Psychedelic trials are difficult to blind. Psychedelic compounds produce extraordinary subjective reactions that are well-known (and expected) by the trial participants. This is called the “set” or mindset issue. In addition to the mindset people have coming into the clinical trials, participants are often required to participate in pre-therapy sessions that prepare them for what they will experience. This increases their expectation of an effect, makes it even clearer when they are not in the study arm getting the psychedelic, and further challenges the ability to distinguish a drug effect from a “placebo” effect. 

“Setting” refers to all that’s going on in your immediate environment during the psychedelic treatment session, such as the people around you and their behaviors, the type of furniture in the room, whether there is music playing, and even the smells and lighting of the room. Clinical trials need to determine how the environment in which the individual takes the compound enhances or detracts from the effects of the drug itself. 

Many of these compounds are being developed as tools to enhance the effectiveness of psychotherapy. For example, some compounds have a capacity to induce an altered or opened sense of self and relatedness to others, which may enhance the psychotherapy experience by increasing trust and openness. Other compounds are thought to increase plasticity, potentially facilitating the uncoupling of fear from the traumatic memory during trauma-focused psychotherapies. For those compounds where the psychedelic therapy is proposed as enhancing the effect of psychotherapy, the FDA will have to consider how they will label a compound that enhances a type of therapy that they do not regulate, i.e., psychotherapy. This also emphasizes the need for the FDA to understand what the drug effect is apart from the psychotherapy effect. In addition, the DEA has designated many psychedelic compounds as Schedule 1, so there are limitations as to who can study them and under what conditions, which reduces the amount of research into these compounds compared with non-Schedule 1 compounds. With fewer studies, it makes evaluating the true effect of these compounds based on a limited number of and relatively small studies very challenging.

A well-designed, regulatory-quality study should determine whether the subjective effects are a necessary part of the “mechanism of action” or whether compounds can be developed that have the same potential effects without the risk of hallucinations, dissociation, or the need of multiple therapists and hours of being watched in a clinic during the administration period. Some drug development companies are specifically developing drugs that act on the same pathways in the brain but do not produce the hallucinations or other effects typically associated with psychedelic compounds.

Many patients with intractable PTSD will likely have previously been on or currently be on drugs with an overlapping mechanism of action such as SSRIs or SNRIs. For some people, if SSRIs or SNRIs were not effective for a patient, then the expected effect of a psychedelic that also works through the serotonergic system may not be as great. In those that did see some benefit from SSRIs or SNRIs, long term use of serotonergic drugs can actually change how the body responds to serotonergic drugs and thus, psychedelic compounds may not be as effective for those people. From a safety perspective, there is also the risk of inducing serotonin syndrome (with symptoms ranging from mild, e.g., agitation, tremor, to more serious, e.g., seizure, vomiting) by using more than one of these serotonergic drugs at a time.