> For keyword and var-arg calls we have three more opcodes -- CALL_FUNCTION_VAR, CALL_FUNCTION_KW, and CALL_FUNCTION_VAR_KW.  I suspect that making them work with LOAD_METHOD would slow them down too, which will probably require us to add three (!) more opcodes for LOAD_METHOD.

I don't think that it's an issue to add 3 more opcodes for performance. If you prefer to limit the number of opcodes, you can pass a flag in arguments. For example, use 2 bytes for 2 arguments instead of only 1?

See also the (now old) WPython project which proposed kind of CISC instructions:
https://code.google.com/p/wpython/