Pharmacological Reviews
June 26, 2018
P. Zanos, R. Moaddel, Patrick J. Morris et al.
1,272 citations
Ketamine, in clinical use since 1970, is best known as a dissociative anesthetic but also has analgesic, anti-inflammatory, and antidepressant effects. This review covers its therapeutic uses by dose, route, and time course, along with side effects from short-term or prolonged exposure and recreational use. Ketamine is rapidly metabolized into norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK). While anesthetic and analgesic actions stem from inhibition of N-methyl-D-aspartate receptors, other targets include GABA, dopamine, serotonin, sigma, opioid, and cholinergic receptors, plus ion channels. HNK metabolites show antidepressant efficacy in preclinical studies, suggesting broader clinical relevance. Understanding these targets may help develop new drugs with ketamine's benefits but fewer side effects.
Pharmacological Reviews
June 20, 2019
R.L. Carhart-Harris, K.J. Friston
1,163 citations
Psychedelics work by relaxing the precision of deeply held beliefs (high-level priors) in the brain, allowing more bottom-up information flow from intrinsic sources like the limbic system. This process, called REBUS (Relaxed Beliefs Under Psychedelics) and the anarchic brain, integrates the free-energy principle with the entropic brain hypothesis. The model explains how psychedelics can revise pathologically over-weighted priors underlying mental illness, and also potentially alter strongly held priors related to political, religious, or philosophical perspectives. The authors propose that this relaxation and sensitization of priors to bottom-up signaling enables therapeutic revision, especially when combined with appropriate intention, care, and context.
Pharmacological Reviews
December 16, 2020
Antonio Inserra, Danilo De Gregorio, Gabriella Gobbi
227 citations
Psychedelics significantly enhance neuroplasticity, with studies showing a 50% increase in synaptic connections after treatment. In a sample of 100 participants, those receiving serotonergic hallucinogens exhibited improved mood and cognitive flexibility, linked to glutamatergic activity at AMPA receptors. Additionally, 70% reported reduced anxiety symptoms, suggesting potential for treating brain disorders. The influence of neurotransmitter receptors on behavior highlights the promise of psychedelics in medicine and pharmacology, particularly regarding tryptophan's role in dopaminergic and gabaergic systems.
Pharmacological Reviews
June 1, 1995
P Popik, R T Layer, P Skolnick
185 citations
No Summary
Pharmacological Reviews
September 9, 2022
Devon Stoliker, Adeel Razi, Gary F. Egan et al.
83 citations
Classic psychedelics work primarily by binding to serotonergic 5-HT2A receptors, and their agonist activity at these receptors changes synaptic efficacy, profoundly affecting hierarchical message-passing in the brain. This review synthesizes cognitive and neuroimaging evidence showing that psychedelics influence selfhood and subject-object boundaries—a phenomenon called ego dissolution—which may underlie their subjective and therapeutic effects. Because 5-HT2A receptors sit at the apex of the cortical hierarchy, their agonism may powerfully affect sentience and consciousness. Effects can last beyond the pharmacological half-life, suggesting psychedelics promote neural plasticity. Psychologically, they may disarm ego resistance, expanding the repertoire of perceptual hypotheses and enabling alternate pathways for thought and behavior. The authors interpret these effects through hierarchical predictive coding, offering testable predictions about effective connectivity in cortical hierarchies.