ThePineapple - Journal Club #37: Reward | T-cells | Sleep | Chemovar

Journal Club #37: Reward, T-cells, Sleep, Chemovar

Week of 04-10-22

Welcome to journal club. A weekly curation of scientific research papers in the field of cannabis science. Fair warning, these are unedited, freshly destilled scientifc publications. In other words, this post is for the cannabis scientists among you, who are likely going to spent at least one day this week eating free pizza and discussing new publications in your respective biomedical graduate departments. So, if you are a graduate student, feel free to save yourself some time and pick one of these :)

Also, if you feel we missed a particularly juicy paper, then leave a comment with the doi: number or pubmed ID ! We'll update the "journal club" as the week goes on.

Neural responses to reward anticipation and feedback in adult and adolescent cannabis users and controls.

Skumlien, M., Mokrysz, C., Freeman, T. P., Wall, M. B., Bloomfield, M., Lees, R., Borissova, A., Petrilli, K., Carson, J., Coughlan, T., Ofori, S., Langley, C., Sahakian, B. J., Curran, H. V., & Lawn, W. 

Neuropsychopharmacology 2022 Apr. 6th

Chronic use of drugs may alter the brain's reward system, though the extant literature concerning long-term cannabis use and neural correlates of reward processing has shown mixed results. Adolescents may be more vulnerable to the adverse effects of cannabis than adults; however, this has not been investigated for reward processing. As part of the 'CannTeen' study, in the largest functional magnetic resonance imaging study of reward processing and cannabis use to date, we investigated reward anticipation and feedback in 125 adult (26-29 years) and adolescent (16-17 years) cannabis users (1-7 days/week cannabis use) and gender- and age-matched controls, using the Monetary Incentive Delay task. Blood-oxygen-level-dependent responses were examined using region of interest (ROI) analyses in the bilateral ventral striatum for reward anticipation and right ventral striatum and left ventromedial prefrontal cortex for feedback, and exploratory whole-brain analyses. Results showed no User-Group or User-Group × Age-Group effects during reward anticipation or feedback in pre-defined ROIs. These null findings were supported by post hoc Bayesian analyses. However, in the whole-brain analysis, cannabis users had greater feedback activity in the prefrontal and inferior parietal cortex compared to controls. In conclusion, cannabis users and controls had similar neural responses during reward anticipation and in hypothesised reward-related regions during reward feedback. The whole-brain analysis revealed tentative evidence of greater fronto-parietal activity in cannabis users during feedback. Adolescents showed no increased vulnerability compared with adults. Overall, reward anticipation and feedback processing appear spared in adolescent and adult cannabis users, but future longitudinal studies are needed to corroborate this.

doi: 10.1038/s41386-022-01316-2. Epub ahead of print. PMID: 35388175.

Cannabis suppresses antitumor immunity by inhibiting JAK/STAT signaling in T cells through CNR2.

Xiong X, Chen S, Shen J, You H, Yang H, Yan C, Fang Z, Zhang J, Cai X, Dong X, Kang T, Li W, Zhou P. 

Signal Transduct Target Ther. 2022 Apr 6;7(1):99. 

The combination of immune checkpoint blockade (ICB) with chemotherapy significantly improves clinical benefit of cancer treatment. Since chemotherapy is often associated with adverse events, concomitant treatment with drugs managing side effects of chemotherapy is frequently used in the combination therapy. However, whether these ancillary drugs could impede immunotherapy remains unknown. Here, we showed that ∆9-tetrahydrocannabinol (THC), the key ingredient of drugs approved for the treatment of chemotherapy-caused nausea, reduced the therapeutic effect of PD-1 blockade. The endogenous cannabinoid anandamide (AEA) also impeded antitumor immunity, indicating an immunosuppressive role of the endogenous cannabinoid system (ECS). Consistently, high levels of AEA in the sera were associated with poor overall survival in cancer patients. We further found that cannabinoids impaired the function of tumor-specific T cells through CNR2. Using a knock-in mouse model expressing a FLAG-tagged Cnr2 gene, we discovered that CNR2 binds to JAK1 and inhibits the downstream STAT signaling in T cells. Taken together, our results unveiled a novel mechanism of the ECS-mediated suppression on T-cell immunity against cancer, and suggest that cannabis and cannabinoid drugs should be avoided during immunotherapy.

doi: 10.1038/s41392-022-00918-y. PMID: 35383142.

Tonic endocannabinoid signaling supports sleep through development in both sexes.

Martin SC, Gay SM, Armstrong ML, Pazhayam NM, Reisdorph N, Diering GH. 

Sleep. 2022 Apr 8:zsac083.

Sleep is an essential behavior that supports brain function and cognition throughout life, in part by acting on neuronal synapses. The synaptic signaling pathways that mediate the restorative benefits of sleep are not fully understood, particularly in the context of development. Endocannabinoids (eCBs) including 2-arachidonyl glycerol (2-AG) and anandamide (AEA), are bioactive lipids that activate cannabinoid receptor, CB1, to regulate synaptic transmission and mediate cognitive functions and many behaviors, including sleep. We used targeted mass spectrometry to measure changes in forebrain synaptic eCBs during the sleep/wake cycle in juvenile and adolescent mice of both sexes. We find that eCBs lack a daily rhythm in juvenile mice, while in adolescents AEA and related OEA are increased during the sleep phase in a circadian manner. Next, we manipulated the eCB system using selective pharmacology and measured the effects on sleep behavior in developing and adult mice of both sexes using a non-invasive piezoelectric home-cage recording apparatus. Enhancement of eCB signaling through inhibition of 2-AG or AEA degradation, increased dark phase sleep amount and bout length in developing and adult males, but not in females. Inhibition of CB1 by injection of the antagonist AM251 reduced sleep time and caused sleep fragmentation in developing and adult males and females. Our data suggest that males are more sensitive to the sleep promoting effects of enhanced eCBs but that tonic eCB signaling supports sleep behavior through multiple stages of development in both sexes. This work informs the further development of cannabinoid-based therapeutics for sleep disruption.

doi: 10.1093/sleep/zsac083. Epub ahead of print. PMID: 35395682.

Beyond Δ9-tetrahydrocannabinol and cannabidiol: chemical differentiation of cannabis varieties applying targeted and untargeted analysis.

Monti MC, Frei P, Weber S, Scheurer E, Mercer-Chalmers-Bender K. 

Anal Bioanal Chem. 2022 Apr 5. 

Cannabis sativa (C. sativa) is commonly chemically classified based on its Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) content ratios. However, the plant contains nearly 150 additional cannabinoids, referred to as minor cannabinoids. Minor cannabinoids are gaining interest for improved plant and product characterization, e.g., for medical use, and bioanalytical questions in the medico-legal field. This study describes the development and validation of an analytical method for the elucidation of minor cannabinoid fingerprints, employing liquid chromatography coupled to high-resolution mass spectrometry. The method was used to characterize inflorescences from 18 different varieties of C. sativa, which were cultivated under the same standardized conditions. Complementing the targeted detection of 15 cannabinoids, untargeted metabolomics employing in silico assisted data analysis was used to detect additional plant ingredients with focus on cannabinoids. Principal component analysis (PCA) was used to evaluate differences between varieties. The overall purpose of this study was to examine the ability of targeted and non-targeted metabolomics using the mentioned techniques to distinguish cannabis varieties from each other by their minor cannabinoid fingerprint. Quantitative determination of targeted cannabinoids already gave valuable information on cannabinoid fingerprints as well as inter- and intra-variety variability of cannabinoid contents. The untargeted workflow led to the detection of 19 additional compounds. PCA of the targeted and untargeted datasets revealed further subgroups extending commonly applied phenotype classification systems of cannabis. This study presents an analytical method for the comprehensive characterization of C. sativa varieties.

doi: 10.1007/s00216-022-04026-2. Epub ahead of print. PMID: 35380230.