Neuroprotection Following Concussion : The Potential Role for Cannabidiol

Jyotpal Singh, John Patrick Neary

Canadian Journal of Neurological Sciences, 2020,  1–12

doi : 10.1017/cjn.2020.23

 

ABSTRACT :

Cannabidiol (CBD) has been generating increasing interest in medicine due to its therapeutic properties and an apparent lack of negative side effects. Research has suggested that high dosages of CBD can be taken acutely and chronically with little to no risk. This review focuses on the neuroprotective effects of a CBD, with an emphasis on its implications for recovering from a mild traumatic brain injury (TBI) or concussion. CBD has been shown to influence the endocannabinoid system, both by affecting cannabinoid receptors and other receptors involved in the endocannabinoid system such as vanilloid receptor 1, adenosine receptors, and 5-hydroxytryptamine via cannabinoid receptor-independent mechanisms. Concussions can result in many physiological consequences, potentially resulting in post-concussion syndrome. While impairments in cerebrovascular and cardiovascular physiology following concussion have been shown, there is unfortunately still no single treatment available to enhance recovery. CBD has been shown to influence the blood brain barrier, brain-derived neurotrophic factors, cognitive capacity, the cerebrovasculature, cardiovascular physiology, and neurogenesis, all of which have been shown to be altered by concussion. CBD can therefore potentially provide treatment to enhance neuroprotection by reducing inflammation, regulating cerebral blood flow, enhancing neurogenesis, and protecting the brain against reactive oxygen species. Doubleblind randomized controlled trials are still required to validate the use of CBD as medication following mild TBIs, such as concussion.

RÉSUMÉ :

Rôle neuroprotecteur potentiel du cannabidiol à la suite d’une commotion cérébrale. Le cannabidiol suscite un intérêt croissant pour la médecine en raison de ses propriétés thérapeutiques et d’une absence apparente d’effets secondaires négatifs. De plus, des travaux de recherche suggèrent que des doses élevées de cannabidiol peuvent être administrées de façon constante avec peu ou aucun risque. Cette étude entend mettre l’accent sur les effets neuroprotecteurs de ce cannabinoïde présent dans le cannabis et insister plus particulièrement sur ses effets lorsqu’on se remet d’un traumatisme cranio-cérébral (TCC) léger ou d’une commotion cérébrale. On le sait, il a été démontré que le cannabidiol peut influencer le système endocannabinoïde, entre autres les récepteurs cannabinoïdes et d’autres récepteurs tels que les récepteurs vanilloïdes de type 1, les récepteurs de l’adénosine et la sérotonine (5-HT), par l’entremise de mécanismes indépendants. Quant aux commotions cérébrales, elles peuvent entraîner de nombreuses conséquences physiologiques pouvant potentiellement produire un syndrome post commotionnel. Bien qu’on sache qu’une série de déficiences physiologiques de nature cérébrovasculaire et cardiovasculaire peuvent apparaître à la suite d’une commotion cérébrale, il n’existe malheureusement pas de traitement unique pour améliorer la récupération des patients. Ceci étant dit, la preuve a été faire que le cannabidiol peut agir sur la barrière hémato-encéphalique, sur les facteurs neurotrophiques dérivés du cerveau, sur la capacité cognitive d’un individu, sur sa « cérébrovasculature », sa physiologie cardiovasculaire et sa neurogénèse, des aspects dont on sait qu’ils sont tous altérés par une commotion cérébrale. En conséquence, il se pourrait que le cannabidiol puisse potentiellement constituer un traitement permettant d’améliorer la neuroprotection des patients en réduisant l’inflammation, en régulant le débit sanguin cérébral, en renforçant la neurogénèse et en protégeant le cerveau contre des dérivés réactifs de l’oxygène. Des essais cliniques randomisés à double insu demeurent toutefois nécessaires afin de confirmer l’utilisation du cannabidiol à titre de médicament à la suite d’un TCC, par exemple une commotion cérébrale.

Keywords : Cannabidiol, Endocannabinoid, Neuroprotection, Concussion, Cerebrovasculature

INTRODUCTION

With over 10 million traumatic brain injuries (TBIs) resulting in death or hospitalization occurring annually,1,2 there is a need for an effective treatment strategy to recover from these injuries. TBIs can cause difficulty in performing day-to-day activities and even return to normal physiological functioning does not assure that symptoms will clear.3 The majority of head injuries, such as concussions, are considered mild traumatic brain injuries (mTBIs) and rarely receive full medical treatment.4 Alongside TBIs, there has been an enormous increase in research done in the area of endogenous cannabinoids (endocannabinoids) and the Cannabis sativa and Cannabis indica plants.5 Research into phytocannabinoids (plant based), endocannabinoids, and the synthetic development of cannabinoids has hinted at TBI as a potential therapeutic target.1,6

Cannabidiol (CBD) is a major nonintoxicating compound found in C. sativa and C. indica, along with hemp and other plants,7,8 and is thought to possess therapeutic potential due to its major neurological and anti-inflammatory properties.9,10 It is thought that when CBD is administered alongside other phytocannabinoids, such as tetrahydrocannabinol (THC or Δ9- THC), there is an entourage effect that elevates the therapeutic properties of both CBD and THC.11-13 Human research in this realm in relation to concussion is very limited, presumably due to ethical issues surrounding administration of intoxicating and often illegal compounds such as THC, even if CBD does have the potential to counteract THC psychosis.14,15 Numerous animal studies have supported the idea that CBD and THC administered simultaneously can lead to changes in behavioral effects16 and altered THC metabolism.17 It is also important to note that human studies observing pharmacokinetic and pharmacodynamic effects
of CBD are also very limited,18-20 although it has been suggested that the maximum measured plasma concentration of CBD increases in a dose-dependent manner, occurring between 0 and 4 h, depending on administration route.19

This review will focus on the neuroprotective effects of cannabinoids, specifically the phytocannabinoid CBD following TBI. Considering the prevalence of the entourage effect, it is also important to discuss what the research suggests regarding the combined effects of endocannabinoids and phytocannabinoids,
specifically related to concussion. While an animal model has suggested a role for CBD to regulate glutamate and gammaaminobutyric acid (GABA)21 responses following mTBI, the fundamental mechanisms underlying these effects are still not clear, especially when considering human studies.

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