Metabolites of Cannabis Induce Cardiac Toxicity and Morphological Alterations in Cardiac Myocytes

Abstract

Cannabis is one of the most commonly used recreational drugs worldwide. Rrecent epidemiology studies have linked increased cardiac complications to cannabis use. However, this literature is predominantly based on case incidents and post-mortem investigations. This study elucidates the molecular mechanism of Δ9-tetrahydrocannabinol (THC), and its primary metabolites 11-Hydroxy-Δ9-THC (THC-OH) and 11-nor-9-carboxy-Δ⁹-tetrahydrocannabinol (THC-COOH). Treatment of cardiac myocytes with THC-OH and THC-COOH increased cell migration and proliferation (p < 0.05), with no effect on cell adhesion, with higher doses (250–100 ng/mL) resulting in increased cell death and significant deterioration in cellular architecture. Conversely, no changes in cell morphology or viability were observed in response to THC. Expression of key ECM proteins α-SMA and collagen were up-regulated in response to THC-OH and THC-COOH treatments with concomitant modulation of PI3K and MAPK signalling. Investigations in the planarian animal model Polycelis nigra demonstrated that treatments with cannabinoid metabolites resulted in increased protein deposition at transection sites while higher doses resulted in significant lethality and decline in regeneration. These results highlight that the key metabolites of cannabis elicit toxic effects independent of the parent and psychoactive compound, with implications for cardiotoxicity relating to hypertrophy and fibrogenesis.

Phytocannabinoids Stimulate Rejuvenation and Prevent Cellular Senescence in Human Dermal Fibroblasts

“…Structural deviations in prematurely aged groups exposed to THC and CBD were associated with slight deformations and increased transparency; in contrast, no significant changes were observed in the pCBs-treated healthy fibroblasts. Merve and colleagues (2022) also reported no changes in cardiomyocyte morphology or viability in response to THC in the low doses (100 ng/mL), whereas treatment with primary THC metabolites 11-hydroxy-D9-THC (THC-OH) and 11-nor-9-carboxy-D9-tetrahydrocannabinol (THC-COOH) in higher doses (250–100 ng/mL) resulted in increased cell death and significant deterioration in cellular architecture [ 41 ]. Recent studies have shown that cannabinoids affect the actin cytoskeleton and other components involved in cellular motility, proliferation, and many biological functions in glioblastoma cell lines [ 42 ].…”

Why Do Marijuana and Synthetic Cannabimimetics Induce Acute Myocardial Infarction in Healthy Young People?

“…There may be other (adverse) cardiac effects of THC or synthetic cannabinoids suggested by in vitro experiments ( Table 4 ): (1) THC, at a high concentration of 30 μM, acted cardiotoxically and stopped cardiac activity in the perfused rat heart [ 169 ]; (2) an enhanced apoptosis caused by endoplasmic reticulum stress in mouse HL-1 atrial cardiomyocytes occurred after treatment with high THC concentrations of 10 and 30 μM [ 203 ]; (3) cell viability in H9c2 cells (rat cardiomyoblast cell line) decreased in response to the synthetic cannabinoids JWH-030, JWH-210, JWH-250 and RCS-4 [ 156 ] and (4) the primary metabolites of THC i.e., 11-hydroxy-Δ 9 -THC (THC-OH) and 11-nor-9-carboxy-Δ⁹-tetrahydrocannabinol (THC-COOH), but not the parent compound THC itself [ 202 ].…”

Case Report Highlighting Cardiovascular Effects of Concomitant Use of Methamphetamine and Marijuana

“…The endogenous endocannabinoid system (ECS) is comprised of receptors that are responsible for regulating blood pressure and heart rate as well as endocrine and immune responses [17]. The CB1R has been shown to facilitate the development of cardiometabolic disease, while the CB2R has been shown to increase antiinflammatory effects [18]. Marijuana use has been associated with an increased prevalence of reactive oxygen species, negative inotropic effects, and creating pro-inflammatory endothelial responses [19].…”