https://support.mozilla.org/en-US/kb/how-to-fix-preferences-wont-save

Note: Some software, like Advanced SystemCare with Surfing Protection, can protect files in the Firefox profile folder against changes. If you have such software then check the settings or uninstall this software.

I am not aware of any software that would do that, is there any way to check?

What are you using as your protection programs?

Open the Profiles Folder and make sure nothing is Read Only.

Start Firefox in Safe Mode {web Link} by holding down the <Shift>
(Mac=Options) key, and then starting Firefox. A small dialog should appear. Click Start In Safe Mode (not Refresh).

Is the problem still there?

Sorry FredMcD I don't understand.

What/where is the profiles folder? If you mean ~/.mozilla/firefox/ then I have read/write permissions to everything there.

I have started FF in safe mode, I can then go into Tools>Add-ons>Plugins and change it to 'Always Activate' but after I reboot it is back to 'Never Activate' again.

https://support.mozilla.org/en-US/kb/how-to-fix-preferences-wont-save

Note: Some software, like Advanced SystemCare with Surfing Protection, can protect files in the Firefox profile folder against changes. If you have such software then check the settings or uninstall this software.