Crossover Trial
Compare two interventions in the same people with a washout between them
- Difficulty
- Advanced
- Time to result
- ~months to results
- Steps
- 5
- Confidence
- 97%
A crossover trial compares two interventions by exposing the same participants to both, rather than assigning separate groups permanently. Participants complete one condition, pause for a washout period intended to reduce lingering effects, and then complete the other condition. Outcomes from each period are measured and compared. Because each person serves as their own comparison, individual differences such as baseline biology are less likely to distort the contrast. In the episode, Mark Hyman uses Kevin Hall's real-food versus ultra-processed-food experiment to explain the design. The approach showed that the same people ate about 500 more calories per day during the ultra-processed condition, supporting a biological rather than purely willpower-based explanation for excess intake.
Origin
Mark Hyman describes Kevin Hall's nutrition experiment, in which the same participants ate real food and ultra-processed food in separate periods divided by a washout.
Core principles
- 01Use the same participants for both conditions
- 02Separate interventions with a washout period
- 03Hold comparison conditions as consistent as possible
- 04Measure outcomes after each condition
How to run it
- 1
Define the paired conditions
Choose two interventions that answer one focused comparison question. Specify the outcomes and measurement method before exposure begins.
Pro tip Keep the conditions comparable on factors that are not being tested.
Watch out A vague intervention makes the final contrast difficult to interpret.
- 2
Run the first condition
Expose participants to the first intervention for a defined period, then record the agreed outcomes.
Watch out Do not change the outcome definitions after seeing early results.
- 3
Wash out carryover
Pause between conditions long enough for the first intervention's temporary effects to diminish.
Pro tip Base washout length on the expected duration of the intervention's effects.
Watch out An inadequate washout can contaminate the second period.
- 4
Run the second condition
Expose the same participants to the comparison intervention and measure the same outcomes over a comparable period.
Watch out Differences in timing or measurement can masquerade as intervention effects.
- 5
Compare within participants
Compare each participant's outcomes across conditions, then aggregate the within-person differences to assess the intervention effect.
Pro tip Inspect both the average effect and variation between participants.
Watch out Account for order and period effects before drawing a causal conclusion.
In the wild
Kevin Hall gave the same participants a real-food diet and an ultra-processed diet in separate periods with a washout between them. Participants could eat as much as they wanted. Hyman reports that they consumed about 500 more calories per day during the ultra-processed period.
→ The within-person contrast linked ultra-processed food to substantially higher voluntary calorie intake.
Common mistakes
Skipping the washout
Residual effects from the first condition can alter outcomes in the second and make the comparison unreliable.
Using irreversible interventions
A crossover cannot cleanly compare conditions when the first intervention permanently changes the participant.
Changing measures between periods
Different measurement rules undermine the within-person comparison that gives the design its value.
Is it for you?
Best for
Researchers testing short-lived interventions whose effects can reasonably clear during a washout period.
Not ideal for
Interventions with permanent effects, strong carryover, or conditions that change substantially over time.
From the transcript
“he did what we call a crossover trial which is one of the best types of study designs where he took the same people gave…”
“let them have a break call a wash out period and then give them another diet for a few weeks and then measured what happened”
“when they were eating Ultra processed food they ate 500 calories more a day because their biology was disregulated ated”
From the episode
Episode 412: Dr. Mark Hyman: How Ultra-Processed Foods Are Fueling America's Obesity Epidemic
Dr. Mark Hyman