The number of loci doesn’t matter very much (perhaps a minimum of 1,000 reusable loci is a good number to aim for), but FAST processing speed is essential. Can you jump to any place (locus) in a second or two, then retrieve the information (decode the mnemonic) almost immediately after that? This is how it’s supposed to work - and yes, it takes some practice and repetition to achieve real speed. But it will make your problem of “retrieving information stored in 5 different memory palaces” quite easy to do quickly.
You seem to be talking about two different things: 1) memorizing data, and 2) solving problems with this data.
Nothing is permanently “locked” - you can always rearrange anything you want. If you find it difficult to forget the associations you make, then congratulations, maybe you don’t need memory palaces at all. Just make the links and let them float around in “one BIG void,” as you said (although it’s not a void). There are entire mnemonic systems that don’t use loci at all - most famously the one by Richard Grey (died 1771), but also Harry Lorayne and many other mnemonists have ignored or played down loci techniques.
On the other hand, the BBC’s Sherlock Holmes uses his “brain attic” to file away tons of data, on criminals and all sorts of things, AND he uses his “mind palace” to solve problems. This program has brought a lot of attention to mnemonic techniques. I’ve watched the entire series so far, and have found the descriptions of mnemonics to be very disappointing, but the gist is correct: solving problems (meditating on them in this way), and storing information, are two of the traditional uses for memory palaces.
Since memory palaces have been used successfully for many centuries, any new discovery of a “major drawback” would be highly unlikely at this point. There are probably as many different ways to implement loci systems as there are people trying to do this. Mnemonic techniques are creative processes, so experimentation is always required. Or to put it another way, if a memory system isn’t functioning correctly, what can you do to change it, to make it work efficiently? Of course any memory system needs to be rock solid - not something you don’t trust or feel good about.
As a medical student, you are probably aware of first-letter mnemonics, used traditionally in medicine. (See books like Mnemonics, Rhetoric and Poetics for Medics, and similar.) This is a very fast way to tie together info that is scattered around in your brain-box. There is no good reason to limit yourself to just one memory system or technique.
Sheldon