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 epidemi ology 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 ∆9-tetrahydrocannabinol (THC), and its primary metabolites 11-Hydroxy-
∆9-THC (THC-OH) and 11-nor-9-carboxy-∆
9
-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 modu lation 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.