Adverse Impact of Cannabis on Human Health

Abstract

Cannabis, the most commonly used recreational drug, is illicit in many areas of the world. With increasing decriminalization and legalization, cannabis use is increasing in the United States and other countries. The adverse effects of cannabis are unclear because its status as a Schedule 1 drug in the United States restricts research. Despite a paucity of data, cannabis is commonly perceived as a benign or even beneficial drug. However, recent studies show that cannabis has adverse cardiovascular and pulmonary effects and is linked with malignancy. Moreover, case reports have shown an association between cannabis use and neuropsychiatric disorders. With growing availability, cannabis misuse by minors has led to increasing incidences of overdose and toxicity. Though difficult to detect, cannabis intoxication may be linked to impaired driving and motor vehicle accidents. Overall, cannabis use is on the rise, and adverse effects are becoming apparent in clinical data sets.

Keywords: cannabis; cannabis use disorder; cannabis-induced psychosis; cardiovascular disease; pulmonary disease.

Figure 1.. Cannabinoids and cognate receptors.

A) Cannabinoid receptor 1 (CB1) agonists. The molecular structure of three representative CB1 agonists that cause psychoactive effects: delta-9-tetrahydrocannabinol (Δ⁹-THC), hexahydrocannabinol (HHC), and delta-8-tetrahydrocannabinol (Δ⁸-THC). B) Cannabinoid receptor 2 (CB2) agonists. The molecular structure of three CB2 agonists: including beta-caryophyllene (BCP), 2-iodo-5-nitrophenyl)(1-((1-methylpiperidin-2-yl)methyl)-1H-indol-3-yl)methanone (AM 1261), and (6AR,10AR)-3-(1,1-Dimethylbutyl)-6A,7,10,10A-tetrahydro-6,6,9-trimethyl-6H-dibenzo[B,D]pyran (JWH 133). C) CB1 activation causes inflammation and oxidative stress via multiple signaling pathways. Δ⁹-THC binding to the CB1 receptor causes activation of the G-protein coupled receptor (GPCR). The Gi/o complex dissociated into the α_i, βγ, and β arrestin subunits. The α_i subunit inhibits adenylyl cyclase causing decreased cyclic AMP production (cAMP) and prevents protein kinase A (PKA) phosphorylation, which modulates transcription. The βγ subunit activates the mitogen activated pathway (MAP) and p38, which activates NF-κβ thus leading to activation of inflammatory gene and down regulation of oxidative-stress protective genes. The βγ subunit simultaneously affects voltage gated calcium channels (CGGC), G-protein gated potassium channels (GIRK), and PI3K/AKT pathway. (D) CB2 activation prevents inflammation and oxidative stress. BCP binding to the CB2 receptor causes activation of the GPCR. The G_ai/o complex dissociates into the α_i, βγ, and β arrestin subunits. Similar to CB1, the α_i subunit inhibits adenylyl cyclase causing decreased cyclic AMP production (cAMP) and prevents protein kinase A (PKA) phosphorylation, which modulates transcription. The βγ subunit activates the mitogen activated pathway (MAP) and p38. However, CB2 activation prevents NF-κβ translocation to the nucleus, thus blocking the expression of inflammatory genes and down regulation of oxidative-stress protective genes. The βγ subunit simultaneously affects voltage gated calcium channels (CGGC), G-protein gated potassium channels (GIRK), and the PI3K/AKT pathway. Created with BioRender.com.

Figure 2.. Modulation of cannabinoid receptor activity.

A) Cannabinoid receptor-1 (CB1) agonists activate the CB1 receptor causing inflammation, oxidative stress, and atherosclerosis. A CB1 agonist such as THC (red) binds to the CB1 receptor and activates the G-protein coupled receptor (GPCR) causing inhibition of adenylyl cyclase, mitogen activated pathway (MAP) kinase phosphorylation, NF-κβ translocation to the nucleus, and activation of B-arrestin pathways. CB1 activation ultimately causes increased expression of inflammatory cytokines and oxidative stress that promote atherosclerosis. B) A CB1 receptor inverse agonist binds and prevents the agonists from binding the CB1 receptor, modulates receptor function, and attenuates CB1 mediated atherosclerosis. An inverse agonist such as rimonabant (blue) blocks CB1 agonist binding (red) and downregulates CB1 receptor activity via the GPCR thus preventing inhibition of adenylyl cyclase, MAP kinase phosphorylation, NF-κβ translocation to the nucleus, and B-arrestin pathway activation. Consequently, inverse agonists abrogate inflammation, oxidative stress, and atherosclerosis that are mediated by CB1-receptor agonist interactions. C) A neutral antagonist blocks CB1 agonist binding and attenuates CB1 mediated atherosclerosis. A neutral antagonist such as genistein (green) blocks CB1 agonist (red) and does not affect CB1 receptor or downstream pathways. Neutral antagonists also abrogate CB1-mediated inflammation, oxidative stress, and atherosclerosis. D) CB2 agonists attenuate the adverse effects of CB1 activation by modulating the immune system, inflammation and oxidative stress, and thus preventing atherosclerosis. A CB2 agonist such as JWH133 (yellow) binds the CB2 receptor and counteracts the effects of a CB1 agonist (red) binding the CB1 receptor by decreasing MAP kinase phosporylation, preventing NF-κβ translocation, and modulating B-arrestin pathways. Because CB2 receptors are expressed on immune cells and the vasculature, CB2 agonists prevent transformation of monocytes into macrophages in addition to suppressing vascular inflammation and oxidative stress which promotes vascular quiescence and prevents atherosclerosis. Created with BioRender.com.