This past May (2019) the symposium “Psychedelic Therapy in Society: Exploring the Mechanisms of Action and Delivery of Care” was hosted by the International Forum on Consciousness at the BioPharmaceutical Technology Center in Madison, WI.
Having the good fortune to work across the street at Promega, I was able to attend this two-day conference and learn from leading researchers in psychedelics and about their use in therapy.
My interest in psychedelics is relatively new. I didn’t experiment with these substances during high school or college years. But in recent years, I’ve seen a close relative struggle with profound anxiety related to terminal disease, and another with substance abuse and depression. The lessons learned from each experience is that the battery of medicines used to treat such illness can result in additional problems for which there are currently not good medication options. And in some cases, traditional medications can cause further health problems.
Many are aware that psychedelic drugs such as psilocybins from “magic mushrooms” and lysergic acid diethylamide (LSD) are being studied for their use in treating post-traumatic stress disorder (PTSD), depression and anxiety. This blog examines some of the ongoing research in a lab that studies these drugs.
McCorvy Lab, Medical College of Wisconsin
In the lab of Dr. John McCorvy, PhD, researchers study cell signaling, in particular the effect of functional selectivity or signaling bias, wherein a drug for a particular receptor can exhibit a variety of signal transduction pathways. Dr. McCorvy’s talk at the 2019 International Forum on Consciousness was entitled “Profiling Psychedelics at the Serotonin Receptors”.
About Serotonin Receptors
Serotonin receptors (also called 5-HT or 5-hydroxytryptamine) are found in the central and peripheral nervous systems. These receptors modulate the release of neurotransmitters such as, serotonin, dopamine, epinephrine/norepinephrine and acetylcholine, as well as hormones like oxytocin, prolactin and cortisol and others. Serotonin receptors influence various biological and neurological processes such as aggression, anxiety, appetite, cognition, learning, memory, mood, sleep and thermoregulation.
Serotonin receptors are the target of a variety of pharmaceutical and recreational drugs, including antidepressants, antipsychotics, antimigraine drugs and hallucinogens.
McCorvy said of his research with LSD at the serotonin receptor, that it is important to note that psychedelics are not mirroring or mimicking serotonin. They show novel signaling compared to what is seen with serotonin.
G-Protein-Coupled Receptors: GPCRs
Serotonin or 5-HT receptors are G protein-coupled receptors (GPCRs). GPCRs are highly druggable targets, making up about 33% of all current pharmaceutical drug targets.
As McCorvy noted, we all take drugs that target GPCRs. Caffeine and alcohol, for instance, interface with GPCRs. These receptors are found in all cells. And of most interest here, signaling of psychedelics occurs via binding to GPCRs.
But signaling at GPCRs can have several different results. McCorvy and others describe signaling via GPCRs as resulting in either “the gas” or go signal, or a “brake” or inhibitory stop signal, known to be due to beta-arrestin. McCorvy refers to this as signaling bias.
Signaling Bias at GPCRs
The McCorvy lab is particularly interested in studying signaling bias of a ligand at a GPCR. They study binding of the psychedelic LSD to GPCRs by examining the structural fit of the drug in the receptor binding pocket, in order to learn how the ligand preferentially activates either G-proteins (the ‘go’ signal) or beta-arrestins (the ‘brake’). Their hope is to develop
“novel beta-arrestin biased ligands as potential antipsychotics and antidepressants, devoid of hallucinogenic potential.”
Here are some recent McCorvy publications:
- Wacker, D. et al. (2017) Crystal structure of an LSD-bound human serotonin receptor. Cell 168(3), 377–89.
- McCorvy, J.D. et al. (2018) Structure-inspired design of β-arrestin-biased ligands for aminergic GPCRs. Nat Chem Biol. 14(2), 126–34.
- McCorvy, J.D. et al. (2018) Structural Determinants of 5-HT2B Receptor Activation and Biased Agonism. Nat Struct Mol Biol. 25(9), 787–96.
The research being done by researchers like Dr. John McCorvy, as presented at the May 2019 “Psychedelic Therapy in Society: Exploring Mechanisms of Action and Delivery of Care” is, in a word, encouraging. It provides great hope knowing that researchers are studying hallucinogenic drugs to harness their power where other drugs have failed, or as auxillary treatments for so many cognition-related benefits. Today these drugs are accessible by some in studies of PTSD and depression. Potentially psychedelics or related compounds will, in the future, be accessible to anyone who needs them for use in anxiety, end of life issues, possibly even memory augmentation.
Videos of all of the speakers at the “Psychedelic Therapy in Society” forum are available here.
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