The potential use of psychedelics in the treatment of various mental health conditions has made these drugs a hot area of scientific research, as well as growing public interest. A variant of ketamine called esketamine is already FDA approved and utilized for treatment-resistant depression, and the FDA has designated formulations of psilocybin and MDMA for the treatment of depression and PTSD, respectively, as “breakthrough therapies,” a process designed to expedite their development and review. NIDA is actively funding research on these compounds—NIDA and the National Institute on Mental Health are the largest funders of psychedelic research at NIH—as they represent a potential paradigm shift in the way we address substance use disorders too. Yet there is much we still do not know about these drugs, the way they work, and how to administer them, and there is danger of the hype getting out ahead of the science.

The promise of psychedelic compounds likely centers on their ability to promote rapid neural rewiring.¹ Recent preclinical studies have suggested that the “neuroplastogen” properties of psilocybin, for example, may have to do with its ability to bind to 5HT_2A (serotonin) receptors inside neurons, something that serotonin itself cannot do.² That rewiring may explain these compounds’ relatively long-lasting effects, even with just one or a few administrations. Some trials have found effects lasting weeks³, but smaller studies (and anecdotes) are suggestive of much longer durations. What is needed is sound scientific research including clinical trials that can substantiate therapeutic efficacy, duration, and safety in large numbers of participants.

As part of a research study, psychedelics are administered by clinicians within highly controlled settings. This is important not only for safety reasons but because contextual factors and expectations play a crucial role in their effectiveness.⁴ Whether a patient has a positive or negative experience depends to a significant extent upon their mindset going into the experience and whether the setting is one in which they feel secure. This raises an important question—the extent (if any) to which the clinician’s time and attention and/or therapeutic approach play a role in psychedelics’ therapeutic efficacy—where much more research is needed. The extent to which psychotherapy is necessary in conjunction with psychedelics and which methods work best is an open question.