A narrative review examined the neurobiological mechanisms that may explain the rapid antidepressant effects of serotonergic psychedelics such as psilocybin, LSD, and ayahuasca. The drugs act as agonists or partial agonists at serotonin 5HT2A receptors, and their rapid effects may involve downregulation of these receptors. They also influence brain-derived neurotrophic factor and immune responses. Neuroimaging studies suggest that psychedelics may disrupt the default mode network, a brain system involved in self-referential thinking that is overactive in major depressive disorder. The review concludes that multiple competing theories are being investigated and more research is needed to identify the most robust evidence.
A critical appraisal of clinical trials on serotonergic psychedelics for major depressive disorder and end-of-life distress finds that current evidence is low-level due to methodological limitations. Small randomized trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy to an active comparator, with similar preliminary positive effects for single-dose ayahuasca in treatment-resistant depression and lysergic acid diethylamide for end-of-life distress. Adverse events were mild and transient. However, small homogenous samples, expectancy bias, functional unblinding, and lack of standardized psychotherapy limit all studies. Psychedelics should remain experimental interventions used within clinical trials.
A virtual Sahaj Samadhi Meditation program did not significantly outperform an active control (Health Enhancement Program) in reducing depressive symptoms among people with chronic pain and moderate depression. Within the meditation group, depressive symptoms decreased by an average of 3.97 points on the PHQ-9 at 12 weeks and 4.96 points at 24 weeks, both exceeding the minimal clinically important difference, while the control group showed no significant change. The trial enrolled 108 participants, with 89 randomized. The findings suggest potential benefits of the meditation program, but larger trials under non-pandemic conditions are needed to confirm effectiveness.