Keywords
psilocybin
MDMA
ketamine
treatment-resistant depression
Abstract
Following decades of prohibition and scientific neglect, psychedelics are re-emerging as potential harbingers of a paradigm shift in modern psychiatry. This comprehensive review examines the historical roots of psychedelic-assisted psychotherapy (PAP), the pharmacological profiles of key molecules (Psilocybin, LSD, MDMA, Ketamine, DMT, Ibogaine, Mescaline), their standardized therapeutic protocols, clinical efficacy, and safety profiles. Despite belonging to diverse chemical classes, it is shown that most of these substances converge on common neurobiological pathways, such as inhibition of the Default Mode Network (DMN) and promotion of neuroplasticity, creating a "window of opportunity" for cognitive flexibility and therapeutic change. Clinical evidence indicates significant promise for MDMA in treating Post-Traumatic Stress Disorder (PTSD), psilocybin and ketamine for Treatment-Resistant Depression (TRD), and ibogaine for opioid use disorder. Therapeutic success is critically dependent on administering these potent molecules within a structured psychotherapeutic protocol (preparation, session, integration). While safety profiles differ significantly depending on the molecule (e.g., the cardiotoxicity of ibogaine, the abuse potential of ketamine), methodological limitations (e.g., challenges in blinding) and socio-political hurdles remain important challenges for the field. In conclusion, psychedelic-assisted psychotherapy holds the potential to revolutionize modern psychiatry by offering short-term, transformative interventions as an alternative to chronic symptom management. However, the safe and effective
realization of this potential depends on further rigorous scientific research, standardized training, and thoughtful regulation.
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