Molecular Neuropharmacology of LSD

-Table of contents-

Introduction (0:11)

Effects of LSD (1:23)

Target Receptor (2:13)

Pathways (3:15)
G-protein pathway (5:03)
β-arrestin pathway (6:46)

Functional Selectivity of LSD (9:28)

Structure of an LSD-Bound Receptor (10:51)

Methods (11:55)

Image of LSD bound to the receptor (13:44)

Intermolecular forces between LSD and the receptor (14:40)

Serotonin Receptor "Lid" (15:53)

Structure-Function Relationships (17:30)

Applications (23:48)
Cluster Headaches (25:13)

Conclusions (28:40)

Further Research (30:17)

CORRECTION: The slide at 5:00 shows the mitochondria involved in cytosolic calcium increase; this should be the endoplasmic reticulum. The ER stores calcium ions, not the mitochondria.

-Background-

This was my senior seminar presentation for my undergraduate degree in chemistry. I recorded it as practice and then figured I might as well upload it. Send me a message if you want the pdf's of any of my references.

Also, constructive criticism is always appreciated. I am by no means a biochemist, my degree was in chemistry. However, keep in mind that this is only intended to be a general overview of how LSD works at the molecular level. I also speculate at certain points, but I make it clear when I am doing so (particularly the part about why LSD alleviates cluster headaches). Feel free to correct me in the comments if there are any concerns about my conclusions.

I do not condone the use of illegal hallucinogenic drugs but I do encourage their study and research, because psychedelic drugs are a fascinating window into the inner-workings of perception and consciousness. The taboo surrounding hallucinogens needs to be lifted in order for further research to be done easily and effectively. Areas of neurobiology and pharmacology would benefit greatly from further elucidation of LSD's effects on the brain.

The mitochondria illustration on the G-protein pathway slide (5:03) comes from Kevin Williams of The Pen Rules. Find his work here http://www.penrules.com/portfolio/illustration/mitochondria.html.
-References-

5:03 and thumbnail - "Mitochondria" ©KWR http://penrules.com

“Crystal structure of an LSD-bound human serotonin receptor”
Wacker, D. et al. Cell 2017, 168, 377

“The Expanded Biology of Serotonin”
Berger, M.; Gray, A. J.; Roth, L. B.; Annu. Rev. Med. 2009, 60, 355

“Structural Features for Functional Selectivity at Serotonin Receptors”
Wacker, D.; Wang, C.; Science 2013, 340, 615

“Response of cluster headache to psilocybin and LSD”
Sewell, A. Neurology 2006, 66, 1920

“Classic hallucinogens in the treatment of addictions”
Bogenschutz, P. M.; Johnson, W. M.; Prog Neuropsychopharmacol Biol Psychiatry 2016, 64, 250

“β-Arrestins and Cell Signaling”
DeWire, M. S.; Ahn, S.; Annu. Rev. Physiol. 2007, 69, 483

“Neural correlates of the LSD experience revealed by multimodal neuroimaging”
Carhart-Harris, L. R. et al.; PNAS 2016, 113, 4853

“Emetic Activity of Reduced Lysergamides”
Johnson N. F. et al.; J. Med. Chem. 1973, 16, 532

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