Dr. Charles Nichols Presents Work at August Dean's Seminar
Dr. Charles Nichols presented for the School of Medicine Dean's Seminar in August. The title of the presentation was “Psychedelics and their therapeutic potential to treat psychiatric and inflammatory disease.”
The presentation started off with a brief background on serotonin, psychedelics, the discovery of lysergic acid diethylamide (LSD), and current clinical trials examining the therapeutic potential of certain psychedelics for the treatment of depression. He then discussed the target of psychedelics, the serotonin 5-HT2A receptor, and its expression in human and rodent brain. However, the majority of cells activated by psychedelics do not express the target receptor, and development of a new flow cytometry methodology was needed in his lab to purify activated cells by FACS for characterization. The activated cells comprise 5-10% of cells within the cortex and are a mixture of excitatory and inhibitory neurons and glia cells. These cells also express higher levels of mRNA for the 5-HT2A receptor. A model was presented suggesting that psychedelics produce desynchrony of local cortical circuits by disrupting interneuron and excitatory neuron function.
Next, data was presented on two rat models of depression where a single treatment with the psychedelic drug psilocybin had long-lasting (>4 weeks) antidepressant-like effects. One was using a genetic model of depression, and the other an adolescent stress-based model. These are the first animal models that recapitulate the therapeutic effects observed in human clinical trials with psilocybin where a single administration can produce an antidepressant effect for 6 months or more.
The seminar then focused on the potent anti-inflammatory effects of the psychedelics in two models of inflammatory disease. The first model used a high-fat fed ApoE knockout mouse to show that the selective 5-HT2A receptor agonist, DOI, prevented high-fat-induced vascular inflammation and increased cholesterol levels, and normalized glucose utilization. In a rat model of allergic asthma, DOI potently prevented allergen-induced pulmonary inflammation, mucus production, and fibrosis. Normal breathing was also restored. Dr. Nichols then presented a model suggesting that 5-HT2A receptor activation on immune cells, including macrophages and T-cells, suppressed proinflammatory cytokine expression (e.g. GM-CSF, IL-5, IL-13) and recruitment of immune cells to the lung. Notably, the anti-inflammatory effects are very potent and far below doses that would produce any behavioral effects. To help explain the variation in the anti-inflammatory effects across the different psychedelics, a structure-activity analysis was performed. No correlation was found between canonical signaling (calcium mobilization) and beta-arrestin signaling in cell culture experiments, indicating that an unknown pathway mediated the anti-inflammatory effects downstream from the receptor. Lastly, drug discovery efforts from the Nichols lab were presented based on the structure-function analysis; these efforts have led to a drug that has reduced behavioral potency, while maintaining anti-inflammatory potency. This drug is being developed for the clinic in partnership with Eleusis Therapeutics.
Check the website for upcoming seminars and topics and learning objectives.