The stresses of the Coronavirus Disease of 2019 (COVID-19) pandemic highlighted the burden of psychiatric disorders within the pediatric population, revealing a pre-existing need for rapid-onset therapies that have since driven efforts to expand effective therapeutic interventions. In this narrative review, we utilized the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines to direct our report and study selection. We explored the current-state efficacy and therapeutic potential of ketamine and psilocybin in comparison to current treatment regimens for pediatric non-psychotic disorders, including Treatment-Resistant Depression (TRD), mood disorders like anxiety and bipolar disorder, and Post-Traumatic Stress Disorder (PTSD). We chose these pediatric disorders to eliminate concerns regarding reality orientation and the use of dissociative and/or psychedelic medicines in patients who are experiencing symptoms of psychosis. Also, we briefly discuss ketamine's more widely accepted utilization by medical providers as a pediatric anesthetic, and how this gives credence to further evaluation of ketamine's multifaceted indications in pediatric psychiatry. Recent studies have shed light on the involvement of glutamate pathways in the pathophysiology of TRD, mood disorders, and PTSD, and both ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, and psilocybin, a 5-hydroxytryptamine receptor 2A (5-HT2A) agonist, have emerged as promising options due to their ability to augment glutamate release. Ketamine's use for pediatric TRD demonstrated rapid-onset relief for signs and symptoms of depression in children and adolescents, and psilocybin also decreased symptoms in patients with longstanding or refractory depression. Ketamine has been well tolerated and exhibited symptom improvements for youth with mood disorders such as anxiety and bipolar depression, while psilocybin showed promise in fostering emotional processing. In youth suffering from PTSD, ketamine-assisted psychotherapy (KAP) brought about decreases in PTSD symptom severity, though outcomes varied across populations. Psilocybin enhanced neural plasticity, allowing patients to revisit and reframe memories under therapeutic guidance, especially for those with complex or treatment-resistant PTSD. Ethical considerations are involved in the use of dissociative and hallucinogenic therapies like ketamine and psilocybin in the pediatric population, and we explore some ethical issues regarding their use. Further research exploring specific brain locations and mechanisms of action underlying glutamate modulation by ketamine and psilocybin, and the subsequent rapid-acting relief of psychiatric symptoms offered by these substances, could pave the way for innovative treatments targeting pediatric mental health disorders.
