[Epistemic Status:  I feel pretty good about most of this, but the life-years-saved-via-medication part is problematic on a number of levels, as pointed out by a few commenters.  I include it since back-of-the-envelope calculations serve a purpose in ensuring we're comparing effects of approximately the appropriate magnitudes in doing risk/benefit analyses, but I wouldn't take it too seriously.]

Note that I’m not a doctor. Please speak to a doctor before doing any of this stuff Or You Will Die.

Introduction

Judging by posts in r/loseit, the existence of effective anti-obesity medications is not particularly well-known (and to the degree it is well-known, it's disapproved of.)  Even posts on LessWrong, which tend to be very well-researched and exhaustive, simply ignore the topic of medication when weight loss methods or obesity are brought up; I suspect this is not because their authors had explicitly considered and discarded the various anti-obesity drugs currently available, but rather, because the existence of these drugs is very poorly-known.  Which I’m attempting to remedy here!  At least for the LessWrong crowd.

Quantifying Life-Years Saved by Losing A Certain Amount Of Weight

[Note: as pointed out by comments below, extrapolation to life-years saved is very speculative, since all the studies on this in humans are going to be confounded all to hell by healthy user bias and socioeconomic correlations and the like.  That said, it feels like a fairly reasonable extrapolation given the comorbidity of obesity to various extremely problematic medical conditions.  Be warned!]

According to Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity | Nature Communications , losing a single unit of BMI roughly corresponds to a 7-month gain in life expectancy in the overweight and obese. This seems basically in line with what I hear from popular sources, such as: “[L]ife expectancy for obese men and women was 4.2 and 3.5 years shorter” than people in the healthy BMI range.

This won’t count as a revelation. Obesity is unhealthy, news at eleven. My goal here is just to quantify what you’re getting relative to the risks involved in doing something to ameliorate it.  

Accordingly:

The U.S. Food and Drug Administration (FDA) recommends pharmacotherapy for weight loss when lifestyle interventions (diet, exercise and behavioural therapy) have failed and the body mass index (BMI) is °30kg/m2 with no concomitant obesity-related risk factors, or if the BMI is °27 kg/m2 and the patient has at least one obesity-related risk factor.

So: let’s talk about weight loss drugs!

Weight Loss Drug Studies

Weigh loss drug studies are always composed of two groups of patients: a group attempting guided diet and exercise along with a placebo pill, and a group doing the diet and exercise plus the drug. That’s important here, since it means we can’t unequivocally recommend drugs as a replacement for diet and exercise, only as a secondary treatment. (Aside: even though basically every article on weight loss is obligated by eternal law to pay tribute to exercise, the evidence for it helping with weight loss on a practical level is minimal.)

These studies are saying, in effect: if you can get X pounds lost from diet and exercise alone, adding pharmaceuticals to these efforts can get you X+Y pounds lost.

That being the case, I’m going to now list the three or so good (as judged by me, a random asshole with a laptop) FDA-approved anti-obesity drugs currently on the market right now; their measured diet-and-exercise-subtracted weight loss; and finally, the amount of life-years you can (maybe? who knows) gain over the long term by losing that much weight. I'll be linking to studies for each.

Note on drugs I'm not discussing here: I’m not going into liraglutide since it seems basically like worse semaglutide at similar cost, and I’m not going into phentermine+topiramate (Qsymia) because in spite of its greater efficacy than phentermine alone, it seems that topiramate has a substantial likelihood of giving people kidney stones and brain fog, which are… not great.  Orlistat is quite popular, but has relatively poor efficacy and unpleasant digestive side effects.  Links provided on request, but that’s a bit far afield of my purposes here, so I’ll move on.

The Drugs (at least, the better ones)

Semaglutide (2.4 mg)

  • Price: 1300ish dollars per month for Wegovy. I've heard insurance has a… spotty… record of covering this. You might have better luck with insurance (provided you have T2D, or at least are at risk for it) with Ozempic, which is the same semaglutide, just at a different dose and with labeling for T2D treatment.
  • MechanismGLP-1 inhibitor; more specifically, it slows gastric emptying resulting in lowered appetite.
  • Average Diet/Exercise-Subtracted weight loss: 12% based on its phase-3 trial. This is the most potent anti-obesity drug on the market.
  • Common Side Effects: Transient nausea and GI upset at treatment onset.
  • Other Notes: This is basically just higher-dose Ozempic, which has been on the market about four years.
  • Approximate BMI drop for a 5’6 female at 200 pounds: In weight, 12% weight loss equates to about 24 pounds. This is a drop in BMI of 32.28 to 28.4 units.
  • Approximate difference between expected life-years of people with these two BMI values: About 28 months, or about 2.3 years.

Contrave [Bupropion + Naltrexone]

  • Price: If you get it generic (and why wouldn’t you?) about 40 bucks a month as naltrexone + bupropion.
  • MechanismPoorly-understood neurochemical effects.
  • Average Diet/Exercise-Subtracted weight loss: 3-7% (varies by study)
  • Common Side Effects: Amped up sex drive and improved focus (Bupropion is sometimes used off-label for ADHD); on the other hand, anxiety and insomnia, plus transient nausea at treatment onset. [My own bias: I’m on bupropion and it’s mostly kickass. Insomnia’s no fun, though.]
  • Other Notes: Both parts of this drug have been in common use for several decades. If there was some godawful long-term side effect we’d know about it by now.
  • Approximate BMI drop for a 5’6 female at 200 pounds: For lower estimates, this is a drop in BMI of 32.28 to 31.31 units (so about 1 unit of BMI); for higher (7%) estimates, this is about 2 units of BMI.
  • Approximate difference between expected life-years of people with these two BMI values: About 7-14 months of life.

Phentermine

  • Price: 23 dollars/month
  • MechanismStimulant.  Most stimulants have weight loss as a side effect; this is just one of the few the FDA has actually approved for the purpose.
  • Average Diet/Exercise-Subtracted weight loss: 3-7% (varies by study)
  • Common Side Effects: This is a mild stimulant, so... pretty much what you’d expect.
  • Other Notes: Technically any use of this longer than 6 months is off-label (the FDA hates stimulants), but several long-term studies of phentermine use find no evidence of addiction or other side-effects when taken for years. Anecdotally this is sometimes taken with Contrave, but this is an off-label combination of drugs on which there is little data.  On the other hand, there doesn’t seem to be any a priori reason to expect this combination to be harmful?
  • Approximate BMI drop for a 5’6 female at 200 pounds: For lower estimates, this is a drop in BMI of 32.28 to 31.31 units (so about 1 unit of BMI); for higher (7%) estimates, this is about 2 units of BMI.
  • Approximate difference between expected life-years of people with these two BMI values: About 7-14 months of life.

Conclusion

Overweight and obesity cause a lot of misery! I’ve lurked r/loseit! And the quest to stop being overweight is the cause of even more misery for lots of people. If you’re in that group, you might be well-served by discussing medication-assisted options with a doctor.

FAQs

Giving a life-years-saved number for if someone takes a drug implies they'll be on it forever. But what about the unquantified risks of being on some drug for the rest of your life? Especially semaglutide, which hasn’t been around very long?

This is a fair concern! It is, however, worth pointing out that the FDA is vigorous about pulling drugs that have been shown to have even small risks of causing life-threatening conditions; a recent example of this is lorcaserin (aka Belviq), which was taken off the market due to a non-statistically-significant increased risk of cancer.  See also: Is lorcaserin really associated with increased risk of cancer? A systematic review and meta-analysis - PubMed (nih.gov)

Think about the implications! If you’re on X drug for your whole life, then by assumption you’ll have also gone your whole life without the FDA having observed any statistical increases in cancer incidence or heart attacks or whatever for people on the drug. That’s a very high bar of safety.

Ultimately, the quantifiable life-years lost by obesity (in the form of statistical heart attacks and various other comorbidities) must be weighed against the mere uncertain prospect of an imperfect drug making it through the FDA approval process.

Besides which, nobody says once you’re done losing weight that you have to continue taking the appetite suppressants. I mean, I probably would? But diff’rent strokes.

If you’re concerned regardless-- semaglutide is the only particularly new treatment on that list (and even that's been around a few years in the form of Ozempic). The others have multi-decade histories of usage, with reams of literature on their effects. Google Scholar: your friend and mine.

Isn't just eating less a much healthier and better-proven means of weight loss than pills?

Nicotine addiction wears off with time. If a person can keep off cigarettes and other nicotine sources for about three months, most surveys show that this leads to a total cessation of a desire to smoke or otherwise consume nicotine.

That being the case, it’s obvious what addicted smokers have to do to cure their addiction: stop smoking cigarettes for three months. Withdrawal is unpleasant, but nevertheless this method is uncomplicated (step one: don't smoke, step two: nothing), extremely cheap as an intervention, and guaranteed to work if performed.

And that is why, even to this day, nobody is addicted to cigarettes.

...

I guess a less snarky answer is that these medications mostly work by making it more pleasant to eat less.

Isn't this just a way of letting lazy people off the hook?

Eh. If you’ve tried it and straightforward dieting makes you miserable, you are under no obligation to power through without assistance.  You don’t win virtue-points for avoiding medication that makes your life easier even if online randos imply otherwise.

If these meds are so great, shouldn’t I have heard about them by now?

Nope!

First: American society has a pretty weird relationship with weight loss; there’s a huge implication in the discourse that thin-ness is a result of righteous self-discipline, and that fat people just need to buckle down and make the effort, and if they fail then they just weren’t trying hard enough.  (This viewpoint is neatly encapsulated in the slogan “eat less move more” and concepts like "the physics diet")  Accordingly, weight loss drugs have acquired the implicit moral status of a cheat enabling one to get the reward without the suffering, which people are suspicious of.

Second, there are also some now-banned medications-- fen-phen and DNP are pretty good examples-- that are both (1) deadly and (2) highly effective at weight loss.  Thus, the popular perception that anti-obesity drugs are intrinsically dangerous,  to be used by people who value their appearance more than their health.  

This isn’t helped by all the truly worthless herbal supplements on the market claiming to be effective weight loss aids; unlike for most other medical conditions, herbal supplements are allowed to claim that they’ll help with obesity (mostly implicitly by calling themselves “fat burners” and the like).  Legitimate drugs can be difficult for uneducated audiences to distinguish from snake oil, so they get rounded off to "snake oil".

These factors have resulted in society collectively memory-holing this entire class of medication.

I had bad experiences on phentermine.

You and a bunch of other people!

Most people have some drugs they'll find unpleasant or that don't work for them.  It seems broadly reasonable to just try different drugs until you find ones that work for whatever condition you're trying to alleviate; the potential risk is one or two weeks of discomfort while the drugs slowly exit your system (after which you move on to something else), and the potential reward is life-years saved from obesity comorbidities, as well as whatever added happiness you get from being at a lighter weight.

[Insert Certification Body Here] doesn't think [Insert Drug Here] passes a cost/benefit analysis, even though the FDA does.

If you're able to read and evaluate the primary literature on this topic, I see no reason to outsource your cost/benefit analyses to some other decisionmaking body rather than evaluating the drugs on their merits based on clinical trial data.

Ultimately, the decisions of these institutions will be colored by a lot of factors that aren't "patient wellbeing"-- by blameworthiness, PR considerations, the perceived second-order effects of their actions, and the crucial distinction between dead-their-fault and dead-not-their-fault.  These tend to lean in the direction of "don't certify the medication," especially for anti-obesity drugs (which tend to be viewed as lifestyle drugs rather than drugs for legitimate illnesses, and so face a higher bar of scrutiny.)

Shouldn’t we just, as a society, just develop a healthier culture around food?  Wouldn’t that be better than medicating ourselves?

There are a lot of things I would change about society if I were made Benevolent Dictator For Life.

Aren’t you, personally, just a lazy trash-person?

Absolutely. But that's unrelated.

I found a factual error in this post.

Leave a comment telling me this (including a source for the info) and I'll correct it!

Are you a doctor? You're a doctor, right?  You’re probably a doctor, so I should take this as medical advice.

Jesus Christ no. If you take any medication here without talking to a doctor about it you’ll definitely swell up and die, or possibly turn inside-out.  Luckily, since I pointed this out in this paragraph I will be absolved of all responsibility.

Good luck!


 

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The fact that there's a correlation between BMI and lifespan that coresponds to one point of BMI being linked to 0.7 years of lifespan doesn't mean that if you intervene and take a drug to reduce your weight you will gain 0.7 years of lifespan per point of BMI that you lower your BMI.

There's unhealthy behavior like eating sugar that does lead to weight-gain but it also messes up the insulin management. 

It is, however, worth pointing out that the FDA is vigorous about pulling drugs that have been shown to have even small risks of causing life-threatening conditions

A drug can reduce your life span for by a few years if you take it over decades without "causing life-threatening conditions". 

Can you give any examples of that happening, where a drug reduces lifespan but not by causing any specific fatal effect?

There's very little money into chosing causation in cases like this but sleeping pills would be one example.

In general many drugs cause the liver to have to do extra work and put stress on it.

I suppose that's reasonable, though i will point out that this is a fully-general argument against taking any drugs long-term at all.

Yes, you should generally minimize the amount of drugs you take long-term. 

I suppose.  But it's also true that you should minimize the number of debilitating medical conditions you're suffering from long-term.

Which brings us back to the thing where we end up having to choose between a chronic condition which is heavily correlated with a whole bunch of secondary health problems and reduced life expectancy, and being on a drug from which we have not (yet) observed long-term ill effects.

The back-of-the-envelope life expectancy calculations were mostly just there to point out that under most plausible assumptions, the risk/benefit calculations seem lopsided to the point where it shouldn't be a terribly difficult decision.

This conversation has basically recapitulated most of the ideas that lead to the antagonist pleiotropy hypothesis, except over "conscious lifelong health interventions" instead of over "blind mutations retained by natural selection".

Short term wins often have long term costs. 

As clever hack piles on top of clever hacks, the combinatorial explosion of possible interactions goes up pretty fast. 

Once wins of this sort pile up, your functional planning horizon shortens. At some point you just say "X will almost certainly get me before the bad parts of Y gets me" and you do Y anyway? But eventually the house of cards topples over.

If your lifelong health meta-strategy is aimed at still being able to ski when you're 85, you probably want to minimize pills in general? Find tiny repeatable actions with numerous positive effects that fit into a weekly routine in a way that adapts to a variety of contexts and have many positive effects and stick the adherence? Green veggies? Walk a mile every day? And so on?

If you're overweight and 51 and smoke and are pre-diabetic and walking gives you back pain and you'd still prefer to die in ~12 years of a new thing rather than in ~4 years from the thing your doctor recently mentioned... sure... try some pills maybe? Or maybe bariatric surgery? Lots of stuff works locally in the short run, and the long term, in general, often can't be touched without running into a morass of interlinked complexity.

This is an interesting argument!  I certainly acknowledge that if you can become non-obese via purely dietary means, that is best.

I wonder whether your analogy holds in the circumstance where dietary means have been attempted and failed, as often happens judging by the truly staggering number of posts online on this very topic-- whether becoming non-obese via medication constitutes a short-term win outweighed by long-term detriments, and whether the effects of the pills turn out to be more harmful than the original obesity it was meant to treat.

But it's not totally clear to me that you have attempted to make an affirmative case for this being true, as opposed to suggesting it as a pure hypothetical.

the existence of effective anti-obesity medications is not particularly well-known

I had at least heard of the ECA stack (ephedrine, caffeine, and aspirin) before. It's available over-the-counter. The prescription meds were news to me though.

Is ECA effective? Yes. Bodybuilders are rumored to use it while cutting. Studies show you lose an extra two pounds per month. Is it safe? At reasonable dosage, yes, relatively. It's not going to kill you or cause psychosis, depression["serious psychiatric events"], or seizures [EDIT: see comments below], but side effects can be unpleasant, including nausea, vomiting, and anxiety, so the ephedrine is kinda restricted. You have to sign for it, and in some places the amount you can get per month is limited. I'm not desperate enough to try it yet, since fasting is keeping my weight under control so far.

the amount of life-years you can expect to gain over the long term by losing that much weight.

Do these drugs actually reduce all-cause mortality? Or are we just guessing based on a proxy measure? Is it the extra weight per se that causes the poor health or is the weight just an obvious side effect of some other underlying metabolic problem that the drugs are doing nothing to address? Inflammation? Insulin resistance? Micronutrients? Toxins? Gut flora imbalance? Fatty liver? Something else? Diet might fix these, while drugs might not.

There's a very thorough paper published in the American Journal of Epidemiology, "Use of a prescribed ephedrine/caffeine combination and the risk of serious cardiovascular events: a registry-based case-crossover study", DOI: 10.1093/aje/kwn191

Apparently, and this really surprised me,

"Use of prescribed ephedrine in Denmark — Letigen was a pharmaceutical product containing 20 mg of synthetic ephedrine and 200 mg of caffeine, available only by prescription. Its recommended dose was 1–3 tablets per day, depending on the user’s tolerance. It was approved for sale in Denmark in 1990. During the peak of its use in 1999, some 110,000 persons, corresponding to 2% of the Danish population, were treated. In 2002, the marketing license was suspended, after a number of reports had suggested a safety problem."

So there's a pretty big sample there. 

Now note, I'm not a doctor and this just my opinion — it seems that some people should never take ephedrine under any circumstances (certain heart problems or family history of certain heart problems, etc) and anyone else ought to be really quite careful taking it if it's legal and approved in one's jurisdiction.

Ephedrine increases metabolic activity and thermogenesis — heat production — and it's more dangerous when it's hot outside, when you're doing any aerobic activity, or if you've had any other stressors on one's heart or get into other contraindication with stressors.

Speculatively, it seems possible that safety rates in Denmark might be higher than elsewhere since it doesn't get very hot there. If you compared someone using ephedrine/caffeine in Siberia in the winter to Dubai in the summer, the increased thermogenesis and physically radiating more heat might seem like a beneficial side effect in an arctic blizzard whereas both uncomfortable and dangerous under a desert sun.

The safety information I had came from here.

RAND reviewed adverse events reported in 52 published randomized controlled clinical trials. No serious adverse events (death, myocardial infarction, cerebrovascular/stroke events, seizure, or serious psychiatric events) were reported in the clinical trials. However, evidence from the trials was sufficient to support the conclusion that the use of ephedrine, ephedrine plus caffeine, or ephedra plus caffeine is associated with 2-3 times the risk of nausea, vomiting, psychiatric symptoms such as anxiety and change in mood, autonomic hyperactivity, and palpitations. The contribution of caffeine to these symptoms cannot be determined.

There seems to be a disagreement in the literature about the facts. This one had randomized controlled trials. Maybe the sample size was too small though? In that case, are the "suggestions" of a safety problem enough to be a concern? How strong were these suggestions? Obesity also increases risk of death. Perhaps ECA still wins on net cost-benefit. Maybe the risks are very small. Death is a very serious side effect, to be taken very seriously, unfortunately, many over-the-counter medications we use routinely carry this risk. Degrees of risks matter. Maybe the ephedrine was correlated but wasn't the cause. We'd need the numbers, and maybe more statistical know-how than I've got.

Oh, I'm guessing based on purely correlational studies, with all the uncertainty and fuzziness that implies. Added a disclaimer to the relevant section to this effect, since it's worth calling out.  

That said, I'd be shocked if the whole effect was due to confounders, since there are so many negative conditions comorbid with obesity, along with the existence of some animal studies also pointing in the direction of improved lifespan with caloric restriction.

Unfortunately, we don't have the ability to run controlled studies over a human lifespan, so we end up needing to do correlational studies and control for what we can.  It seems like a bad idea to simply throw up our hands in complete epistemic helplessness and say that we don't know anything for sure; we need to act in the presence of incomplete information.

Also, re: the specific point of

Diet might fix these, while drugs might not.

Keep in mind that these drugs cause weight loss by way of causing dietary changes.

 It seems like a bad idea to simply throw up our hands in complete epistemic helplessness and say that we don't know anything for sure; we need to act in the presence of incomplete information.

Pretending you know something that you don't is not something you want to do in the presence of incomplete information.

In this case you would want to look for studies that actually look at the lifespan effects of successful weight loss. Estimating confidence intervals to be more explicit about one's uncertainty is also helpful.

I feel my disclaimer in the post:

>[Note: as pointed out by comments below, extrapolation to life-years saved is very speculative, since all the studies on this in humans are going to be confounded all to hell by healthy user bias and socioeconomic correlations and the like.  That said, it feels like a fairly reasonable extrapolation given the comorbidity of obesity to various extremely problematic medical conditions.  Be warned!]

should be sufficient to exempt me from charges of "pretending to know things."

The confidence intervals thing is probably a good idea, but I have no idea where to start on that, really, since the confidence intervals would be mostly driven by "how confident am I feeling about using correlational studies on health outcomes to make causal claims about the effects of a treatment" more than any objective factor. 

I'm not actually sure about whether a study looking at the effects of successful weight loss on mortality would be all that helpful for this conversation, since that would still end up being a totally correlational study with enormous error bars and confounders, and successful long-lasting weight loss isn't very common (itself which will introduce yet more confounders).   Also I don't think such a study exists.

Is that really how all of them work? In the case of ECA, I thought it was due to increased metabolism. But it might also have an effect on appetite.

And even when it is, is that good enough? It's possible for dietary changes to promote weight loss, but still be unhealthy. If you just eat junk food, and then the drugs reduce your appetite so you eat less food, but it's still junk food, then technically that's "dietary changes", but you're still not getting the micronutrients, fiber, prebiotics, and possibly bacteria that you would from fruits and vegetables. To the extent that the poor health is caused by excess Calories, it helps. But to the extent that poor health is caused by eating the wrong things, then simply eating less of them can only go so far.

Of course, I expect that using the prescription drugs as directed would be a last resort after dietary improvements prove insufficient, but doctors can only do so much to influence behavior.

Whoops, sorry, I don't actually know anything about ECA.  Possibly that's how it works, at least partially!  I'm pretty sure it's true that stimulants are appetite suppressants, but it's also possible it has another mechanism of action having to do with non-exercise activity thermogenesis or similar.

Anyway: the way I was thinking about this is, obesity is caused by excess calories.  That being the case, there's no particular reason to anticipate obese people wouldn't be getting appropriate amounts of fiber/micronutrients/etc; or at very least, I have not heard anyone make such a case.

So while it's definitely true that drugs wouldn't help with nutritional deficiencies, it's also not clear to me that this is necessarily relevant to the health impacts of obesity.

I haven’t fully understood why weight loss drugs are so little used in the US given the health effects of being overweight/obese either. I think it’s good that you’ve shined a light on this and your overview is helpful guidance to someone getting oriented. Many aspects of this feel aligned with my research on the topics.

That said, Plenity (https://www.myplenity.com/) is a non-drug option that looks particularly promising and should potentially be at the top of the list here.

I haven’t looked into the longevity effects of weight loss yet myself, but the treatment here seems pretty unsophisticated and strikes me as likely incorrect. The cited study appears to be correlational rather than causal (only read the abstract, could be wrong). Additionally I would expect that age at which you lose weight has an impact, for example, and last I read a BMI that was borderline healthy/overweight is actually what maximizes longevity. I think there’s significantly more work to be done before the longevity conclusions would seem well-substantiated to me.

That said, I think putting numbers on it is totally fine and a good thing to do as directional information, I’d just prefer their (seemingly high) uncertainty was highlighted.

The mechanism for Plenity, a dry cellulose matrix that expands with water, seems extremely promising, but the experimental results don't seem that good even when selected by the manufacturer.  The one study has weight loss of 6.4% of body weight with Plenity vs. 4.4% with placebo, over six months.  Given the publication biases, that's nothing. 

That said, I think the metrics used for most weight loss studies, including this one, are wrong. The control and treatment groups were on equally calorie-restricted diets, and my belief on hearing the mechanism was never that Plenity would accelerate calorie deficits (although it might smooth out sugar spikes), it's that it would make calorie restriction more bearable, which the study doesn't seem to have checked for (which is normal for weight loss studies).

A second argument I'd consider is that weight loss is held back by different things for different people, and Plenity is extremely good for a handful of people for which satiety is their main problem. I don't see anything in the paper that would suggest that, but it does seem possible. 

Also, good point about highlighting the uncertainty; I've added a disclaimer to that effect at the beginning of the section.

All fair points!  That said, I think extended lifespan is a very reasonable thing to expect, since IIRC from longevity research that caloric restriction extends lifespan (from animal studies); this seems like a very natural extrapolation from that.

I think metformin was supposed to have effects similar to caloric restriction, and does appear to reduce all-cause mortality, even though most users are diabetic.

have there been any updates on the wellbutrin (edit: meant metformin) front? My understanding is that berberine has a similar mechanism of action and is OTC.

Oh, Wellbutrin (bupropion) is totally a thing you can use for weight loss, and is even found in Contrave (one of the drugs I listed) for that reason.  Lesser effect, though, since its weight loss effects are additive with naltrexone.

Berberine is one I hadn't heard of before; unfortunately I can't find any articles discussing its use in weight loss.

whoops, meant metformin. Always confuse those two.

Not a drug I've looked into!  I ended up confining my research into FDA-approved weight loss medication, so I probably missed a number of non-FDA-approved medication that also works for weight loss.

Is topiramate taken on its own expected have any noteworthy diet/appetite/weight-loss effects? I know someone who's on it to try and control their migraines.

Yup!  It's branded as "Topamax", but I've heard that some users refer to it as "Stupamax" because of the brain fog effect.  It doesn't sound awesome.

Also, it sounded like it increases probability of getting a kidney stone by a lot, though I'd need to track down the reference.  All told, feels like one of the worse options out there.

As far as I understand it, "combination" drugs don't really do anything together that each component doesn't do alone.  For example, bupropion causes weight loss if you take it alone; it just causes more when you pair it with naltrexone, which also causes weight loss.

God to know, thanks. 

I could have imagined a case where the weight-loss effects were coming solely from the phentermine, with topiramate added to the combination for other reasons. But it having its own independent/added effect makes sense. For the person I know taking it, her appetite does seem quite reduced since switching from amitriptyline (I think that one increases appetite, so there will have been a double-effect from switching off that and onto something that suppresses it)

The brain fog is unfortunate, but also still less bad overall than the migraines were.