Harmful Effects of Smoking Cannabis: A Cerebrovascular and Neurological Perspective

Abstract

Apart from being used as a medicine, cannabis or marijuana is the most widely abused recreational drug all over the world. The legalization and decriminalization of cannabis in Canada and various states of USA may be the underlying reason of the widespread popularity of it among young population. Various studies have reported about the relationship between cannabis use and different detrimental effects like cardiovascular, cerebrovascular, and neurological complications among different age groups. Specifically, the young population is getting adversely affected by this, harmful yet, readily accessible recreational drug. Although the mechanism behind cannabis mediated neurological and cerebrovascular complications has not been elucidated yet, the results of these studies have confirmed the association of these diseases with cannabis. Given the lack of comprehensive study relating these harmful complications with cannabis use, the aim of this narrative literature review article is to evaluate and summarize current studies on cannabis consumption and cerebrovascular/neurological diseases along with the leading toxicological mechanisms.

Keywords: abuse; cannabis; cerebrovascular; drug; neurodegenerative; oxidative stress; recreational; stroke.

Figure 1

Chemical structure of two of the major cannabinoids contained in Marijuana. Depicted on the left is the chemical structure of tetrahydrocannabinol (THC). THC is the principal psychoactive constituent of cannabis. THC acts as a partial agonist at the cannabinoid receptor CB1 (primarily located in the brain and spinal cord as well as CB2 receptor expressed in cells of the immune system. On the right is depicted the chemical structure of cannabidiol (CBD). By contract with THC, CBD does not have any psychotropic effects, but appears to have some have anti-anxiety and anti-psychotic properties. CBD has a lower affinity for both CB1 and CB2 receptor when compared to THC. Highlighted in red are the chemical structure differences between CBD and THC.

Figure 2

Schematic illustration of the primary location of CB1 and CB2 receptor. Note that CB1 receptor are primarily located in the brain and spinal cord and to a much lesser extent there are also present in the gastrointestinal tract, reproductive organs as well as muscles and vascular system. CB2 receptors are primary located in spleen, skin, and bones as well as the immune cells.

Figure 3

Subcellular localization and activity of CB1 receptors. CB1 receptors are primary located on the cell membrane where their activation lead to inhibition of adenylate cyclase and a resulting reduction of cyclic AMP. In parallel CB1 activation promotes the upregulation of mitogen-activated protein kinase (MAPK) which is involved in directing cellular responses to mitogens, heat shock, osmotic stress, and proinflammatory stimuli (e.g. cytokines). At the mitochondrial level, CB1 activation leads to inhibition of mitochondrial respiration and production of cAMP. CB1 receptors are also present at the level of lysosomes where they prompt a release of calcium from these internal storage units and increase the intracellular calcium levels. Lysosome permeability is also increased.

Figure 4

Schematic illustration of the Activation of the cellular antioxidative response system under normal and stress condition. Under normal conditions, the response to injury is adaptive, designed to restore homoeostasis and to protect the cell from further injury. In response to excessive oxidative stress stimuli, NADPH oxidase is activated, producing an excess of O₂^‑ which in the presence of nitric oxide (.NO; also abundant in CS and release in response to IR) results in formation of peroxinitrite (ONOO^‑). Furthermore, the excess of H₂O₂ leads to the formation of hydroxyl radicals (OH; Fenton’s reaction). The unchecked OS leads then to mitochondrial depolarization, lipid peroxidation, DNA fragmentation and inflammation which at the cerebrovascular level can cause BBB damage and ultimately facilitate the onset of CNS diseases.