I've found that using O2 via a cannula makes longer flights less tiring.
have quite a few 5+ hour flights this year usually at fl080 to fl160 with O2 they are a non issue.
Had a few last year without O2 and the downsides range from just tiring to mild headaches to inability to process mild complexity.
using a modern metered supply system such as provided by Mountain High (I'm sure others are available) means your O2 lasts a stunning duration and makes a huge difference.
You can operate quite high without O2, but why bother ?
flights are easier and quantifiably safer on O2.
If not yet convinced, try some simple arithmetic next time you have spent an hour above fl080, you'll be horrified at your decrease in ability.
I put the system online above 6k now, costs sweeties to run and adds minimal hassle.