Depression and anxiety are common psychiatric diagnoses with low quality of life and poor response to current drugs, driving research into alternative compounds. Psychedelic medicine, particularly low doses of LSD and psilocybin, has shown antidepressant effects in anecdotal reports and clinical studies. These compounds modulate mood through serotonergic, dopaminergic, and glutamatergic systems; LSD interacts with 5-HT1A, 5-HT2A, D2, and NMDA receptors. Randomized clinical studies have confirmed antidepressant and anxiolytic effects in humans. This chapter reviews psychedelic pharmacology, presents clinical evidence for therapeutic potential in mood disorders, and discusses future directions.
LSD alters the firing patterns of neurons in the reticular thalamus, which controls information flow to the cortex. In anesthetized mice, low doses of LSD decreased activity in half of these neurons, while higher doses increased activity in the other half. This was accompanied by increased firing in the mediodorsal thalamus, a relay station to the cortex. LSD only excited neurons in the prefrontal cortex at the highest dose. A dopamine D2 receptor blocker reversed some effects, suggesting LSD acts partly through this receptor. These changes in thalamocortical gating may explain how LSD alters consciousness in humans.