A compound's therapeutic index is defined as:

$$TI = \frac{LD_{50}}{ED_{50}}$$

What range are the therapeutic indices of benzodiazepines in? For the method of administration I would prefer intravenous as with it one can estimate the therapeutic indices via other routes. Of course for humans it is difficult to find LD50's but a rat/mice LD50 will suffice provided the ED50 is for the same respective species. Such benzodiazepines I am interested in are (Although I will accept your answer if you just give me an estimate of the therapeutic indices of the drugs in bold, the others are just icing on the cake):

  • Alprazolam
  • Brotizolam
  • Clonazepam
  • Clorazepate
  • Diazepam
  • Estazolam
  • Flurazepam
  • Lorazepam
  • Lormetazepam
  • Midazolam
  • Nitrazepam
  • Temazepam

2 Answers 2


Wikipedia quoted this article as a reference for its statement about alprazolam having a therapeutic index of 100:1, although I can't confirm that, since I can only read what's immediately available in that link. There's a figure saying less than 100:1 for diazepam though.

  • $\begingroup$ Thanks, an answer is better than none at all. I'm afraid I probably won't accept your answer. I will, however, upvote it, since I know just how tricky it is to find an answer to this question, hence why I'm asking it. $\endgroup$
    – Josh Pinto
    Feb 11, 2013 at 5:27

A first pass answer is 662-4342.

The Therapeutic index is calculated from rat tolerances; LD50 is a rare number to see for human beings(!). The toxic dose of a compound can vary widely over a class of compounds as well as does the Effective Dose (ED) midpoint (ED50).

But I found this book reference:

Benzodiazepines have a wide margin of safety based on experimental studies in animals. In the rat for example, the lethal dose of alprazolam is 331-2171 mg/kg. The effective therapeutic dose for alprazolam is 0.5 mg/kg which results in a therapeutic ratio of ... 662-4342.

The page goes on to say, at rather great length, that human evidence is that despite the fact that this is a popular class of drugs to try to kill yourself with, there are relatively few human deaths, which is pretty ultimate a judge for toxicity, though you could look for FDA warnings on the class of drugs.

I would bet that you can find relatively toxic benzodiazepines, but for the ones that pass screening they seem pretty benign as a class. There are other issues with these drugs rather than mere toxicity - they are quite addictive, so therapeutic index is not an ultimate judge of the adverse effects of a drug.

BTW taken literally, this is a hard question you ask. If you are expecting a compiled list of all such drugs, cross referenced to their Therapeutic index, that is really more like the work for a paper rather than 25 points of stackexchange karma IMHO. On the other hand maybe someone has this information at their fingertips...

  • $\begingroup$ Is the effective dose of 0.5mg/kg for humans or rats? In order for a therapeutic index to be a fair estimate both the lethal and effective doses have to be for the one species. $\endgroup$
    – Josh Pinto
    Feb 11, 2013 at 6:49
  • $\begingroup$ That was for rats as well. The therapeutical index is, in general, not suitable for quantitative comparison though. The figures may even vary wildly for one substance. It's at best a rough indicator of safety margin. Have you looked into an alternate definition, TD50/ED50? Defined for humans, where TD50 is the dose that produces a toxic response in half the test subjects. $\endgroup$
    – user3032
    Feb 11, 2013 at 7:57
  • $\begingroup$ Yeah I know of the therapeutic window but the problem is that we know more about therapeutic indices for other drugs so it's a more useful comparison for me. $\endgroup$
    – Josh Pinto
    Feb 11, 2013 at 8:37
  • $\begingroup$ That information would have to be dug up through pharmacology texts or the literature. Maybe someone could know that off hand and post, but you need to name specific drugs... there could be dozens of drugs in the class. That's asking a lot. $\endgroup$
    – shigeta
    Feb 11, 2013 at 15:23

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