Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Licit use of illicit drugs for treating depression: the pill and the process
Alejandro Torrado Pacheco, Bita Moghaddam
Alejandro Torrado Pacheco, Bita Moghaddam
Published June 17, 2024
Citation Information: J Clin Invest. 2024;134(12):e180217. https://doi.org/10.1172/JCI180217.
View: Text | PDF
Review

Licit use of illicit drugs for treating depression: the pill and the process

  • Text
  • PDF
Abstract

Psilocybin, MDMA, and ketamine have emerged as potentially effective treatments for rapid amelioration of the symptoms of mood and related psychiatric disorders. All clinical data collected so far with regard to psilocybin or MDMA, which have reported positive outcomes for treating depression, anxiety, posttraumatic stress disorder, and drug or alcohol use disorders, have involved clinician-assisted intervention. While the case for ketamine is assumed to be different, the first report of the successful use of ketamine in psychiatry for treating depression was in combination with psychotherapy, and an emerging literature suggests that the subjective state of individual experiences with ketamine predicts clinical outcome. This Review will focus on (a) a brief review of the literature, showing that the context or the process of drug administration has been an integrative component of published work; (b) the importance of clinical trials to compare the efficacy of the drug (“pill”) as a stand-alone treatment versus drug in combination with clinician-assisted psychological support (“process”); and (c) suggestions for future approaches in animal models that take into account the role of systems and behavioral neuroscience in explaining a potential role for context, experience, and expectancy in drug effect.

Authors

Alejandro Torrado Pacheco, Bita Moghaddam

×

Figure 1

Two potential paths for the mechanism of action of rapid-acting psychotherapeutics: the pill and the process.

Options: View larger image (or click on image) Download as PowerPoint
Two potential paths for the mechanism of action of rapid-acting psychoth...
(A) In the “pill” model, ketamine, MDMA, and psilocybin produce their clinical efficacy by acting purely as pharmacological agents. In this view, their actions on specific receptors and individual neurons influence isolated brain networks that directly lead to behavioral changes and alleviation of symptoms. (B) In “the pill and the process” model, an interaction between the brain state and drug effect leads to engagement of new brain networks that lead to alleviation of symptoms in a context-dependent manner. Thus, the receptor activity and other neurophysiological effects of these drugs produce an interactive network state that changes the ongoing and future computation of context, memory, or subjective states (such as states brought upon by concurrent psychological intervention). This interactive state will then result in a different mode of network engagement than the drug alone. In this model, positive effect on symptoms of psychiatric illness will, therefore, depend on the effectiveness of the coinciding intervention.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts