Cannabidiol

We collected a total of 428 compounds (structures in Tables S1–S6) to be investigated using CANDO and categorized them into 291 phenethylamines and 109 tryptamines described by Alexander Shulgin^{54 ,55} , and 6 cannabinoids (cannabinol, cannabidiol, and tetrahydrocannabinol) using a subgraph based search methodology based on the structure of the parent molecule (see Supporting Information for full description of this method). An additional 22 compounds are not strictly classified as phenethylamines but have structural similarity to the phenethylamine class are included as unclassified. We further subdivided the 291 phenethylamine compounds into 149 amphetamines and 20 cathinones, the remaining 122 phenethylamines are simply referred to as phenethylamines. The CANDO v1 compound library includes these 428 psychoactives and their proteomic interactions signatures to repurpose psychoactives for indications/diseases^{9 (link)}. Most of these psychoactives are classified as Schedule I substances by the United States Drug Enforcement Agency, indicating they have no known medicinal use, no accepted standards for safety, or have a high potential for abuse. Thus, when such a substance is discussed, the potential pitfalls are presented along with that substance. We selected this set of compounds as almost all of them are known to affect mental physiology upon ingestion^{54 ,55 ,92 (link)}. A notable exception in the compounds evaluated is cannabidiol which is not strictly psychoactive^{92 (link)} but is structurally similar to other cannabinoids and therefore warrants an investigation into its potential therapeutic value.
The CANDO v1 compound-proteome interaction signature (see Supporting Methods) includes all associations of treatment and side effects caused for each compound via the proteomic signature as this is composed of all target, anti-target, and off-targets proteins for each indication/disease. The compound proteomic interaction signature similarity yields therapeutic predictions by considering similarity to known drug signatures for each disease. It should be noted that this methodology can also match a psychoactive to a compound known to worsen a given indication in addition to predicting a compound known to ameliorate the same indication. Therefore, the set of compounds that were used as therapy for a given indication did not include any of the aforementioned psychoactive compounds given that the nature of these compounds as treatments is still controversial. As a result, the ability of the platform to predict a psychoactive from another psychoactive compound-proteome signature is not investigated in this work. Most importantly, all predictions are made based on similarity to an approved non-psychoactive drug for a mental health indication, without any knowledge of therapeutic target associations for making predictions for psychoactive compounds. Therefore, no association between an indication and a protein target is used to weight the similarity between two compounds. For example, the interaction score of a psychoactive and the dopamine receptor is not given a special weight for Schizophrenia.

Synergies between Δ⁹-tetrahydrocannabinol or cannabidiol and gemcitabine, cisplatin, or a combination of gemcitabine/cisplatin were studied using the checkerboard assay in T24 cells. Synergy was also assessed between Δ⁹-tetrahydrocannabinol or cannabidiol and cannabivarin or cannabichromene. Briefly, the synergy assay was performed with 3000 cells in 96-well plates with a final volume of 100 μL per well. Cannabinoid concentrations ranged from 0 to 10 mM and gemcitabine and cisplatin concentrations between 0 and 100 mM. Fluorescence was quantified as described before using alamar Blue® after 48-h treatment. The analysis was performed using SynergyFinder 2.0 (Ianevski et al. 2020 (link)), where the Bliss independence drug interaction model was used. A synergy score of <  − 10 was considered as antagonistic, a range from − 10 to + 10 as additive, and >  + 10 as synergistic (Ianevski et al. 2020a (link); 2020b (link)). Drug combination responses were also plotted as concentration–response curves using GraphPad Prism software and were used to determine statically significant and synergistic combinations.

Gemcitabine, cisplatin, Δ⁹-tetrahydrocannabinol, and cannabidiol were obtained from Millipore-Sigma. Cannabichromene, cannabivarin, rimonabant, SR 144,528, and A-967079 were obtained from Cayman Chemical.