Pursuing a question raised in these comments:

Are there any known pharmaceuticals that increase in potency or toxicity during storage, or over periods of months to years?

If not, what if we broaden the question to include any bioactive chemical?

My hypothesis is that the answer is no due to the following considerations:

  1. If we limit the scope to pharmaceuticals we often find that the bioactive components of a chemical are specific isomers. In that case other isomers are relatively inert. Over time racemization can only decrease the concentration of the bioactive isomers,* so under this mechanism potency can only decrease with time. (I can't find any examples in which non-therapeutic isomers are more toxic than the therapeutic isomers.)

  2. The other mechanisms of chemical change that I can think of chemically affecting a bioactive substance during extended storage are heat, light, evaporation, and atmospheric oxidation and moisture. We might rule out all of these but heat in the case of properly stored pharmaceuticals, which are formulated and/or packaged to prevent exposure to these influences. But even if we allow for exposure to any or all of these (keeping heat within reason – say under 60°C) I can't think of any examples by which these processes increase toxicity of any chemical.

Any specific examples or general suggestions to the contrary are welcome!

* Silas W. Smith, Chiral Toxicology: It's the Same Thing…Only Different, Toxicological Sciences, Volume 110, Issue 1, July 2009, Pages 4–30, https://doi.org/10.1093/toxsci/kfp097 provides an extensive survey of this question. I certainly could have missed something during reading, but it does state early on that in drugs offered only as enantiomers "...the other isomer has no clinical effect or adverse effects in vivo." Some examples show that while "adverse" effects (which I'll classify under "toxicity") can be found in non-therapeutic isomers, they do not exceed the adverse effects found in the therapeutic isomer. So in the worst case it appears that a pharmaceutical can lose potency but not toxicity over time due to racemization, but this does not constitute an increase in "toxicity."

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    $\begingroup$ See nytimes.com/2014/02/11/science/… and consumerreports.org/drug-safety/… $\endgroup$ – DrMoishe Pippik Mar 1 '20 at 21:55
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    $\begingroup$ @DrMoishePippik the first article mentions anecdotal evidence that "old" tetracycline was associated with some adverse reactions, but then cites a 2004 review that concludes no causal link has been established (much less any hypothesis for how tetracycline might degrade into something toxic, or what the toxic chemical might be). The second link just repeats the FDA's generic advice to "throw out expired meds because they may have reduced potency." Neither is informative to this question. $\endgroup$ – feetwet Mar 1 '20 at 22:13
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    $\begingroup$ In The Wolf of Wall Street, it's asserted that old Quaaludes (specifically Lemmon 714's) increased in potency. See this clip for the cinematic treatment. $\endgroup$ – Todd Minehardt Mar 2 '20 at 3:23

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