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
Psychedelic compounds such as ketamine, MDMA, psilocybin, and LSD show promise as novel psychiatric treatments. Their therapeutic effects are thought to involve the serotonergic system (via 5-HT2A and 5-HT1A receptors) and the glutamatergic system (via NMDA and AMPA receptors). Key mechanisms include neuroplasticity through mTOR, BDNF, and early growth response pathways; immunomodulation via the HPA axis, NF-κB, and cytokines; and modulation of multiple neurotransmitter systems. While preliminary results are promising, larger studies are needed to confirm findings and address concerns about neurobiological changes, dependence, and immunosuppression.
Pharmacological Reviews
June 1, 1995
P Popik, R T Layer, P Skolnick
185 citations
No Summary
Pharmacological Reviews
June 1, 2011
Christopher W Cunningham, Richard B Rothman, Thomas E Prisinzano
109 citations
Salvinorin A, the psychoactive compound in the Salvia divinorum plant, activates kappa-opioid receptors (KOP) to produce its intense hallucinogenic effects, making it the first known non-nitrogenous opioid receptor agonist. Unlike classic hallucinogens such as LSD and mescaline, its effects do not involve the 5-HT(2A) receptor. Research into its structure has yielded receptor probes and tools to study its psychological effects. Salvinorin A shows therapeutic potential for treating pain, mood disorders, substance abuse, and gastrointestinal disturbances, and suggests that nonalkaloid compounds can serve as scaffolds for developing drugs targeting aminergic G-protein coupled receptors.
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.
Pharmacological Reviews
April 23, 2025
Benjamin R. Cummins, Gerald Billac, David E Nichols et al.
62 citations
Serotonin 5-HT2A receptors are found throughout the body and are most dense in brain cortical layer V. They are involved in normal physiology and neuropsychiatric diseases like schizophrenia. Atypical antipsychotics block these receptors, while psychedelic drugs such as psilocybin, dimethyltryptamine, and lysergic acid diethylamide activate them to produce lasting therapeutic effects in clinical trials for major depression and substance use disorders. The three main agonist scaffolds—tryptamines, ergolines, and phenylalkylamines—engage different amino acid residues in the receptor binding pocket, leading to functionally selective outcomes. Understanding these ligand-receptor interactions guides future drug discovery for optimized therapeutics.
Pharmacological Reviews
October 1, 2022
Anna U. Odland, Jesper L. Kristensen, Jesper T. Andreasen
23 citations
Psychedelic-assisted psychotherapy shows promise for treating mental health disorders, and research on 5-HT2AR agonist psychedelics has grown rapidly. In humans, these compounds alter consciousness and affect emotional, social, and self-referential information processing. The translational value of animal behavior studies is debated. In rodents, acute psychedelic treatment produces head twitches, disrupts sensorimotor gating, stimulates motor activity, inhibits exploration, and shows anxiolytic-like effects while inhibiting repetitive behavior. Effects on depression-like behaviors, cognitive function, and social interaction are discrepant. Lasting effects are sensitive to experimental protocols. Improving animal studies by assessing lasting effects, publishing negative findings, and relating behaviors to neuroplastic changes will enhance translational value.
Pharmacological Reviews
May 1, 2025
Merel Dagher, Catherine M Cahill, Anne M. Andrews
10 citations
Antidepressant use during pregnancy has limited adverse effects on fetal health and child development, particularly for SSRIs and SNRIs, while untreated maternal depression carries well-researched harms. Pregnancy alters drug disposition and metabolism, affecting both mother and fetus. The FDA advises caution due to a lack of safety studies, as pregnant individuals are often excluded from clinical trials. The review asserts that individuals should be counseled on risks and benefits of treatment, as withholding treatment has possible negative outcomes. Newer therapeutics like ketamine and κ-opioid receptor antagonists warrant further investigation for use during pregnancy.