The possible place for psychedelics in pharmacotherapy of mental disorders.

The serotonergic theory of depression, which emerged in the 1960s, led to many antidepressant drugs that have helped millions, but recent studies question their effectiveness compared to placebo, noting slow onset and side effects. Research now focuses on rapid-acting antidepressants like ketamine, an NMDA receptor antagonist that quickly alleviates depression symptoms, though its effects last only about two weeks and it has severe side effects. A safer, more efficient approach may involve hallucinogenic 5-HT2A receptor agonists—psychedelics—which are being reconsidered in clinical practice after their 1970s stigma. This review examines current literature and recent clinical studies on the antidepressant potential of LSD, psilocybin, DMT, and 5-MeO-DMT, along with other applications.

Study at a glance

Abstract

Since its emergence in the 1960s, the serotonergic theory of depression bore fruit in the discovery of a plethora of antidepressant drugs affecting the lives of millions of patients. While crucial in the history of drug development, recent studies undermine the effectiveness of currently used antidepressant drugs in comparison to placebo, emphasizing the long time it takes to initiate the therapeutic response and numerous adverse effects. Thus, the scope of contemporary pharmacological research shifts from drugs affecting the serotonin system to rapid-acting antidepressant drugs. The prototypical representative of the aforementioned class is ketamine, an NMDA receptor antagonist capable of alleviating the symptoms of depression shortly after the drug administration. This discovery led to a paradigm shift, focusing on amino-acidic neurotransmitters and growth factors. Alas, the drug is not perfect, as its therapeutic effect diminishes circa 2 weeks after administration. Furthermore, it is not devoid of some severe side effects. However, there seems to be another, more efficient, and safer way to target the glutamatergic system. Hallucinogenic agonists of the 5-HT2A receptor, commonly known as psychedelics, are nowadays being reconsidered in clinical practice, shedding their infamous 1970s stigma. More and more clinical studies prove their clinical efficacy and rapid onset after a single administration while bearing fewer side effects. This review focuses on the current state-of-the-art literature and most recent clinical studies concerning the use of psychedelic drugs in the treatment of mental disorders. Specifically, the antidepressant potential of LSD, psilocybin, DMT, and 5-MeO-DMT will be discussed, together with a brief summary of other possible applications.