ThePineapple - Journal Club #44: Macrophages | Oligodendrocytes | Delta-9 THC | Adolescents

Journal Club #44: Macrophages, Oligodendrocytes, Delta-9 THC, Adolescents

Week of 06-05-22

After last week’s drought of notable cannabinoid research releases we again have a number of papers that are interesting for our journal club. There are two papers on cell proliferation, differentiation and migration. First, there is a paper on the role of cannabinoid receptor 1 in the suppression of macrophage polarization and another one looking at proliferation, migration and differentiation in oligodendrocytes. This is followed by a study on the effects of delta-9 THC for reward-related brain activity and a paper on the differential cognitive effects in adults versus adolescents after THC exposure.

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 suppresses M2 macrophage polarization in colorectal cancer by downregulating EGFR.

Deng YM, Zhao C, Wu L, Qu Z, Wang XY. 

Cell Death Discov. 2022 May 31;8(1):273. 

Cannabinoid receptors, CB1 and CB2, have been implicated as emerging targets for cancer therapy. Herein, we investigated the potential regulation mechanism of CB1 and its implications in colorectal cancer. CB1 and EGFR expression were examined in colorectal cancer cell lines. The effects of CB1 agonist ACEA and its antagonist AM251 on the proliferation, migration and invasion of colorectal cancer cells and the expression of M1 and M2 macrophage markers were examined. EGFR overexpression was performed with plasmids containing EGFR gene. Tumor xenografts were constructed to explore the effects of CB1 activation on tumorigenesis. We showed that CB1 was downregulated while EGFR was upregulated in colorectal cancer cells. The activation of CB1 suppressed the proliferation, migration and invasion of colorectal cancer cells and the differentiation of M2 macrophages, while CB1 inhibition had opposite effects. Moreover, the alterations in tumorigenesis and M2 macrophage activation induced by CB1 activation were counteracted by EGFR overexpression. Besides, CB1 silencing promoted tumor cell proliferation and M2 polarization which was counteracted by EGFR knockdown. In vivo, CB1 activation also repressed tumorigenesis and M2 macrophage activation. The present study demonstrated that CB1 activation suppressed M2 macrophage through EGFR downregulation in colorectal cancers. These findings first unveiled the potential avenue of CB1 as a targeted therapy for colorectal cancer.

doi: 10.1038/s41420-022-01064-8. PMID: 35641479; PMCID: PMC9156763.

Cannabinoids modulate proliferation, differentiation, and migration signaling pathways in oligodendrocytes.

de Almeida V, Seabra G, Reis-de-Oliveira G, Zuccoli GS, Rumin P, Fioramonte M, Smith BJ, Zuardi AW, Hallak JEC, Campos AC, Crippa JA, Martins-de-Souza D. 

Eur Arch Psychiatry Clin Neurosci. 2022 May 27. 

Cannabinoid signaling, mainly via CB1 and CB2 receptors, plays an essential role in oligodendrocyte health and functions. However, the specific molecular signals associated with the activation or blockade of CB1 and CB2 receptors in this glial cell have yet to be elucidated. Mass spectrometry-based shotgun proteomics and in silico biology tools were used to determine which signaling pathways and molecular mechanisms are triggered in a human oligodendrocytic cell line (MO3.13) by several pharmacological stimuli: the phytocannabinoid cannabidiol (CBD); CB1 and CB2 agonists ACEA, HU308, and WIN55, 212-2; CB1 and CB2 antagonists AM251 and AM630; and endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The modulation of cannabinoid signaling in MO3.13 was found to affect pathways linked to cell proliferation, migration, and differentiation of oligodendrocyte progenitor cells. Additionally, we found that carbohydrate and lipid metabolism, as well as mitochondrial function, were modulated by these compounds. Comparing the proteome changes and upstream regulators among treatments, the highest overlap was between the CB1 and CB2 antagonists, followed by overlaps between AEA and 2-AG. Our study opens new windows of opportunities, suggesting that cannabinoid signaling in oligodendrocytes might be relevant in the context of demyelinating and neurodegenerative diseases. Proteomics data are available at ProteomeXchange (PXD031923).

doi: 10.1007/s00406-022-01425-5. Epub ahead of print. PMID: 35622101.

Δ9-THC reduces reward-related brain activity in healthy adults.

Murray CH, Glazer JE, Lee R, Nusslock R, de Wit H.

Psychopharmacology (Berl). 2022 May 25. 

Greater availability of cannabis in the USA has raised concerns about adverse effects of the drug, including possible amotivational states. Lack of motivation may be assessed by examining acute effects of cannabinoids on reward processing. This study examined single doses of delta-9-tetrahydrocannabinol (delta-9 THC; 7.5, 15 mg oral) in healthy adults using a version of the monetary incentive delay (MID) task adapted for electroencephalography (EEG; e-MID) in a within-subjects, double blind design.Two phases of reward processing were examined: anticipation, which occurs with presentation of cues that indicate upcoming reward, punishment, or neutral conditions, and outcome, which occurs with feedback indicating hits or misses. During anticipation, we measured two event-related potential (ERP) components: the P300, which measures attention and motivation, and the LPP, which measures affective processing. During outcome processing, we measured P300 and LPP, as well as the RewP, which measures outcome evaluation. We found that delta-9 THC modulated outcome processing, but not reward anticipation. Specifically, both doses of delta-9 THC (7.5 and 15 mg) reduced RewP amplitudes after outcome feedback (hits and misses) relative to placebo. Delta-9 THC (15 mg) also reduced P300 and LPP amplitudes following hits compared to misses, relative to both placebo and 7.5 mg delta-9 THC. These findings suggest that delta-9 THC dampens responses to both reward and loss feedback, which may reflect an "amotivational" state. Future studies are needed to determine generalizability of this effect, such as its pharmacological specificity and its specificity to monetary vs other types of reward.

doi: 10.1007/s00213-022-06164-y. Epub ahead of print. PMID: 35612654.

Adolescents are more sensitive than adults to acute behavioral and cognitive effects of THC.

Murray CH, Huang Z, Lee R, de Wit H.

Neuropsychopharmacology. 2022 Jun;47(7):1331-1338. 

Increased cannabis availability has contributed to increased use with concomitant incidence of adverse effects. One risk factor for adverse drug reactions may be age. There is preclinical evidence that acute effects of delta-9-tetrahydrocannabinol (THC), the primary active constituent of cannabis, are greater during adolescence, but this has not been fully studied in humans. The present study sought to determine whether adolescent men and women are more sensitive than adults to acute THC. Adolescents aged 18-20 (N = 12) and adults aged 30-40 (N = 12), with less than 20 total lifetime uses of THC-containing products, received capsules of THC (7.5, 15 mg) and placebo across three study sessions in randomized order under double blind conditions. During each session, subjective, cardiovascular, behavioral, and EEG measures were obtained. Behavioral measures included Simple Reaction Time, Stop Task, Time Production and N-back and EEG measures included P300 amplitudes during an auditory oddball task and eyes-closed resting state. THC affected subjective state and heart rate similarly in both age groups. However, adolescents were more sensitive to performance impairing effects, exhibiting dose-dependent impairments on reaction time, response accuracy, and time perception. On EEG measures, THC dose-dependently decreased P300 amplitude in adolescents but not adults. Adolescents were more sensitive to behavioral and cognitive effects of THC, but not to cardiovascular effects or subjective measures. Thus, at doses that produce comparable ratings of intoxication, adolescents may exhibit greater cognitive impairment and alterations in brain function.

doi: 10.1038/s41386-022-01281-w. Epub 2022 Feb 2. PMID: 35110688; PMCID: PMC9117219.