The chart shows that the uptick begins in 2014, roughly when the meth epidemic became a true epidemic, spreading to every part of the USA, so meth in particular, and drugs in general, are the most likely explanation. So these deaths fit in with the narrative of "rising deaths of despair."
That also correlated with the times that a number of states began to legalize marijuana for recreational use[1]. There are studies looking at this relationship and finding a correlation between road death increases and marijuana legalization.
If we're guessing about correlations I'd point to something else that happened in 2014 that's much more significant and directly related: the death of Mike Brown in Ferguson, after which police who were roundly criticized for pulling over too many people committed to performing drastically fewer traffic stops. The second visible spike follows the death of George Floyd, which resulted in a redoubling of that commitment [0].
https://www.sciencenews.org/article/deaths-of-despair-depres...