Publication date: Jun 24, 2025

The use of drugs with psychedelic and dissociative effects for the treatment of psychiatric illnesses has become increasingly popular in recent years. However, few trials have been conducted to determine the efficacy of these agents in the specific setting of treatment-resistant major depressive disorder (MDD) in older adults. In this paper, we review notable aspects of treatment-resistant MDD in older adults, review classical and nonclassical psychedelic agents and dissociative agents presently being trialed mostly in younger populations for the treatment of depression, and review what is known about trialing these agents in older adults with treatment-resistant MDD. Given the limitations to extant standard treatment and the potential risks associated with first-line pharmacological agents such as selective serotonin reuptake inhibitors (SSRIs) in this population, psychedelic-assisted psychotherapy may offer an important alternative for managing treatment-resistant MDD in older adults. This subset of patients is understudied and stands to benefit significantly from improved treatment regimens. The limited research available that details psychedelic-assisted treatment in this specific group is promising. Here we focus on reviewing those agents with the most controlled data available, beginning with the dissociative anesthetic ketamine/esketamine, and the hallucinogenic agent psilocybin, and concluding with a brief review of related substances including lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), ayahuasca, ibogaine, 3,4-methylenedioxymethamphetamine (MDMA), and mescaline. Treatment-resistant MDD is highly prevalent among older adults, and while preliminary findings seem promising regarding the safety and tolerability of psychedelics, concerns remain owing to insufficient data, and therefore further research is crucial to establish the safety, efficacy, and applications of psychedelic therapy in this population.

Semantics