Handbook of experimental pharmacology
January 1, 2018
Clinton E. Canal
48 citations
Recent small but well-controlled clinical trials indicate that serotonergic psychedelics such as psilocybin and LSD show promise for treating psychiatric disorders like treatment-resistant depression. Neuroimaging studies reveal dynamic effects on brain activity and connectivity across neural systems, leading to testable hypotheses about mechanisms underlying psychedelic effects and therapeutic benefits. Despite evidence that brain serotonin 5-HT2A receptors are central to these effects, lingering questions about molecular neuropharmacology remain. This chapter discusses these questions in the context of preclinical experimental approaches for studying mechanisms of action of classic and new serotonergic psychedelics.
Handbook of experimental pharmacology
January 1, 2018
Michael Freissmuth, Thomas Stockner, Sonja Sucic
44 citations
Mutations in solute carrier 6 (SLC6) family transporters cause misfolding and lead to diseases such as infantile dystonia (from dopamine transporter mutations), mental retardation (from creatine transporter mutations), and hyperekplexia (from glycine transporter mutations). Compounds that correct these folding defects, known as pharmacochaperones, were first discovered in serotonin transporter mutants, where ibogaine and its metabolite noribogaine were found to rescue folding-deficient mutants. Additional compounds have since been identified that restore function in dopamine transporter mutants. These agents not only offer therapeutic potential for affected children but also serve as tools to study transporter folding, potentially enabling the rational design of pharmacochaperones.
Handbook of experimental pharmacology
January 1, 2019
James E Barrett, Clive Page, Martin C Michel
4 citations
The 100th anniversary of the Handbook of Experimental Pharmacology coincides with the founding of experimental pharmacology itself, both rooted in Germany. Arthur Heffter founded the handbook in 1919 and also isolated mescaline as the active psychedelic component from the peyote cactus. The discipline was built on the systematic work of Rudolf Buchheim and his student Oswald Schmiedeberg. Despite early resistance, their persistence established pharmacology as a vital medical science that spread globally, leading to current understanding of drug action. The article recounts these beginnings and the early international spread of pharmacology, setting the stage for documenting contributions over the past century and anticipating future developments.
Handbook of experimental pharmacology
January 1, 2019
Nuri B Farber
NMDA antagonists, particularly ketamine, show promise for the 15-30% of patients with major depressive disorder who do not respond to monoaminergic antidepressants. A brief low-dose infusion of ketamine rapidly improves depressive symptoms for several days, though it produces psychotomimetic and cognitive side effects. Multiple infusions (e.g., 2-3 times per week for several weeks) provide relief, but symptoms return when treatment stops. A 96-hour higher-dose infusion with add-on clonidine mitigated side effects and resulted in about 40% of subjects still having a good response 8 weeks later, though this was a pilot study requiring confirmation. Nitrous oxide also showed positive results.
Handbook of experimental pharmacology
January 1, 2018
Torsten Passie, Simon D Brandt
Scientists and therapists have a long tradition of self-experimenting with psychoactive substances, dating back to the mid-eighteenth century. Substances producing complex effects—such as altered space/time experience, ego dissolution, and heightened insights (e.g., hallucinogens, entactogens)—have been the focus of the vast majority of these self-experiments, while those producing simple effects like euphoria or emotional blunting (e.g., cocaine, opioids) are much rarer. Self-experimenters fall into two types: exploratory, seeking expanded awareness and insight, and compensatory, aiming to cope with psychiatric symptoms or personality deficits. Scientific limitations are clear compared to double-blind, randomized, placebo-controlled trials, and adverse effects include loss of objectivity, increased risk of addiction, isolation, and problematic group dynamics.
Handbook of experimental pharmacology
January 1, 2018
Jason Wallach, Simon D Brandt
Phencyclidine (PCP), discovered in 1956, became the model dissociative drug and later a street drug, with about 14 analogs identified as such between the 1960s and 1990s. In the 2000s, the Internet enabled communities to explore new PCP analogs, some previously unknown in scientific literature. This chapter provides an introductory overview of recent PCP-derived new psychoactive substances (NPS) and their pharmacology. Because N-methyl-D-aspartate receptor (NMDAR) antagonism underlies the subjective effects of many dissociatives, data from other analogs not currently identified as NPS are also included.
Handbook of experimental pharmacology
January 1, 2018
Jason Wallach, Simon D Brandt
Beyond the well-studied dissociative drugs phencyclidine (PCP) and ketamine, hundreds of related compounds have been developed since the late 1950s, some through legitimate research and others originating from clandestine chemists. The internet in the 1990s enabled global collaboration on designing novel dissociative compounds with goals like improved duration, analgesia, and reduced toxicity. These creations, marketed as "research chemicals" or "legal highs," have entered wider distribution and sometimes reached academic labs for potential clinical applications. Two structurally distinct classes of dissociative new psychoactive substances (NPS) are the 1,2-diarylethylamines (e.g., diphenidine, fluorolintane) and β-keto-arylcyclohexylamines (e.g., methoxetamine, deschloroketamine). This chapter introduces these emerging NPS and their known pharmacology.