I built a 4e Skill Challenge around curing yourself of a disease/poison that began when you took a cursed version of a Certain Little Blue Pill. (Potion of Extraordinary Endowment) The cure was to eat an XL meal of aphrodisiacal foods (which I never described in any detail). The fun part consisted of trying to locate ingredients and prepare them correctly.
Athletics - you have to do something physically challenging, such as climbing half-way down a cliff to collect bird eggs from a nest.
Streetwise - Somebody else in town fell for it too, and has a supplier on the sly. Locate the supplier.
Nature - Find the RIGHT mushroom, not the near-lookalike poisonous mushrooms
Endurance - (final check only) Hard: Eat the meal in one sitting. Medium: As Hard plus you prepared yourself all day by not eating, exercising, &c to build up hunger. Easy: As Medium plus you eat the meal in several courses over several hours.
NOTE: If you succeed at the Hard Endurance check (and only the Hard check) you get a +2 bonus to all social skills while in town, as word of your prodigious feat spreads.
The effect of the 'disease' was purely fluff, but you could use a level of 5e Exhaustion.