Psychedelic medicines for mood disorders: current evidence and clinical considerations

Serotonergic psychedelics, including psilocybin, ayahuasca, LSD, and MDMA, show promise for treating mood disorders and PTSD, often combined with psychotherapy. Psilocybin with psychological support has been effective for depression, including treatment-resistant cases, in randomized placebo-controlled trials. LSD has shown anxiolytic effects, and MDMA has Phase III evidence for PTSD. Microdosing has not been found to improve mood in a controlled trial. Challenges remain with blinding, small sample sizes, and lack of definitive Phase III studies (except MDMA for PTSD). Further research into novel formulations, pharmacogenomics, microbiome interactions, and inflammatory pathways is needed.

Study at a glance

Abstract

Purpose of review Despite advances in treatment modalities for mood disorders over recent decades, further therapeutic options are still required. Increased research is occurring, with the pursuit of psychedelic-based pharmacotherapies for a range of mood disorders and other conditions. Recent findings Serotonergic psychedelics have been found to modulate brain networks underlying various psychiatric disorders, as well promoting neurogenesis and neuroplasticity. Randomized placebo-controlled trials have found psilocybin with psychological support effective at treating depression, including treatment-resistant depression; with emergent research also signalling N , N -dimethyltryptamine/ayahuasca also as a potential option for the treatment of depression. Lysergic acid diethylamide has been found to have anxiolytic effects, whereas 3,4-methylenedioxymethamphetamine (MDMA) has been used effectively to treat post-traumatic stress disorder (PTSD), with Phase III clinical trial evidence. Microdosing of psychedelics is a growing phenomenon that has shown benefits in some preclinical data; however, a recent self-directed controlled trial reported no evidence of improved mood. Summary Current research with medicinal psychedelics, usually as an adjunct to psychotherapy, has shown encouraging results in treating mood disorders. However, there are challenges regarding blinding and sample sizes remain small, and there have been no definitive Phase III studies (aside from MDMA for PTSD). Further work exploring novel formulations, interface with pharmacogenomics and the microbiome, and inflammatory pathways can be advised.