5 ms·

> 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

> 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. Therapeutic ratio, not dosage.

civilitty 9y ago
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.
- philipkglass 9y ago
  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.
  - civilitty 9y ago
    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).
    - philipkglass 9y ago
      I didn't know that extra context about the numbers for fentanyl. Thanks for correcting me. I was going to post something long about LSD but it turns out I am just wrong. So thanks twice, and have my upvote.
      - civilitty 9y ago
        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.
- sevenfive 9y ago
  Excuse me, index. A dimensionless quantity. Nothing to do with potency. And you could hardly pick worse drugs to spread misinformation about.
  - civilitty 9y ago
    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.
    - sevenfive 9y ago
      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.
      - civilitty 9y ago
        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.

civilitty 9y ago

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.

philipkglass 9y ago
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.
- civilitty 9y ago
  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).
  - philipkglass 9y ago
    I didn't know that extra context about the numbers for fentanyl. Thanks for correcting me. I was going to post something long about LSD but it turns out I am just wrong. So thanks twice, and have my upvote.
    - civilitty 9y ago
      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.
sevenfive 9y ago
Excuse me, index. A dimensionless quantity. Nothing to do with potency. And you could hardly pick worse drugs to spread misinformation about.
- civilitty 9y ago
  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.
  - sevenfive 9y ago
    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.
    - civilitty 9y ago
      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.