An increasing number of clinicians and researchers have become interested in the potential of psychedelic drugs for the treatment of mental health disorders, including depression, anxiety, posttraumatic stress disorder, eating disorders, and addictions.1,2
Currently, most psychedelic compounds are illegal under federal law. They were placed on the most restrictive class of drugs, Schedule I, in the 1970s as part of the “war on drugs,” meaning that they were considered to have high potential for abuse with no accepted medical use.2 However, the ever-growing global mental health crisis, coupled with the shortage of effective therapeutic strategies, has given rise to a reconsideration of the therapeutic potential of these compounds in recent years.
Classic psychedelics have rapid and profound effects on perception, cognition, and consciousness that result in part from their actions at serotonin 5-HT2A receptors.1 This can result in heightened awareness of one’s internal states and feelings of connectedness that last for several hours. Psychedelics can also induce challenging and difficult experiences and need to be used carefully and in the presence of facilitators or therapists who are trained to work with people experiencing nonordinary states of consciousness. But these compounds offer unique therapeutic possibilities in their ability to promote openness to engage with things that are often avoided and suppressed. In fact, before they were determined to be Schedule I drugs, psychedelics were used therapeutically to help patients open up and identify and discuss emotionally triggering material in psychotherapy.2
The study by Raison et al provides an excellent example of the promise of this new approach using psilocybin therapy for patients with major depressive disorder.3 Although the trial was relatively small, it demonstrated that a single dose of psilocybin in the context of a 6-week period that included active psychotherapy resulted in a rapid, robust, and sustained reduction in depressive symptoms.
Psilocybin is a naturally occurring compound belonging to a class of compounds known as tryptamines, similar to lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), and mescaline. Understanding its therapeutic efficacy requires an appreciation of the context in which it is used, and not just its pharmacological profile or biological mechanism of action. The psychotherapy that occurs with the psychedelic medication is a critical component of this approach.4
When a psychedelic is taken with the proper preparation, intention, facilitation, and therapeutic environment, the patient can use the experience to gain new insights that can catalyze healing and recovery. The psychedelic allows feelings such as self-compassion, forgiveness, understanding, and self-acceptance to surface that can be powerful antidotes to shame, guilt, anger, isolation, disconnection, or other negative emotions that patients find difficult to discuss in therapy and that do not seem to be mitigated by traditional antidepressants.1 Furthermore, a sense of boundlessness or ego dissolution may be felt as a mystical or spiritual experience, helping people find meaning, perspective, and connection with others and the world. These experiences have been associated with symptom reduction and may represent an important mechanism of action.4
The psychedelic approach Is radically different from traditional approaches that seek to suppress depressive symptoms by targeting presumptive underlying pathophysiology or biological dysregulation. Dysphoria, irritability, anxiety, and sleep problems can respond to classic antidepressants and help patients manage symptoms and improve functioning. But the benefits of psychopharmacotherapy and psychotherapy are often small and incremental, and true remission is generally not obtained for months or years.5,6 Furthermore, psychotropic medications require chronic use, can be difficult to discontinue, and cause a variety of adverse effects, including weight gain, sexual dysfunction, and feelings of sedation or emotional numbing. Symptoms can reappear, even in stabilized patients, when the medications are discontinued, creating a heartbreaking dilemma for patients.
In contrast, psychedelic therapies address the cause of symptoms rather than merely suppressing them. Here, a medication is administered acutely for only a few sessions—sometimes even a single medication session—in the context of a therapeutic framework that provides the opportunity to integrate and synthesize the revelations that occur during the medication session. The acute pharmacological effects of the medicine, including potential adverse effects, resolve quickly and the safety profile is good. Clinically significant response rates are robust and can be maintained for weeks or months.
However, it is clear that despite the enthusiasm, psychedelic therapies do not represent a panacea for every patient. There are no silver bullets in psychiatry. In the study by Raison et al, similar to all other reports, there are a significant number of patients who did not respond to therapy.3,7 It is important to analyze and understand adverse outcomes in psychedelic trials and conduct longitudinal studies to determine how sustained the effects will be and what may initiate a recrudescence of symptoms. Future studies will help identify who is most likely to benefit from psychedelics, whether booster or repeated treatment is safe and beneficial, and what the optimal dose and therapeutic frameworks are.
Nonetheless, psychedelic therapy represents a novel way of approaching mental health treatment that may benefit many people. It will also bring new knowledge regarding molecular bases of mental illness and how they relate to consciousness. Inquiries into the mechanisms of action of psychedelics will open new windows of understanding regarding neuronal plasticity and brain functioning.1
Psychedelic therapies necessitate a rethinking of mental health care delivery in which medication is integrally paired with psychotherapy and delivered in a novel setting and framework. This will require an investment of time and resources, and it is not likely that these approaches will be broadly available to psychiatric patients except in clinical trials for the next few years. However, if the gains are strong and enduring and patients report symptom reduction and existential and spiritual transformation, the investment may be warranted. Meanwhile, clinicians should be knowledgeable about these new treatments as public interest and the empirical base grow.
The social, economic, and public health impacts of untreated mental disorders demand solutions. If psychedelic therapies do prove to have enduring effects after just a single or a few administrations in the context of a few sessions for preparation and integration, they have the potential to offer not just a new approach to mental health care, but an entirely new paradigm of care.
Article Information
Corresponding Author: Rachel Yehuda, PhD, James J. Peters VA Medical Center, 130 W Kingsbridge Rd, 526 OOMH, Bronx, NY 10468 (rachel.yehuda@va.gov).
Published Online: August 31, 2023. doi:10.1001/jama.2023.12900
Conflict of Interest Disclosures: Dr Yehuda reported receiving nonfinancial support from MAPS PBC (Multidisciplinary Association for Psychedelic Studies Public Benefit); grants from COMPASS Pathways, Steven and Alexandra Cohen Foundation, and The Bob and Renee Parsons Foundation; and honoraria for talks at the National Institute for the Clinical Application of Behavioral Medicine, Danish Psychiatric Society, Boston Trauma Conference, and UPenn Nursing School outside the submitted work and reported consulting for TeraMind, Wesana, and the Noetic Fund. Dr. Lehrner is an investigator on a trial sponsored by MAPS PBC financially supported by the Steven and Alexandra Cohen Foundation and a trial sponsored by COMPASS Pathways and reported receiving honoraria for talks at Psychedelic Science 2023 and Philadelic 2023.
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