ThePineapple - Journal Club #40: Genistein, CUD, Osteoporosis, Delta 8-THC vs. Delta 9-THC

Journal Club #40: Genistein, CUD, Osteoporosis, Delta 8-THC vs. Delta 9-THC

Week of 05-01-22

It is sunday again and you know what that means! - That’s right, another journal club. This week we got a rare treat in the form of a landmark cannabis science paper that was published in the journal CELL. The research group around Joseph Wu, MD, PhD (Stanford Cardiovascular Institute) published some beautiful work on THC-induced inflammation in the cardiovascular system and identified “Genistein” as an antagonist that allows mitigating the cardiovascular risks without blocking the psychoactive effects on the brain. I am sure the paper will be the hotpick in journal clubs around the world this week. Enjoy.

Note: This is a post for cannabis scientists. A weekly curation of fresh papers that help advance our understanding of cannabis and the endocannabinoid system.

Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation. 

Wei TT, Chandy M, Nishiga M, Zhang A, Kumar KK, Thomas D, Manhas A, Rhee S, Justesen JM, Chen IY, Wo HT, Khanamiri S, Yang JY, Seidl FJ, Burns NZ, Liu C, Sayed N, Shie JJ, Yeh CF, Yang KC, Lau E, Lynch KL, Rivas M, Kobilka BK, Wu JC. 

Cell. 2022 Apr 29:S0092-8674(22)00443-3. 

Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana, binds to cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis was an risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells were used to model Δ9-THC-induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference, and genistein attenuated the effects of Δ9-THC. In mice, genistein blocked Δ9-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. Genistein is a CB1 antagonist that attenuates Δ9-THC-induced atherosclerosis.

doi: 10.1016/j.cell.2022.04.005. Epub ahead of print. PMID: 35489334.

The Relationship Between Circulating Endogenous Cannabinoids and the Effects of Smoked Cannabis.

Kearney-Ramos T, Herrmann ES, Belluomo I, Matias I, Vallée M, Monlezun S, Piazza PV, Haney M. 

Cannabis Cannabinoid Res. 2022 Apr 29. 

The endogenous cannabinoid system (ECS), including the endocannabinoids (eCBs), anandamide (AEA), and 2-arachidonoylglycerol (2-AG), plays an integral role in psychophysiological functions. Although frequent cannabis use is associated with adaptations in the ECS, the impact of acute smoked cannabis administration on circulating eCBs, and the relationship between cannabis effects and circulating eCBs are poorly understood. This study measured the plasma levels of AEA, 2-AG, and Δ-9-tetrahydrocannabinol (THC), subjective drug-effects ratings, and cardiovascular measures at baseline and 15-180 min after cannabis users (n=26) smoked 70% of a cannabis cigarette (5.6% THC). Cannabis administration increased the ratings of intoxication, heart rate, and plasma THC levels relative to baseline. Although cannabis administration did not affect eCB levels relative to baseline, there was a significant positive correlation between baseline AEA levels and peak ratings of "High" and "Good Drug Effect." Further, baseline 2-AG levels negatively correlated with frequency of cannabis use (mean days/week) and with baseline THC metabolite levels. Conclusions: In a subset of heavy cannabis smokers: (1) more frequent cannabis use was associated with lower baseline 2-AG, and (2) those with lower AEA got less intoxicated after smoking cannabis. These findings contribute to a sparse literature on the interaction between endo- and phyto-cannabinoids. Future studies in participants with varied cannabis use patterns are needed to clarify the association between circulating eCBs and the abuse-related effects of cannabis, and to test whether baseline eCBs predict the intoxicating effects of cannabis and are a potential biomarker of cannabis tolerance.

doi: 10.1089/can.2021.0185. Epub ahead of print. PMID: 35486827.

Effects of CB2 and TRPV1 Stimulation on Osteoclast Overactivity Induced by Iron in Pediatric Inflammatory Bowel Disease.

Tortora C, Di Paola A, Creoli M, Argenziano M, Martinelli M, Miele E, Rossi F, Strisciuglio C.

Inflamm Bowel Dis. 2022 Apr 26

The reduction of bone mineral density and osteoporosis have high impacts on the health of patients with inflammatory bowel diseases (IBD). We have previously shown that a dysregulated iron metabolism occurs in IBD and leads to a decrease in circulating iron concentration and excessive intracellular sequestration of iron. Studies suggest that iron overload significantly affects the bone, accelerating osteoclast (OC) differentiation and activation, promoting bone resorption. Moreover, we demonstrated that iron overload causes OC overactivity. The cannabinoid receptor type 2 (CB2) and the transient receptor potential vanilloid type-1 (TRPV1) are potential therapeutic targets for bone diseases. The aim of this study was to evaluate the roles of CB2 and TRPV1 receptors and of iron in the development of osteoporosis in pediatric IBD. We differentiated OCs from peripheral blood mononuclear cells of patients with IBD and healthy donors and evaluated CB2 and TRPV1 receptor expression; OC activity, and iron metabolism by Western blot, TRAP assays, bone resorption assays, and iron assays. Moreover, we analyzed the effects of the pharmacological modulation of CB2 and TRPV1 receptors on OC activity and on the iron metabolism. We confirmed the well-known roles of CB2 and TRPV1 receptors in bone metabolism and suggested that their stimulation can reduce the OC overactivity induced by iron, providing new insights into the pathogenesis of pediatric IBD-related bone resorption. Conclusions: Stimulation of CB2 and TRPV1 could reduce IBD-related osteoporosis due to their direct effects on OC activity and to modulating the iron metabolism.

doi: 10.1093/ibd/izac073. Epub ahead of print. PMID: 35472140.

A crowdsourcing survey study on the subjective effects of delta-8-tetrahydrocannabinol relative to delta-9-tetrahydrocannabinol and cannabidiol.

Bergeria CL, Strickland JC, Spindle TR, Kalaba M, Satyavolu PU, Feldner M, Vandrey R, Bonn-Miller M, Peters EN, Weerts E.

Exp Clin Psychopharmacol. 2022 Apr 25.

Delta-8-tetrahydrocannabinol (Δ8-THC) has emerged as a new retail cannabinoid product in the U.S. This study queried Δ8-THC users about product use characteristics and self-reported drug effects. Participants were recruited via a large online crowdsourcing platform (Amazon Mechanical Turk). Adults (N = 252) with past year Δ8-THC use (35% with at least weekly use) completed surveys and open-ended questions related to their reasons for using and past experiences with Δ8-THC-containing retail products. Participants with past year use of Δ9-tetrahydrocannabinol (Δ9-THC) and/or cannabidiol (CBD; 81% and 63%) compared the effects of Δ8-THC to those of Δ9-THC and/or CBD by rating drug effects on a visual analog scale from -50 to + 50 where negative scores indicated Δ8-THC effects are weaker, positive scores indicated Δ8-THC effects are stronger, and a score of 0 indicated equal effects to Δ9-THC or CBD. Compared to Δ9-THC, self-reported ratings for "Drug effect," "Bad effect," "Sick," "Anxiety," "Paranoia," "Irritability," "Restlessness," "Memory Problems," and "Trouble Performing Routine Tasks" were lower for Δ8-THC (d = -0.21 to -0.44). Compared to CBD, ratings for Δ8-THC effects were higher for "Drug effect," "Good effect," "High," "Relaxed," "Sleepy," "Hunger/Have the Munchies," "Memory Problems," "Trouble Performing Routine Tasks," and "Paranoia" (d = 0.27-1.02). Qualitative responses indicated that participants used Δ8-THC because it is perceived as (a) legal, (b) a substitute or similar to Δ9-THC, and/or (c) less intense than Δ9-THC. Δ8-THC is an understudied psychoactive component of cannabis that shares more characteristics with Δ9-THC than CBD and should be characterized further with human laboratory studies. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

doi: 10.1037/pha0000565. Epub ahead of print. PMID: 35467921.