective).
I lost 15kgs in the pandemic as I was turning 50 and decided I didn't want to be fat and 50.
The only way I did it was to log all my food and keep to a calorie limit every day. I get people that ask me how I did it all the time and I tell them I ate less food and they all look disappointed like I was going to tell them some magic trick. I've managed to keep the weight off by really only eating one meal per day, in the evening.
Exercise is good and important in itself but it won't help you lose weight, outside of extreme levels of activity.
I exercise quite a bit, and have struggled with my weight when I exercise. It's kind of a paradox: I could lose weight or exercise, but not both.
Recently I accepted a $500 challenge to get down to a certain weight by a certain date, so I started taking the calorie in- calorie out bit seriously. I won the challenge of losing 30+ pounds and in so doing became very suspicious of the low-carb mentality I had adopted 25 years ago or so when the problem really surfaced.
To get through cardio I need carbs, and suspect that I would increase my overall calorie intake to get them as I was keeping my carb percentage low. Stop the exercise and I could take the weight off.
So I'm definitely back to the opinion that calorie balance is the real key (short of some metabolic disease). I'm 61 years old.
I'm 40 and it's been more or less the same. I weigh more now, but when I was skinny it was because I'd eat a salad a day, and now I eat considerably more.
When I switch to salads and cut sugar, I still lose weight quite quickly.
Perhaps being aware that it can make you suicidal (according to this article at least) will be some help. You know the suicidal thoughts are coming, so you can brace yourself for them and let others know it is a known side effect.
Not an argument against what you said, just an interesting anecdote.
I had a pool-related concussion a few years ago, and had to go back to the doctor because of persistent suicidal thoughts. The doctor told me, using more words than this, “This is normal, and statistically you are not likely to do anything about it. You should talk to your friends and wait for it to go away.” I was extremely frustrated that she hadn’t warned me about this at the first visit, in the way she had gone over other symptoms like light sensitivity and sleeping a lot.
She was right, though; the thoughts did stop after a few weeks. When I looked into it afterwards, what I found was typically doctors are advised not to tell patients that suicidal thoughts are a potential side effect, because knowing that made them more likely to happen.
Being severely obese can make you feel suicidal. Many users of these drugs will likely be familiar with those thoughts before they start.
And a measurable drop in weight may be give them more hope than any antidepressants could do.
(Antidepressants can be like taking painkillers for toothache if there's an obvious physical cause of the depression. They may offer some relief, but the real problem remains, and may be getting worse, e.g. if the antidepressants lead to further weight gain)
I wonder which way the arrow of causality flows, though? Everyone knows that severe obesity is a unhealthy and effectively already a slow form of suicide. A lot of the people you see on the extreme obesity programs have a childhood trauma.
Depression -> comfort eating/alcohol -> weight gain -> depression.
Doesn't matter what initiates the cycle, but once you're in it, it's very hard to get out. You're not likely to manage to 'just exercise more'/'just eat less' once the depression sets in.
It's easy to not be too bothered to begin with, when you're just 'a bit fat' and 'mildly depressed', but the problems can slowly build up year upon year until you're morbidly obese and having regular thoughts of suicide.
Sedendary screen-based jobs don't help, neither does work-related stress. And the Covid period (lockdowns/WFH/isolation) put the cycle into overdrive for some.
These new drugs are a possible escape from that cycle, significantly reducing the willpower required to eat less.
I heard someone say that our current food "environment" (highly tasty calorific food with adverse nutritional value; "unhealthy" food being cheap; etc) is a bit like when you are in a casino. Every aspect of it is designed to make you spend (or eat) more.
My wife is overweight, and I (as someone who works as a researcher into an unrelated area of diabetes) had a look at what it does and whether it might be helpful for her.
Semaglutide appears to have two main methods by which is works. Firstly, it increases the production of insulin, and secondly it makes you eat less.
Drugs that increase the production of insulin are typically prescribed for type 2 diabetes (which is a disease strongly linked with excess weight). However, in a lot of ways they are the exact opposite to what you want. With excess weight and type 2 diabetes, the immediate problem that the doctors are trying to treat is that you have too much sugar in your blood. Increasing insulin helps temporarily because it causes various cells around the body to pull sugar out of the bloodstream and store it in an alternative form. This includes fat cells. However, in the case of excess weight or type 2 diabetes, these cells are already full, and the body is effectively having to use higher and higher amounts of insulin to cram all that circulating sugar away. Adding more insulin causes further increases in weight and makes the problem worse in the long term. The problem isn't too little insulin - the problem is too much blood sugar, exacerbated by the fact that all the very full cells are reluctant to soak it up.
For this reason, not eating is extremely effective at fixing excess weight and type 2 diabetes. Since the problem is too much blood sugar, reducing the amount of sugar that we shove into the blood from our food is the right way to treat it. However, diets are difficult. The keto diet is great, but it's hard to stick to effectively, unless you absolutely love it and make a habit of it. The urge to eat a little bit more than you should or the wrong thing is extremely difficult to shake, and it's hard to get the right portion sizes in some societal setups. It can actually be easier to do fasting. That way you have set yourself a very simple rule to stick to, and it's completely obvious what breaks the rule. Don't worry, you won't starve if you have more than a small amount of body fat. Humans can survive for an extraordinarily long amount of time without food. The current record is 392 days[0]. The other great thing is after a couple of days you don't really feel hungry any more, and all sorts of other health benefits cut in. Willpower becomes much less of a problem than with restrictive dieting. There isn't any harm with not eating for a couple of days in a row every few weeks. I'd definitely consult with a doctor if you plan to fast for longer, but make it clear to the doctor that you're doing this and you want support to do it safely, not that you are open to being persuaded out of it.
Fasting is a scary thing to many people, including doctors, so you'll often get them tell you you're crazy or advise against it, but there's no reason for that. People have been fasting for all sorts of reasons, including religious, for millennia, without any serious problems.
Not eating is the single most effective treatment for type 2 diabetes. There are multiple people who have been diagnosed with type 2, and then after just a few days of fasting no longer have it. My conclusion having looked at Semaglutide was that it might help treat type 2 diabetes, but it'd only do that really by making you eat less because you feel like crap, and it has all sorts of other bad effects as well, so it'd be better to eat less while not feeling like crap instead.
So, my wife has had a few rounds of fasting about a week or two at a time. That anecdote shows about an average of a pound weight loss per day with no exercise, and the weight has stayed off. I have heard other people say that the weight tends to stay off after fasting when it wouldn't after just dieting.
My completely uninformed and generally useless guess is that obese people with depression may have been pinning their hopes on massive weight loss as a silver bullet that would solve all their problems. And when a drug comes out that actually does deliver the weight loss they’ve always dreamt of, they find that the depression still remains, creating a new sense of hopelessness that leads to suicidal thoughts.
This would be an interesting hypothesis to test—especially in cases where obesity may have been an outcome of people self medicating with food. Fits my own experience too (keto is basically the only intervention that worked for me, and only after I've been able to peel myself away from carbs for a few weeks)
I've been doing a good job avoiding GLPs just because I want it as a last resort option. But still, it wouldn't at all surprise me if this turns out to be one of a few explanations for the link.
For what it's worth, that just means 3 more people disagreed than agreed. But what you described at least lines up with my experience, which is worth a smidge at least.
More and more, I appear to be an ideal candidate for GLP1 agonists. I saw absolutely incredible results for the 3 months I was on dulaglutide before I stopped being able to get any. At the same time, I already have a long history of suicidal thoughts and I'm on track to get a thyroid ablation for toxic multinodular goiter (another major risk of these drugs seems to be thyroid cancer shenanigans).
> The U.S. Food and Drug Administration has received 265 reports of suicidal thoughts or behavior in patients taking these or similar medicines since 2010, Reuters found in an examination of the agency's adverse-event database.
Seems statistically insignificant to me, and more of a story because Ozempic is so famous.
Well that is far on a limb. I just googled Ozempic sales, seeing they did 50,000,000,000 DKK sales in Q1 '23 for Novo Nordisk, the manufacturer. Also 'blockbuster' and Ozempic are often used in one phrase. It all suggests a lot of pills are being sold. IMO it is almost certain statistically insignificant.
A far simpler explanation is that people who don't eat enough and have low blood sugar can end up feeling depressed, and Ozempic makes it easy to accidentally not eat enough
This is a weird comment. We focus on suicidal thoughts because suicidal thoughts are scary to people in a way that vomiting or a rash or blurred vision is not, because the former makes people consider a potentially life ending outcome, while the latter do not. Whether or not you agree with the relative ranking of these concerns, it ought to be easy to understand why.
And the rate of suicidal ideation per reported adverse event is irrelevant as something to compare unless you've also confirmed that the rate of adverse event reports is comparable between the two drugs. Have you? If so, why are you citing the rate per adverse event case rather than the rate relative to number of users, or doses?
Even so, even if they are in fact comparable, we're focusing on these drugs because they're fairly new and have seen an explosive increase in use, just like we've focused on other drugs when they've seen the same explosive increase in use. That people are extra interested in any potentially serious effects of a fairly new drug should not be surprising at all. Why does it surprise you?
Don't worry, I could have made it a much weirder comment. You know what else was reported in similar numbers as suicidal ideation, for Ozempic? Death. I'm pretty sure that's a whole lot scarier than thinking about death! That's a definitely life ending outcome! Incidentally, in a way really emblematic of how useful adverse event reports are, Wegovy has a single case of a gunshot wound, and I don't think the new exciting drug caused that.
Yes, I do play tricks with the aspirin comparison, but only to show just how wacky the original article is. If you think my two numbers are hard to compare, presumably you also agree that using a random case count with literally no context is effectively meaningless.
Furthermore, I think journalists doing statistics must be destroyed.
You do see a lot of really poor understanding of statistics out there, but on reflection, I want to say the latter is much worse. If journalists with an agenda were actually good at manipulating data, it would be much harder to put trust in anything.
I totally understand that, statistics really is a double edged sword. I think a good journalist can do a lot of wonderful things with data. If we end up living in a world where journalists are banned from using data at all, that would be very disappointing.
I’m pretty sure the nausea side effects of Ozempic/Wegovy is very widely reported and is included in nearly every article that talks about those drugs.
I think it should be pretty obvious why one would talk about suicidal ideation as opposed to nausea, blurry vision, etc.
And this might be one of the first articles I’ve come across talking about the suicidal ideation. The vast majority tend to focus on the other side effects.
My point was that the data doesn't seem point at suicidal ideation in any particular way. Adverse event reports contain literally every outcome in connection with every drug, you need a strong trend to claim that you aren't just seeing report noise. (But you're right that a newly discovered side-effect would be more interesting than a well known one.)
That’s not how much research works. You never have data at the outset. You have to have anecdotal information and/or sometimes even just an unfounded hypothesis before you can collect useful data to prove/disprove the hypothesis.
This would fall into the anecdotal side of things, and should hopefully drive more rigorous research on whether any such concerns exist.
In reality, even if the research is proven, the only likely change is screening out a few people who are at an elevated risk of suicidal ideation and/or better monitoring, or even prescribing regular therapy along with the medication (which might be a good idea anyways).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2749439/