Using In Silico Molecular Docking to Explain Differences in Receptor Binding Behavior of HHC and THCV Isomers: Revealing New Binding Modes.

Even slight structural differences between phytocannabinoid isomers are usually enough to cause a change in their biological properties. In this study, we used in vitro CB1 agonism/antagonism assays to compare the receptor binding functionality of THCV (tetrahydrocannabivarin) and HHC (hexahydrocannabinol) isomers and applied molecular docking to provide an explanation for the difference in the activities. No CB1 agonism was observed for ∆9- and ∆8-THCV. Instead, both isomers antagonized CP 55940, with ∆9-THCV being approximately two times more potent than the ∆8 counterpart (IC50 = 52.4 nM and 119.6 nM for ∆9- and ∆8-THCV, respectively). Docking simulations found two binding poses for THCV isomers, one very similar to ∆9-THC and one newly discovered pose involving the occupation of side pocket 1 of the CB1 receptor by the alkyl chain of the ligand. We suggested the latter as a potential antagonist pose. In addition, our results established 9R-HHC and 9S-HHC among partial agonists of the CB1 receptor. The 9R-HHC (EC50 = 53.4 nM) isomer was a significantly more potent agonist than 9S (EC50 = 624.3 nM). ∆9-THC and 9R-HHC showed comparable binding poses inside the receptor pocket, whereas 9S-HHC adopted a new and different binding posture that can explain its weak agonist activity.

A double-blind, randomized, placebo-controlled study of the safety and effects of CBN with and without CBD on sleep quality.

The present study sought to determine the effects of cannabinol (CBN) alone and in combination with cannabidiol (CBD) on sleep quality. This was a double-blind, randomized, placebo-controlled study conducted between May and November 2022. Participants were randomized to receive either (a) placebo, (b) 20 mg CBN, (c) 20 mg CBN + 10 mg CBD, (d) 20 mg CBN + 20 mg CBD, or (e) 20 mg CBN + 100 mg CBD for seven consecutive nights. Participants were 18-55 years of age who self-rated sleep quality as "very poor" or "poor." The primary endpoint was sleep quality, while secondary endpoints included sleep onset latency, number of awakenings, wake after sleep onset (WASO), overall sleep disturbance, and daytime fatigue. In a modified intent-to-treat analyses (N = 293), compared to placebo, 20 mg CBN demonstrated a nonsignificant but potentially meaningful effect on sleep quality (OR [95% CI] = 2.26 [0.93, 5.52], p = .082) and significantly reduced number of awakenings (95% CI [-0.96, -0.05], p = .025) and overall sleep disturbance (95% CI [-2.59, -0.14], p = .023). There was no difference from placebo among any group for sleep onset latency, WASO, or daytime fatigue (all p > .05). Individuals receiving 20 mg CBN demonstrated reduced nighttime awakenings and overall sleep disturbance relative to placebo, with no impact on daytime fatigue. The addition of CBD did not positively augment CBN treatment effects. No differences were observed for latency to sleep onset or WASO. Findings suggest 20 mg of CBN taken nightly may be helpful for improving overall sleep disturbance, including the number of times one wakes up throughout the night, without impacting daytime fatigue. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Chemistry, Crystal Structure, and In Vitro Receptor Binding of Δ10-THC Isomers.

Introduction: The psychoactive properties of Δ10-THC isomers (trans- and cis-Δ10-THC) are poorly understood. To shed more light on the biological effects of these compounds, we studied in vitro receptor binding of Δ10-THC isomers at cannabinoid CB1 and CB2 receptors. Materials and Methods: We first optimized and simplified catalytic synthesis of trans- and cis-Δ10-THC to allow their safe and cheap large-scale synthesis. In our synthesis, BuLi was replaced with KOtBu, and DMSO/anisole or NEt3/heptane solvent systems were used instead of HMPA/toluene. Single crystal X-ray analysis confirmed the structure of both isomers and the configuration of their chiral centers. Results: In the radioligand replacement assay, both isomers showed strong affinity toward the CB1 receptor, with IC50=29.1 nM for the trans isomer and IC50=294.2 nM for the cis counterpart. However, the IC50 values were significantly higher than that of Δ9-THC (2.1 nM), a naturally occurring psychoactive component of cannabis sativa, suggesting a lower affinity of Δ10-THCs toward this receptor. In function assays, in contrast to Δ9-THC, both isomers failed to show any agonist properties at concentrations up to 10 µM suggesting a lack of THC-like psychoactivity for trans- and cis-Δ10-THC. Conclusions: Our results established Δ10-THC isomers among antagonists of the CB1 receptor as both cis and trans isomers antagonized CP55,490 with IC50=460 nM for trans and IC50=1040 nM for cis. This functional property has not been previously observed for any other THC isomers.

The Long-Term, Prospective, Therapeutic Impact of Cannabis on Post-Traumatic Stress Disorder.

Introduction: Given the increasing availability and use of cannabis among individuals with post-traumatic stress disorder (PTSD) and the addition of PTSD as an eligible diagnosis in several U.S. medical cannabis programs, the efficacy of dispensary-obtained cannabis needs to be thoroughly examined. Materials and Methods: This prospective study assessed PTSD symptoms and functioning every 3 months over the course of a year in two samples of participants diagnosed with PTSD: (1) those with PTSD using dispensary-obtained cannabis (cannabis users) and (2) those with PTSD, who do not use cannabis (controls). Linear mixed-effects models and generalized estimating equations tested whether trajectories of symptoms differed between the two subsamples. Results: A total of 150 participants (mean [standard deviation] age, 50.67 [15.26] years; 73% male) were enrolled in the study. Over the course of 1 year, the cannabis users reported a greater decrease in PTSD symptom severity over time compared to controls [group×time interaction=-0.32 (95% confidence interval [CI]=-0.59 to -0.05, R2=0.13; t=-2.35, p=0.02). Participants who used cannabis were 2.57 times more likely to no longer meet DSM-5 criteria for PTSD at the end of the study observation period compared to participants who did not use cannabis (95% CI=1.12-6.07; p=0.03). Conclusions: This study provides evidence that the types of cannabis available in recreational and medical cannabis dispensaries might hold promise as an alternative treatment for PTSD. Randomized placebo-controlled trials are needed to assess safety and determine how different preparations of cannabis impact PTSD and functioning.