Therapeutic Potential of Natural Psychoactive Drugs for Central Nervous System Disorders: A Perspective from Polypharmacology

Abstract

: In drug development, the creation of highly selective ligands has been unsuccessful for the treatment of central nervous system disorders. Multi-target ligands, from the polypharmacology paradigm, are being proposed as treatments for these complex disorders, since they offer enhanced efficacy and a strong safety profile. Natural products are the best examples of multi-target compounds, so they are of high interest within this paradigm. Additionally, recent research on psychoactive drugs of natural origin, such as ayahuasca and cannabis, has demonstrated promising therapeutic potential for the treatment of some psychiatric and neurological disorders. In this text, we describe how research on psychoactive drugs can be effectively combined with the polypharmacology paradigm, providing ayahuasca and cannabis research as examples. The advantages and disadvantages are also discussed.

‘Cannabis’ ontologies I: Conceptual issues with Cannabis and cannabinoids terminology

“…Notably, since 1961, the chemical composition of C. sativa oleoresin has been figured out: it was found to be exceptionally diverse and variable (Baram et al., 2019), with components interacting and interplaying above and beyond their individual pharmacological activity (Ben-Shabat et al., 1998; Rather et al., 2013; Russo, 2011). This dramatically influences the oleoresin’s overall therapeutic effects far beyond that of dronabinol, dependent on ‘complex interaction between molecules and multiple targets’ (Atakan, 2012; Baker et al., 2000; Baram et al., 2019; Russo, 2011) – a phenomenon which is typical of herbal medicines (Rather et al., 2013), called ‘cooperative effect’ or ‘entourage effect’ (Ben-Shabat et al., 1998; Oña and Bouso, 2019). This entourage effect results in C. sativa drugs binding to different neuronal targets, an effect in turn called ‘polypharmacology’ (Gertsch, 2011; Oña and Bouso, 2019).…”

“…This dramatically influences the oleoresin’s overall therapeutic effects far beyond that of dronabinol, dependent on ‘complex interaction between molecules and multiple targets’ (Atakan, 2012; Baker et al., 2000; Baram et al., 2019; Russo, 2011) – a phenomenon which is typical of herbal medicines (Rather et al., 2013), called ‘cooperative effect’ or ‘entourage effect’ (Ben-Shabat et al., 1998; Oña and Bouso, 2019). This entourage effect results in C. sativa drugs binding to different neuronal targets, an effect in turn called ‘polypharmacology’ (Gertsch, 2011; Oña and Bouso, 2019).…”

Role of Clathrin and Dynamin in Clathrin Mediated Endocytosis/Synaptic Vesicle Recycling and Implications in Neurological Diseases

“…Firstly, a note on the use of small molecule inhibitors. All small molecules have potential off-target effects, even those published as specific inhibitors (Hopkins, 2008 ; Hafner et al, 2019 ; Oña and Bouso, 2020 ). To ameliorate these potential effects and to strengthen evidence associated with the observed phenotypes, that are ascribed to the inhibition of the target protein, it is strongly recommended (a) that more than one chemical scaffold that inhibits the target protein is used in the biochemical study (it is unlikely that two (or more) chemical scaffolds will display the same off target effects); and (b) inactive control compounds using as close a structural analogue as possible is used (chemically similar but with no in vitro target efficacy).…”

Traditional East Asian Herbal Medicine for Post-Stroke Insomnia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…Numerous clinical practice guidelines for insomnia provide CAM recommendations, including HM, for insomnia [28]. As HM works through multi-component and multi-pathway mechanisms, it has been attracting attention as a new alternative to conventional pharmacology [29]. Recent systematic reviews have provided evidence that HM provides significantly better results in insomnia treatment than placebo, with few adverse effects [30].…”