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Official websites use. Share sensitive information only on official, secure websites. Address correspondence to: Andrew R. There is not a single pharmacological agent with demonstrated therapeutic efficacy for traumatic brain injury TBI. With recent legalization efforts and the growing popularity of medical cannabis, patients with TBI will inevitably consider medical cannabis as a treatment option. Pre-clinical TBI research suggests that cannabinoids have neuroprotective and psychotherapeutic properties. In contrast, recreational cannabis use has consistently shown to have detrimental effects. Our review identified a paucity of high-quality studies examining the beneficial and adverse effects of medical cannabis on TBI, with only a single phase III randomized control trial. However, observational studies demonstrate that TBI patients are using medical and recreational cannabis to treat their symptoms, highlighting inconsistencies between public policy, perception of potential efficacy, and the dearth of empirical evidence. We conclude that randomized controlled trials and prospective studies with appropriate control groups are necessary to fully understand the efficacy and potential adverse effects of medical cannabis for TBI. Keywords: cannabidiol, cannabinoids, medical cannabis, medical marijuana, THC, traumatic brain injury. Traumatic brain injury TBI is a major public health problem, causing a significant number of hospitalizations, morbidity, mortality, and increased healthcare utilization and per capita costs attributable to disability in the United States each year. Thus, there is a great public need for interventions that are either neuroprotective or have the ability to reduce the symptom burden associated with TBI. One relatively unexplored possibility is medical cannabis, which has gained recognition for its potential neuroprotective and psychotropic qualities in pre-clinical studies. The recent legalization efforts across much of the United States and Canada have increased accessibility, such that more patients with TBI may consider medical cannabis as a possible treatment. The current review addresses the gap in the literature by providing the reader with the theoretical rationale for medical cannabis treatment for TBI, including the pathophysiology of TBI and pharmacology of cannabis. Given that human studies of medical cannabis and TBI are limited five published studies, three published abstracts , a discussion is provided from supporting literature on the potential therapeutic and adverse effects of medical cannabis on TBI in the domains of neuroimaging and cognitive, psychiatric, and physical functioning. This is followed by a critical review of the literature on the effects of cannabis on TBI in humans, as well as current challenges and future directions for research. There is currently no consensus on the definition or set criteria for the diagnosis of TBI; however, most define TBI as an injury resulting from an external force to the head followed by an alteration in brain function. TBI is associated with a complex cascade of neurometabolic events. The endocannabinoid system ECS plays a critical role in the support and protection of the central nervous system CNS , as evidenced by increased endocannabinoid brain levels in response to injury, 16 making the ECS a target for potential intervention. Moreover, as detailed in the sections below, not only does medical cannabis influence the biological cascade that follows an acute TBI, but it also has the potential to reduce several common psychiatric sequelae associated with TBI. Cannabinoids include plant-derived phytocannabinoids, synthetically produced cannabis, and endogenous cannabinoids such as anandamide N-arachidonoylethanolamine; AEA and 2-arachidonoylglycerol 2-AG. In contrast, CB 2 receptors are localized in the periphery and immune system, which may explain cannabinoids' potential impact on pain and inflammatory responses. There are many routes of cannabis administration, each with their own pharmacokinetics that can influence potential beneficial and harmful effects. However, research on the effects of these routes of administration is limited. Pre-clinical trials in rodent models have investigated several effects on TBI-induced pathophysiology with cannabinoid administration, including the prevention of neuronal cell death, activation of cell structure and remodeling processes, reduction of excitotoxicity, increased blood—brain barrier integrity, and reduction of neuroinflammation through increased anti-inflammatory cytokines and growth factors or reduced proinflammatory cytokines. For example, one study showed that the oral administration of CBD oil to mice with mild TBI resulted in alleviation of behavioral alterations, such as pain behaviors, anxiety, aggressiveness, and depression. TBI is heterogeneous in nature, manifesting in different clinical features depending on TBI severity, nature of the lesion s , mechanism of the injury, underlying pathology, and pre-morbid factors. Further, it is possible that cannabinoids may improve some symptoms of TBI, while simultaneously worsening or causing other symptoms. As demonstrated in our systematic review, there is a dearth of literature only eight published studies on the effects of cannabis on TBI in humans. The following sections therefore briefly review the extant literature of medical and recreational cannabis use broadly to hypothesize its potential beneficial and adverse effects on TBI. Findings on neuroimaging are proxy measurements for underlying primary and secondary brain-related biological mechanisms associated with both TBI and cannabis use and therefore may elucidate how cannabis interacts with TBI in the CNS. Moderate and severe TBI is commonly associated with frank pathology on structural imaging and eventual atrophy. Traditional structural imaging techniques typically show no abnormalities for persons with mild TBI, 41 although more advanced imaging sequences frequently suggest other types of abnormalities such as reduced cerebral blood flow CBF or microstructural injuries. Studies across the full range of TBI severity typically have found local and global decreases in CBF and inverse neurovascular coupling. Notably, there has been one study of medical cannabis's effects on functional magnetic resonance imaging that suggests medical cannabis may provide beneficial alterations in neural functioning. Gruber and collegues 55 conducted a 3-month longitudinal study in persons using medical cannabis for a variety of conditions e. The results suggested an improvement in executive function task performance with increased activation in the cingulate cortex and frontal regions relative to baseline, similar regions that impact TBI. The authors suggested that besides potential effects from cannabis directly, other factors, including a reduction in conventional medications and improvement in psychiatric and physical symptoms, may have influenced the changes. However, as has been observed in the TBI literature, increased neural activity may also be the result of deleterious changes to the brain. Studies on recreational cannabis use show alterations in CBF, and resting-state and task-evoked brain activations relative to healthy controls. Recreational cannabis is generally associated with increased CBF after acute exposure and decreased CBF with chronic use, which is particularly prominent in frontal regions. Recreational cannabis use is also associated with decreased resting-state connectivity in the default mode network, which typically includes medial and lateral parietal, medial pre-frontal, and medial and lateral temporal cortices. Findings from neuroimaging studies suggest that both TBI and cannabis commonly affect pre-frontal and limbic neuronal circuitry, 66 , 67 providing the rationale for the potential synergistic effects on neural functioning. Whereas some effects on neuroimaging in both TBI and cannabis studies are associated with poorer task performances compared with healthy controls, 63 , 68 , 69 some studies, particularly ones that show increased activity relative to healthy controls, show no differences in performance in both TBI 52—54 and cannabis users. Cognitive changes are one of the most common sequelae after TBI. Studies have been limited in examining the effects of medical cannabis on cognition. However, the few that exist suggest that cognition may remain stable or improve with use. Participants reported a reduction in conventional pharmacological interventions use, reduction in depressive symptoms and impulsivity, and improved quality of life after 3 months of use. There was also improvement in performance on tasks of processing speed, set-shifting, and inhibition, 76 which may have also been attributed to improvements in psychiatric functioning. However, there were no differences between groups in performance on a cognitive screening measure and tests of psychomotor speed at baseline or after 3 months, suggesting that medical cannabis did not cause cognitive changes. In contrast, recreational cannabis and experimental administration of cannabinoids to healthy controls have shown to adversely affect the domains of memory, attention, executive functioning, psychomotor speed, and motivation, 78—80 which overlap with the cognitive impairments observed in TBI. Further, impaired cognition resulting from medical cannabis can potentially impact everyday functioning, such as driving, 86 , 87 which may already be impacted as a result of TBI. CB 1 receptor activation increases 5-HT neuron firing and reduces hypothalamus-pituitary-adrenal axis activity. However, while PTSD is an approved condition for medical cannabis, depression, and anxiety are not in the United States. Little is known about the adverse psychiatric effects associated with medical cannabis. Persons with TBI may seek medical cannabis to treat physical symptoms associated with their injury, such as pain or sleep disturbance. THC is associated with sedation, which may be related to increasing adenosine or inhibition of the arousal system. Placebo-controlled studies examining cannabis's effects on sleep are limited, however. Cannabis may only have a short-term beneficial impact on sleep that diminishes over time attributable to increased tolerance or habituation to its sleep-related effects. Despite the promising results from pre-clinical studies, human studies of medical cannabis and TBI have been limited. An exhaustive search of the literature was completed with consultation with an expert medical librarian. Importantly, a formal systematic or scoping review was attempted, but could not be completed because of to the paucity of literature. Articles were included if they met the following criteria: 1 peer-reviewed original research articles i. The abstracts were reviewed for each of these articles. One phase II clinical trial on TBI and medical cannabis was found through one of the articles in this search because it was a commentary on the clinical trial. Eighty records were retrieved. Thirty-eight records were retrieved. PRISMA flow diagram detailing identification, screening, evaluation, and inclusion of articles in this review. Three of the authors D. Disagreements between the reviewers were reconciled with consensus. Published abstracts by McVige and colleagues , and Shetty and colleagues were included in the review because of the paucity of published research articles. Because of this limitation, they were not given SORT ratings because of limited information. A total of eight studies were included in this review, including four case-control studies, two RCTs, one prospective cohort study, and one focus-group survey-based study. Four of eight studies examined TBI outcomes related to medical cannabis, whereas the remaining studies focused on recreational use. One of the case-control studies used International Classification of Diseases codes related to TBI and positive toxicology screen of THC for participant inclusion criteria. However, the remaining studies were less specific with their TBI criteria and used questionnaires or medical record review to assess cannabis use information see Table 1 for full diagnostic criteria for each study. Treatment effects included a reduction in intracranial pressure, cerebral perfusion pressure, and systolic blood pressure, with trending effects on neurological outcome measures, including the Glasgow Outcome Scale and Galveston Orientation and Amnesia Test. The next group of studies was largely uncontrolled and suggests that patients with TBI may use recreational or medical cannabis to treat their symptoms. The last group of studies provides some support for the neuroprotective hypothesis of cannabinoids for TBI. A recent study examining the effects of recreational cannabis, alcohol, and cigarette use on concussion within 2 weeks post-injury found that of the participants in the study, At 3- and 4-week follow-up, acute post-injury cannabis use was associated with reduced symptom severity scores on the Sport Concussion Assessment Tool 5 SCAT5 compared with non-users. Cannabis use, however, was not associated with physician-determined recovery, given that it did not impact additional markers of recovery such as changes in everyday functioning and exertion tolerance. Another study compared mortality rates of persons who had a positive toxicology screen for THC at the time of injury. Compared to those who had a negative toxicology screen, those who had a positive screen had a statistically lower mortality rate 2. THC has a long terminal half-life attributable to its pharmacokinetics, 14 so in polysubstance users, THC may be the only substance present in the body in active amounts. Alternatively, polysubstance use, rather than THC alone, may be a protective factor in acquired trauma. One possibility for this is that acute substance use may be associated with less severe TBIs attributable to their association with lower impact events, such as falls or violence. There are considerable challenges in both the research and clinical care of patients using medical cannabis. Medical cannabis is not carefully controlled or regulated, with studies showing discrepancies between product labels and actual active ingredient in the medical cannabis product. Additionally, those who are using cannabis for medical purposes may not be registered to use medical cannabis and may self-medicate. Therefore, healthcare providers may be unaware of their patients' use. Further, medical cannabis users have also reported negative social and economic aspects of medical cannabis, which include high cost and stigma of use from the public and their doctors. Specifically, as summarized above, there are reports of reduced psychiatric symptoms, 17 pain, sleep disturbance, , and improved cognition 76 in the medical cannabis literature whereas research from the recreational literature suggests opposite and deleterious effects. First, medical cannabis users are more likely to use cannabis almost daily, be in poorer medical health, and are less likely to meet criteria for a substance use disorder or use illicit substances. In contrast, medical cannabis products may contain higher concentrations of CBD than recreational cannabis, which may mitigate the effects of THC, 76 , although contrary evidence for this concentration difference also exists. That is, effects will likely differ based on distinct pathophysiology of different disorders and how that overlaps with alterations in CB signaling or in how the brain responds to cannabis intake. Extrapolating the potential effects of medical cannabis for TBI treatment primarily based on recreational use is problematic because of potentially different publication biases. Specifically, recreational studies tend to focus on harmful outcomes whereas medical studies often focus on beneficial outcomes. Moreover, the uncontrolled nature of the majority of medical cannabis studies do not account for potential placebo effects, and recruitment generally consists of convenience or self-selected samples obtained in the course of regular clinical care. To date, there are no nationally representative samples. This is also true for pre-clinical studies, given that negative studies may be less likely to be published and may explain some of the issues with translating pre-clinical studies to humans. Notably, the current systematic review was limited to medical cannabis treatment for TBI rather than also covering pre-clinical findings as well as recreational use. In addition to exploring which cannabinoids and ratios of cannabinoids are most efficacious for TBI, an understudied area is the differences among routes of administration. Different routes of administration have vastly different pharmacokinetics e. The lack of these types of studies will likely remain a challenge given cannabis's illicit history and current status as a Schedule I controlled substance. This means that cannabis is considered to have no acceptable medical use and has a high potential for abuse see dea. This may be changing, given that the U. However, even with new studies, results may not generalize to all potential medical cannabis users, given that often in clinical trials, persons with complex medical, psychiatric, and substance use histories are excluded. Several general key outstanding questions remain. Clinical trials are needed to determine appropriate dosage and THC-to-CBD ratios, method, and duration of use to maximize potential benefits and minimize risks. These studies should include indices associated with the pathophysiology of TBI e. It is also currently unknown how genetic factors associated with TBI prognostication or effects of cannabis can affect outcomes of patients with TBI using medical cannabis. Studies will also benefit from incorporating neuroimaging techniques, cognitive testing, and monitoring of psychiatric and physical symptoms, given that past research has demonstrated both positive and negative associations with cannabis in these domains. Although some studies of medical cannabis in non-TBI populations show some promising findings on neuroimaging, cognitive testing, and psychiatric and physical symptoms, there also is the concern that the large body of research on recreational cannabis shows detrimental effects across these domains. Thus, additional information is needed about what variables moderate these potential effects. Additionally, little is known about symptom or performance validity in medical cannabis users although, in mild TBI, symptom and performance validity is quite well understood. This view must be balanced with the fact that many recreational users of cannabis may, in fact, be using it through a self-medication regime. In conclusion, medical cannabis may represent a viable treatment for TBI, but the research is very much in its infancy. The lack of high-quality experimental studies makes it difficult to draw concrete conclusions about the positive and negative effects of medical cannabis on TBI. Pre-clinical studies of medical cannabis demonstrating its neuroprotective qualities have yet to translate into human studies, mainly because very few studies on the topic exist. This review has identified several key research directions in TBI in the topics of neuroimaging, cognition, psychiatric, and physical symptoms that need to be addressed. As a library, NLM provides access to scientific literature. J Neurotrauma. Find articles by Danielle C Hergert. Find articles by Cidney Robertson-Benta. Find articles by Veronik Sicard. Find articles by Daniela Schwotzer. Find articles by Kent Hutchison. Find articles by Dan P Covey. Find articles by Davin K Quinn. Find articles by Joseph R Sadek. Find articles by Jacob McDonald. Find articles by Andrew R Mayer. Issue date Jul Copyright , Mary Ann Liebert, Inc. Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. 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