What is your anti-virus software?

I use CCleaner and Walwarebytes. Unfortunately, Windows Defender is also on my computer, hopefully not running, but I have not been able to remove it. When is was an active part of my computer it really slowed things down.

Windows Defender is also on my computer, hopefully not running,

You should ask in a Microsoft forum.

Try to start Windows in safe mode with networking enabled. - Win10 https://support.microsoft.com/en-us/help/12376/windows-10-start-your-pc-in-safe-mode

Still in Windows safe mode, start Thunderbird in safe mode. - https://support.mozilla.org/kb/safe-mode

Does the problem go away?

Please go back and re-read the original post. You answer is included.

I missed that.

Windows safe mode disables anti-virus software, which is most likely the culprit.

First of all you should fix that potential Malwarebytes/Windows Defender conflict. There should only be one anti-virus software with a real-time scanner running at a time. Personally I'd opt for Defender.

Then, create an exception in your anti-virus software for the Thunderbird profile folder, so that the anti-virus real-time scanner will not scan it. http://kb.mozillazine.org/Profile_folder_-_Thunderbird

Don't let your anti-virus software scan incoming and outgoing messages.

Don't let your anti-virus software scan attachments.

Don't let your anti-virus software intercept your secure connection to the server.

Remove any add-ons your anti-virus software may have installed in Thunderbird.

Keep it working. http://kb.mozillazine.org/Keep_it_working_-_Thunderbird

And last but not least, backup your Thunderbird profile on a regular basis. https://support.mozilla.org/kb/profiles-where-thunderbird-stores-user-data#w_backing-up-a-profile

It was working just fine with each other until a couple of months ago or so. Why did it change? Wont those changes make my computer vulnerable to threats?

They won't. It has been explained in this forum countless times why they won't make your computer vulnerable. But you can do your own research, and the decision what to do is ultimately up to you. These articles may be a good start. https://thunderbirdtweaks.blogspot.de/2011/07/anti-virusfirewall-programs.html https://thunderbirdtweaks.blogspot.de/2017/01/anti-virus-again.html

Why did it change? I don't know. You should ask that question to your anti-virus software vendor.

see also https://wiki.mozilla.org/Thunderbird:Testing:Antivirus_Related_Performance_Issues

I have even deleted Malwarebytes and Thunderbird is still having "not responding" issues.

There were other suggestions beyond removing Malwarebytes. Please re-read https://support.mozilla.org/en-US/questions/1179526#answer-1016464 and confirm you did follow the suggestions.

My "Trend Micro Internet Security" is set to not scan emails and/or attachments. The only plug-in is Shockwave Flash and it is disabled. Still get the "not responding"

mspeedp5,

please start a new topic for your problem. https://support.mozilla.org/questions/new