Psychedelic pharmacology
Summary
Binding affinities for DMT, LSD, and psilocybin, given by a meta-analysis performed by Shinozuka2023.
Subtopics
- Psychedelics act on the 5-HT2a receptor
- psychedelics are trkb positive allosteric modulators
- Psychedelics increase striatal dopamine
- Psychedelics and NMDA antagonists have downstream effects on serotonin
Notes
Psychedelics bind targets including alpha-adrenergic receptors & most serotonin receptors, while some bind monoamine trace amine, and sigma receptors Nichols2016
Preclinical work is calling into question the role of the thalamus in the action of psychedelics Puig2003
- 5-HT2AR expression is low in the thalamus (Beliveau2017)
Possible inhibitory role of 5-HT1a in action of psychedelics Pokorny2016 Strassman1995
Theorized that the hallucinogenic effects of psychedelics arise from biased agonism at 5-HT2a (Pottie2020)
- LSD does not induce head twitch response in mice without the gene encoding beta-arrestin (Rodriguez2021)
- Contrasting evidence on biased agonism
- LSD preferentially recruits beta-arrestin2 (Schmitz2023)
- No significant differences between beta-arrestin2 recruitment and G-protein signaling (as measured by calcium mobilisation nad inositol triphosphate formation) by Shinozuka2023
- Contrasting evidence on biased agonism
- psilocybin is a “balanced” agonist with respect to beta-arrestin
- 5-HT2AR agonism induces asynchronous mode of glutamate release Aghajanian1999 and spike-to-field decoherence Celada2008. This irregularity accounts for Psychedelics decrease oscillatory power across frequency bands at the population level.
Psychedelics decrease oscillatory power across frequency bands
Because 5-HT2a receptors are densely expressed in the cortex, 5-HT2a agonism results in dysregulation of population-level oscillatory rhythms including alpha and beta frequency bands Muthukumaraswamy2013.
- LSD, psilocybin, and ayahuasca induce decreases in -power (Muthukumaraswamy2013, Kometer2013, Valle2016, Kometer2015)
- Closely related to subjective effects (Muthukumaraswamy2013, Carhart-Harris2016)
Celada2008 showed DOI markedly reduces amplitude of low frequency oscillations in the mPFC, thereby disrupting cortical activity. Furthermore, the authors found that DOI desynchronized Pyramidal neurons discharge from active phases of slow oscillations. (src: Nichols2016)