When working with biological systems, most of the time your acceptable error margin is between 10-25%. There are a few compounds (like fentanyl or LSD) where the dosages are so small and the compound so potent that 10-25% makes a difference but for the majority, precision isn't that critical. The ones where it does matter are tightly controlled and clinically applied by a professional with active monitoring.
The only drugs that weren't within 10% of their original concentrations, according to the study, were amphetamines and aspirin. I can't think of any uses off the top of my head for those two where even 25% would make much of a difference to outcomes - amphetamines are mostly used as general purpose stimulants or to treat ADD and aspirin is not the blood thinner of choice for life and death situations. With amphetamines especially, what you eat and small factors like blood pH can have a massive impact on their effectiveness so we're already talking 10-20% differences day by day, let alone person to person.
Those 122 compounds were also over-representing publicly available products, as opposed to medically regulated compounds. You would need more rigor for a study where the compound efficacy actually mattered to make a general finding, across all classes of drugs. 25% difference in a beta blocker, glycerine, or blood thinner is a fatal change. These drugs are monitored with physical symptoms (metroprolol) and/or regular blood testing (sodium warafin/heparin/lovenox).
And to add into that, dosage studies are rarely adequately done for most drugs. The dose we take is often a best guess and may be twice or more than we need, so 10% is even more inconsequential.
Dosage studies happens between Phase 2 and Phase 3 trials (and Phase 4 "post marketing" too) and are the most expensive, longest and most scientific process that arguably any business engages in in the entire world.
Phase 1 is a safety test in healthy ~men. These seek to find the maximum dose before adverse effects appear in the healthiest humans.
Phase 2 is a safety/dosage test in a much larger and varied sample. We know dose ranges and begin testing them for efficacy in a varied population.
Phase 3 is the big one. It's a randomized, controlled, double blind test of SPECIFIC dosages in SPECIFIC target populations to scientifically prove efficacy over placebo.
The dose we take is not a "BEST GUESS"
It is the result of a billion dollars of scientific study and that PRECISE NME (new molecular entity) has been studied, at that PRECISE dose, in a target population, for it's effectiveness, and it must be better than existing-treatments and better than placebo.
It should be highlighted that this process takes on average 10 years, costs $1 billion dollars, and has a success rate (success meaning FDA approval) of about 1 in 10,000 attempts (hence the price tag).
The $1 billion dollar cost per drug is risk adjusted, so it includes all failed attempts at clinical trials and compounds that didn't make it through pre-trial screening.
Edit: The $1 billion number is meaningless outside the context of large pharmaceutical companies. The cost for phase 3 trials is in the tens or hundreds of millions of dollars so the floor is a wide range and there have been instances of companies getting incredibly lucky and developing a drug for much less than a full billion.
Sounds like you don't know what you are talking about. Your source is a book written with heavy influence by the Pharmaceutical industry to justify the obscene costs of their drugs, making billions in profits off of sick, poor people.
You are the one who is completely wrong.
The dosages most certainly do start out with a "best guess" in the pre-clinical phase. For any given drug we would guess at the doses based on our calculations, and give a range on either end. If we thought the effective dose would be 1 mg/kg, we would run an LD50 of doses much higher than that, 10mg/kg, 100mg/kg. Sometimes our guesses would be wrong, and the low dose animals would die as a result. After figuring out a safe dose, we would then split it further into different dosing groups to test the effectiveness of the compound. Most people in the field are underpaid, overworked, and do sloppy work
Please talk to someone who has actually worked in the Pharma research field, they will tell you most of what they do is just guessing.. why do you think only 1 in 10,000 make it through?
It's all a guess until the end, and even then we're often not sure. Look at anti-depressants. We still don't know how a lot of those work but prescribe them to millions of people regardless. How do you think they determined the dose when they don't know how the drug works?
You and the GP talking about entirely different things. You're talking about how investigators choose the initial dose for the clinical trials, he's talking about the dosage that is actually prescribed by doctors.
Hence the 'The dose we take is not a "BEST GUESS"' (emphasis mine). Unless you're a lab animal or a person in a clinical trial, the does you take is the end result of lots of money spent on first figuring out maximum safe dosages (Phase 1) to prescribing guidelines that doctors are taught (Phase 3).
Antidepressants are a unique group of drugs because the dosage is highly dependent on each person's unique brain chemistry and a huge part of a good psychiatrist's job is working with their patients to find the right dosage and combination. The problem is that many psychiatrists don't have the time (due to insurance billing practices) or the patience to do the work but any decent psychiatrist will tell you that recommended doses for antidepressants are just a safe starting point for most patients, not the dosage that they will eventually find most effective.
For the record, I have worked in the pharmaceutical industry on pre-clinical drug development and Phase 1-3 marketing applications and the GP's description is largely accurate whereas you seem to have a chip on your shoulder. I wouldn't trust a single book about the drug development process that wasn't heavily influenced by the pharmaceutical industry in one way or another just like I wouldn't trust anyone without semiconductor industry experience when talking about Intel's cutting edge fabrication processes.
> Antidepressants are a unique group of drugs because the dosage is highly dependent on each person's unique brain chemistry and a huge part of a good psychiatrist's job is working with their patients to find the right dosage and combination.
How does one accomplish this absent trial and error?
This fact undermines the entirety of your argument.
You do know what "unique" means in this context, right? Hint: it means that antidepressants are the exception to my argument because psychopharmacology is so much more dependent on genetic/environmental factors than the rest of the pharmacological field that we cannot draw conclusions on the effectiveness of dosages pre-treatment without spending 100-1000x more time and money on the clinical trials than we do now.
Please take your clearly ignorant bias and anti-pharma prejudice somewhere else - you have no idea what you're talking about.
It is not a guess. It is statistics. Typically, the dose is either effective or partially effective and often on the smaller side as Phase 3 also looks at side effects.
>It's all a guess until the end, and even then we're often not sure. Look at anti-depressants. We still don't know how a lot of those work but prescribe them to millions of people regardless. How do you think they determined the dose when they don't know how the drug works?
We know how antidepressants work, the chemical reaction is well known and can be quantified at different doses. We just don't know why they work because we don't understand why/how the brain works.
No, we don't know the antidepressive mechanism of antidepressants, therefore we don't know how they work.
Understanding some neurochemical reactions and biological adaptations they cause is not enough.
(We also don't have a complete understanding of depressive disorders, we don't really have very effective medication/therapy for many depressive people, etc.)
SSRIs, SSRIs, MAOIs and TCAs all have reasonably well understood pharmacology. As an extreme example, there are very detailed guidelines on how to prescribe venlafaxine, to whom, and who should supervise. You're free to dispute these claims but I think you need to produce more than a blanket dismissal, especially as the OP offers a seemingly reasonable source.
You're talking about the study linked as "2006 study of 122 drugs", right? I can't find amphetamines in the tables or the text, what page is it on? (or was it maybe another paper linked in the article?)
I have a prescription for dexamphetamine, but I don't use/need it a lot, so I have some bottles left that are a bit old--not past the expiration date, which appears to be slightly less than 3 years (after the date of the recipe), on the bottle I'm currently looking at. So I was curious about the amphetamines in particular, and if it's just efficacy deteriorating a bit that's fine, because in my personal experience the effect (which is quickly and clearly noticeable) varies easily by 25% already, depending on so many other factors (like what/how much I eat, how well I slept, stuff like that).
> There are a few compounds (like fentanyl or LSD) where the dosages are so small and the compound so potent that 10-25% makes a difference but for the majority, precision isn't that critical.
Wrong. LSD and fentanyl have polar opposite therapeutic indexes - the therapeutic index is specific to toxicity whereas I'm talking about clinical outcomes in general. There are drugs that have threshold doses below which there is essentially no effect on the patient but aren't toxic until 10-1000x that threshold dose. Fentanyl just happens to have an effective threshold dosage that is dangerously close to its LD50.
LSD has an exceptionally wide therapeutic index, but fentanyl's therapeutic index of 270 is pretty good as prescribed drugs go. That's a far wider TI than over the counter painkillers like ibuprofen. Warfarin, a common narrow-therapeutic-index drug, has a TI of ~2.
Fentanyl's therapeutic index is NOT 270 except when used as an opioid supplement for surgical anesthesia cocktails, where the dosage is less a microgram per kilogram and it's balanced with several other drugs and opioid antagonists. The maximum recommended dose for fentanyl is 50 mcg/kg and that requires ventilation because it is well above the estimated LD50 of 30 mcg/kg. The recommended low dose for fentanyl on its own is 1 mcg/kg so at best we're talking about a therapeutic index of 30.
LSD's therapeutic index is unknown because its LD50 has never been established in humans or monkeys and you can't extrapolate from non-primate animals to humans (for example, rats can handle a dose of fentanyl that is a thousand times higher per kg than monkeys can, which is where many of our LD50 estimates come from).
Glad I could enlighten. The therapeutic index is a very subjective measurement that makes some drugs sound safer (or more dangerous) than they really are. Both the numerator and denominator in the ratio are very situation dependent. For example, trazadone is a hypnotic at doses in the tens of milligram but an anti-depressant at doses in the hundreds of milligrams so depending on what you're using it for, its therapeutic index could be different by up to 100x.
Likewise, in a clinical setting (i.e, with a trained anesthesiologist in fentanyl's case), the dose at which 50% of patients die from a given drug is usually much higher because trained professionals can quickly receive feedback by monitoring the patient's symptoms and apply drugs or medical devices to keep them alive well beyond what could kill someone on the street.
I do not believe that you have the requisite knowledge of pharmacology to talk intelligently on these topics so you should stop correcting people who do, especially when your other comments suggest that your knowledge is based entirely on recreational drug databases. Anyone who has spent time working in the pharmaceutical industry knows that "therapeutic index" and "therapeutic ratio" are used interchangeably and that I never said anything even remotely related to either of those until you brought it up out of nowhere.
The therapeutic index is the ratio of the therapeutic dose to the dose at which the drug starts becoming toxic in 50% of the sample. I repeat, for the third time, I was not talking about toxicity. We are discussing drug expiration dates and you will not experience toxicity from a drug that has been degraded over time to a dosage lower than the one you were prescribed, except in extremely rare circumstances. A drug's therapeutic index is entirely irrelevant to what I am talking about - I don't know how I can make that any more clear.
But what you said was still totally wrong, regardless of whether you're talking about toxicity or anything else. LSD is not so finicky that a 25% change in the dose makes a noticeable difference -- most people would be hard pressed to tell the difference between a 100 ug tab and a 125 ug one.
It also does not follow that because a drug is active in small amounts, i.e. micrograms instead of milligrams, that a small percent change in the dosage will be more important. Full stop illogical, and also not true in practice.
So yes, I'm not a doctor and I don't know the jargon. And when I read your comment I forgot the article was about expiration dates, i.e. percent decrease. And yet you were still wrong on that particular point.
LSD is an agonist for most classes of serotonin, dopamine, and adrenergic receptors - most of which have sensitive, nonlinear responses and all of which uptake the agonist at very different rates depending on individual biochemistry. We don't have the data to say for certain because of prohibition and the DEA's reluctance to allow researchers to study LSD but every other drug combination that operates on such a diverse set of receptors is extremely sensitive to dosage because all of those receptors have interdependent feedback loops - which makes them mostly useless for therapeutic uses. This is also why monoamine oxidase inhibitors (MAOIs) are so dangerous with such a wide array of drugs - the enzymes that break down monoamine neurotransmitters are regulated by serotonin+dopamine receptor interactions and even a tiny amount of MAO inhibitors can wreck havoc on that balance, causing some severe symptoms up to and including death. This happens because, even though MAOs are rather indiscriminate on which monoamines they target, their effect on each different neurotransmitter is variable and nonlinear.
In my personal experience (a decade of Burning man), when you do have a known concentration of liquid LSD (measured with an LCMS) that you carefully handle, store, and dilute for dosages, 100 mcg and 125 mcg can mean the difference between a good trip and a bad one in at least a tenth of my sample size and can drastically change the intensity of hallucinations (going from zero to fractal visuals to aliens) in a good quarter - not to mention the effect on the body high and introspection. If you're buying tabs, the chances that you are even close to the original concentration falls rapidly the further removed you are from the original source. Most people can't tell the difference between a 100mcg and 125mcg tab because those dosages are exaggerated and many people feel stereotypical effects at lower dosages. You can easily test this by eating a significant fraction of a blotter: you are extremely unlikely to experience the effects described by the literature of 50 ng/mL blood concentrations even if you're lucky enough to get to 5 ng/mL effects with a few tabs.
IME bad trips are mostly determined by how neurotic the tripper is. If you can accurately say that a 25% increase causes a 10% increase in bad trips, you must have quite a lot of experience. I at least know that if some people take one tab and others take two at the same time, the ones who took two don't go flying off the walls.
Saying that a 25% change is more significant for more potent drugs is illogical on the face of it, because a % is a dimensionless quantity. If there is some subtle reason why this trend exists I'd love to hear it.
> Saying that a 25% change is more significant for more potent drugs is illogical on the face of it, because a % is a dimensionless quantity. If there is some subtle reason why this trend exists I'd love to hear it.
Actually, the reverse is illogical because few biochemical systems have linear responses, especially when you're talking about something as complicated as the neurotransmitter systems that LSD effects. Potency depends on two factors: the affinity of the drug, or how well it binds to its target receptors, and efficacy, or the relationship between the concentration of the drug (and second order neurotransmitters) and the ability of the receptors to initiate a cellular response. Neither of those two factors are linear and they both change as the concentrations of the drug and its byproducts change. As neuron receptors are activated by LSD, they cause cells to release a flood of other neurotransmitters at varying concentrations (dependent on LSD concentration and individual brain chemistry) that start interacting in complex ways like preventing the LSD and other neurotransmitters from binding as effectively (lowering their affinity), potentiating the cellular response (increasing its strength aka increasing efficacy), or building tolerance (lowering efficacy due to exposure). Each receptor and neurotransmitter pair behaves differently. Neurotransmitters in general can't activate cellular responses before they are above a threshold potential that causes the neuron to react, after which the cellular response is never linear. A 2x increase in concentration will rarely achieve a 2x response unless it falls in a small range where the curve is mostly linear, and even then the complex interactions between all of the neurotransmitters will usually compound into a nonlinear response anyway.
These interactions get so complicated, for example, that you get many cases were an opiate A, which is technically 10x more potent than an opiate B, can actually be less potent at treating mild pain because it has a steep response curve that doesn't ramp up until a certain dose. 10mcg/kg of opiate B might be 10x stronger than 10mcg/kg of opiate A (which could be too low to even feel the painkilling effects of opiate A) but once you hit 50mcg/kg concentrations, opiate A might be 10x more potent than opiate B, whose effects plateau with doses higher than 20mcg/kg. Potency is typically expressed as the [A]50 - the concentration of the drug at which you reach 50% of the maximum effect, which depends on the therapeutic effect you're looking for. So in this example, the [A]50 of opiate A in mild pain scenarios can be 25mcg/kg versus opiate B's 7 mcg/kg while with severe pain, the [A]50 of opiate B can be above its LD50 and opiate A's can be 30 mcg/kg because from 25 to 30 mcg/kg opiate A has an exponential response curve. Like I said, it's very complicated and when measuring potency, you're actually measuring the effects of concentration on "arbitrary units," which could be something concrete like a chemo drug's effectiveness at killing cancer cells or something subjective like pain relief. When it's the latter, especially, potency has a very specific meaning in pharmacology that is very different from how the word is used colloquially.
This is just throwing around a lot of irrelevant details to obscure the fact that your original statement violates the dimensional analysis smell test -- I could make a shitty prodrug of LSD where the threshold dose is 1g instead of 50ug, but you wouldn't expect the 1g version to be less sensitive to a 25% change because it's "less potent." If you wanted to give examples of a drug where a 25% change is a big concern then warfarin or synthroid are much better examples than LSD. As it turns out, you know your shit, but it is still a sloppy statement.
I tried explaining why you are wrong but I give up. You are incapable of accepting basic facts about biological systems and neuroscience that have been known for many decades, no matter how hard I try to explain it to you. Your "dimensional analysis smell test" is entirely idiotic in the face of those basic facts as accepted by the entire medical and biological research fields.
Please don't talk about pharmacology. Period. You don't know what you are talking about and someone might make the mistake of believing otherwise and do something dangerous.
> There are a few compounds (like fentanyl or LSD) where the dosages are so small and the compound so potent that 10-25% makes a difference but for the majority, precision isn't that critical.
As in, typical dosages for fent or LSD are on the order of micrograms, so we expect them to be sensitive to a 25% change, for other drugs where a typical dose is measured in mg or grams, 25% is less likely to be a big deal, etc. This is the only way to interpret what you wrote, and it doesn't make sense. No such trend exists. None of the "basic facts" which you "explained" above (which I already knew) go anywhere near supporting this assertion.
Put another way, if you know the [A]50 you know one point on the dose-response curve, but in general that tells you nothing about the slope or shape of the curve near that point.
Judging from your comment history, you are not an actual doctor or biomed researcher, just a programmer in that industry. Which makes your teeth-gnashing about what an authority you are a tad less persuasive.
Aspirin is a bad actor in this regard. It tends to revert back to salicylic acid, which is ok for some specific topical uses, but has potential to be pretty harmful orally. Sniffing an old bottle of aspirin will tell you whether they're still good enough
For the record, what you're smelling for is acetic acid (vinegar). When aspirin (acetylsalicylic acid) hydrolyzes into salicylic acid, the other product of that reactions is acetic acid, which is what's in vinegar.
It's not that harmful if you know what you're dealing with. Have to be careful about liver toxicity and dosage but in a pinch it will work just fine as an antipyretic. It was used before aspirin has been invented.
The only drugs that weren't within 10% of their original concentrations, according to the study, were amphetamines and aspirin. I can't think of any uses off the top of my head for those two where even 25% would make much of a difference to outcomes - amphetamines are mostly used as general purpose stimulants or to treat ADD and aspirin is not the blood thinner of choice for life and death situations. With amphetamines especially, what you eat and small factors like blood pH can have a massive impact on their effectiveness so we're already talking 10-20% differences day by day, let alone person to person.