Cannabinoids in traumatic brain injury and related neuropathologies: preclinical and clinical research on endogenous, plant-derived, and synthetic compounds

Abstract

Traumatic brain injury is common, and often results in debilitating consequences. Even mild traumatic brain injury leaves approximately 20% of patients with symptoms that persist for months. Despite great clinical need there are currently no approved pharmaceutical interventions that improve outcomes after traumatic brain injury. Increased understanding of the endocannabinoid system in health and disease has accompanied growing evidence for therapeutic benefits of Cannabis sativa. This has driven research of Cannabis’ active chemical constituents (phytocannabinoids), alongside endogenous and synthetic counterparts, collectively known as cannabinoids. Also of therapeutic interest are other Cannabis constituents, such as terpenes. Cannabinoids interact with neurons, microglia, and astrocytes, and exert anti-inflammatory and neuroprotective effects which are highly desirable for the management of traumatic brain injury. In this review, we comprehensively appraised the relevant scientific literature, where major and minor phytocannabinoids, terpenes, synthetic cannabinoids, and endogenous cannabinoids were assessed in TBI, or other neurological conditions with pathology and symptomology relevant to TBI, as well as recent studies in preclinical TBI models and clinical TBI populations.

Traumatic Brain Injury Outcomes After Recreational Cannabis Use

“…However, even though not statistically significant, mortality was numerically higher among patients who tested negative for cannabis compared to their positive counterparts, underscoring the possibility that cannabis may need to be further investigated in the setting of moderate or severe TBI, as suggested by recent reviews. 7 , 28 Similarly difficult is the comparison to the study by Leskovan et al since their secondary outcome measures were days in intensive care unit, days on ventilator, and duration of stay. 40 The only comparable outcome measures were mortality at discharge and the duration of hospital stay.…”

“…Our findings are overall in line with the previously observed neuroprotective effects of various cannabinoids and are not necessarily in conflict with negative results of the dexanabinol trial that tested one synthetic cannabinoid rather than the plant-derived product with multiple constituents. 28 , 35 , 50 The entourage effect of all of the cannabinoids, terpenes, and flavonoids may be contributing to and enhancing the individual effects of specific cannabinoids such as CBD. 54 However, our study was not designed to evaluate this effect and it would not be possible to design such a study in an uncontrolled setting, where the intra- and inter-subject variability of the used cannabis products are likely high.…”

“… 35 The main criticism of this particular RCT is that dexanabinol is a synthetic rather than a naturally occurring cannabinoid and that the study was limited to a single synthetic cannabinoid molecule rather than a plant-derived assembly of various phytocannabinoids, terpenes, and flavonoids, many of them with specific therapeutic potential. 28 …”

“…26,27 The interaction between phytocannabinoids, terpenes, and flavonoids and the ECS and other homeostatic systems has been studied in a substantial detail. 28 This includes not only anti-inflammatory and neuroprotective investigations but also research into the effects of phyto-and endocannabinoids on epileptogenesis and cognition. [29][30][31] Thus, basic and clinical science work has made important strides toward understanding the divergent roles of the ECS and the dynamics of its receptors (CB 1 R/CB 2 R) and neurotransmitters (2-arachidonoylglycerol (2-AG); anandamide (ANA)).…”

Depletion of Endothelial-Derived 2-AG Reduces Blood-Endothelial Barrier Integrity via Alteration of VE-Cadherin and the Phospho-Proteome

“…Evidence has increased in the last decade of decreased endocannabinoid tone in neuropathologies, including dementia, traumatic brain injury, and migraine [ 15 , 25 , 26 , 27 ]. These neuropathologies also disrupt BBB integrity, and methods to increase endocannabinoid tone have shown promise as therapeutic interventions, suggesting a role for the endocannabinoid system in BBB homeostasis [ 2 , 15 , 18 , 19 , 20 , 26 , 27 , 28 ].…”