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.
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.
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.