Washout

A washout looks like a protocol detail and is in fact a commercial decision, and in our opinion it is the sharpest dividing line in European psychedelic development. Requiring one shrinks the population a therapy can practically reach, because treatment-resistant patients are by definition already medicated, and it imports a relapse risk and weeks of delay before anyone is dosed. That makes every reimbursement conversation harder before it starts. The opposite design, dosing on top of existing medication, is easier to deliver and rests on the bet that the drug still works on an occupied receptor. Both camps cannot be right, and when you read a protocol, the eligibility rule tells you which bet the company has placed.

We set out what a washout actually involves in Issue 5, from the Compass protocol: "Its protocol has patients taper off antidepressants inside the first four weeks of screening, then sit at least two weeks completely unmedicated before the baseline visit, with some drug classes requiring immediate cessation and a longer clearance. Germany's EPIsoDE trial, the blinded readout we have tracked since Issue 2, did the same: taper before, stay off for weeks after."

The reasoning behind it, from the same issue: "The rationale is mechanistic. SSRIs occupy and downregulate the same serotonergic receptors psilocybin acts on, so the worry is that a medicated brain dampens the drug."

And the cost: "A therapy that demands a supervised multi-week washout imports a relapse risk, a discontinuation-syndrome risk, and weeks of delay before anyone is even dosed. That shrinks the practically treatable population and complicates every reimbursement conversation before it starts."

The evidence that it is necessary is thinner than either side implies, and we said so: the most useful data is Compass's own published analysis of 233 treatment-resistant patients comparing those who discontinued antidepressants to enter a trial against those who arrived medication-free.

The opposite design is called adjunctive, meaning the drug is given on top of a stable existing regimen. Issue 11 records both Lilly brenipatide depression trials describing themselves in their official titles as adjunctive treatment, "given on top of a stable standard-of-care regimen rather than after a washout."