thanks you guys!
Intermission!TL; DR
-You can't plug units tweaked for fx returns into amp inputs, and vice versa
-units tweaked for fx returns cannot work with amp inputs due to ADDITIONAL gain stages
-units tweaked for amp inputs cannot work with fx returns because they DEPEND on additional gain stages
-fx return units sound more consistent from amp to amp; amp input units change slightly depending on what you plug into (i.e. it can potentially sound better with better amps) - choose which one fits your gigging needs better
NOTE: If it's not clear by now,
a multi-effects setup for the effects return cannot be plugged into the amp input directly, and vice-versa. Setting your multi-effects for either method means you're taking into consideration the number of "gain stages" you're manipulating (for starters, modern clean amps have at least 2 gain stages, vintage ones 3 or 4, and high gain distorted signals 5 or more) and whether you're getting most your sound from the amp or your effects unit.
Plugging into the effects return means you're bypassing most, if not all, of your amp's useable gain stages. This is why you might often find yourself breaking into a cold sweat the moment you plug in your multi's high gain setting into a high volume amplifier's input - all you'll probably hear is uncontrollable feedback and mush due to your (at least) 5 "virtual" gain stages being cascaded into the amp's built in ones.
In other words, the perfect setting you tweaked on, say, a computer, a smaller amp, or through headphones, is potentially exposed to
further distortion via the gig-level amp at high levels - the kind of distortion that ruins the tonal balance you oh so carefully crafted at lower volumes. Additionally, your amp's natural voicing (i.e. what makes Fender, Vox, Marshall, Mesa, etc. amplifiers sound different from one another) and EQ will interact further with your unit, even with the controls set at 12 o'clock.
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On the other hand,
plugging into the amp input means you're building on the gain stages (at least 2) of the amp. This way, you're using your unit like a programmable analog pedalboard, and your sound will rely largely on the tonal quality of the amp you plug into.
The good news is that
plugging into an awesome amp will, more often than not, make YOU sound awesome The bad news is that
plugging into worse amps will require you to compensate for its poor quality via extensive tweaking on the amp EQ, as well as on the unit itself.
Plugging the multi-effects meant for an amp input into an effects return will yield safer, but nonetheless lousy, sounds. A couple of gain stages less, and no amp EQ to "carry" the unit's tonality, your tone will sound dull, and the volume will probably be slightly lower than what you'd expect.
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At the end of the day, the two methods I have described above fulfill the same duties in slightly different ways.
The emphasis of effects return-based units is
consistency - the same general feel and tonality can be achieved on pretty much any amp with the required inputs, with minimal or no tweaking.
The emphasis of amp input-based units is
"naturalness" of tone - since more often than not you'll find yourself plugging into something analog, tube or solid state, you're already going to be "riding" on analog preamp circuitry, using your unit only to enhance whatever sound that's already in the amp. Again, plugging into a tube Fender or Marshall almost always guarantees that you'll sound awesome, carrying with it the risk that one day you'd eventually find yourself staring down a stinky, dilapidated solid state with AM radio quality tone.
Granted, even the fx return method won't save you from such horrible amps, but such a scenario still needs to be taken into consideration. Thankfully, the "worst" amps I've seen used for live gigs so far are Laney LX65 combos, which aren't too bad, and are accommodating of both methods of tweaking.
to be continued...