A total of case reports involving cannabis both raw and synthetic intake and neurovascular complications have been studied since to Table 1 and it has been postulated from all these reports that there may be a link between these two events although this correlation has not been established strongly yet.
Table 1 List of case reports related to neurovascular complications after natural and synthetic cannabinoid use according to year; — Considering Table 1 it is found that, young population is experiencing alarming number of neurovascular complications due to recreational use of cannabis. However, the occurrence of neurovascular complication among middle aged and older people was significantly lower compared to the young and adult population with a value of 5.
This data clearly indicates that, young people are severely affected by neurovascular diseases as they consume cannabis in higher amount compared to older people. Moreover, compilation of these case reports indicates that along with cannabis or cannabinoids use, other risk factors like alcohol, tobacco, dyslipidemia, migraine without aura, hypertension etc. Interestingly, it can also be noted from these case reports that the occurrence of neurovascular diseases such as stroke has drastically increased after Widespread availability of cannabis or synthetic cannabinoids and its legalization across the world may be the underlying reasons behind this.
Due to the alarming effect of cannabinoids on public health, several population-based studies have been performed to correlate the relation between cannabinoid exposure as well as cerebrovascular diseases. Various studies demonstrated that cannabinoids may act as a risk or prognostic factor for cerebrovascular diseases such as stroke Westover et al.
Table 2 summarizes all the findings from population-based analysis, conducted between and Table 2 Summary of population-based analysis related to cannabis use, conducted between and The result from these large sample size studies provide information on the temporal relationship between cannabis use and cerebrovascular complications like intracerebral hemorrhage ICH , subarachnoid hemorrhage SAH , and ischemic strokes IS.
Along with cannabinoids, other predominant risk factors were also considered in the assessments however, these studies have several limitations. This include lack of consideration for the high lipid solubility of cannabis metabolites which helps them to persist in fatty tissues, therefore they may be detected in the urine weeks after the initial use Mateo et al. It is evident from various studies that, consumption of cannabinoids through inhalation and combustion, is associated with the occurrence of cerebral infarcts Garrett et al.
Natural cannabis and synthetic cannabinoids may act as possible trigger for reversible intracranial vasoconstriction Wolff et al. Different types of mechanisms might be involved in the development of stroke in cannabis users including orthostatic hypotension with the secondary impairment of the CBF autoregulation, altered cerebral vasomotor function, supine hypertension, and fluctuations in blood pressure, cardioembolism with atrial fibrillation, vasculopathy and vasospasm Singh et al.
Although none of these mechanisms have been fully vetted to explain the association between use of cannabis and stroke occurrence, reversible cerebral vasoconstriction triggered by cannabis could be the most convincing theory to explain it Wolff and Jouanjus, It was shown in different case reports that, cannabis use was associated with reversible multifocal intracranial arterial stenosis Noskin et al. Along with this, another eye-catching mechanism to explain the relationship between cerebrovascular complications and cannabis use could be the cellular effect of cannabis on brain mitochondria.
A recent in vivo study conducted on mice has shown that THC inhibited the complexes I, II, and III of the respiration chain of mitochondria and increased the amount of hydrogen peroxide production Wolff et al.
This strongly suggests that ROS production and therefore, oxidative stress, could be the linking mechanism between cannabis use and stroke.
This well cope with current knowledge that oxidative stress and inflammation are established prodromal factors for the onset of stroke and other neurological disorders in humans Chen et al. 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. 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.
Different preclinical studies demonstrated the effects of cannabinoids and cannabinoid receptors on stroke outcome, One of particular interest is the fact that cannabinoids not only decreased infarct volume following an ischemic stroke both transient and permanent occlusion models , but also improved early and late functional outcome England et al. Furthermore activation of the endogenous cannabinoid signaling pathway as indirectly demonstrated by a study conducted on CB1 receptor knockout mice which exhibited increased mortality, severe infarct size, and neurological deficits after transient local cerebral ischemia, reduced cerebral blood flow, and increased N-methyl-d-aspartate NMDA neurotoxicity when compared to wild type Parmentier-Batteur et al.
Post-stroke inflammatory responses can be reduced by CB2 ligands whereas, activation of CB1 receptors promotes chemical hypothermia. Both processes result in a reduced stroke infarct volume Leker et al. Specifically, activation of CB1 receptor activation reduces glutamate release Hayakawa et al.
On the other hand, CB2 receptors activation results in reduced pro-inflammatory cytokines release, neutrophil recruitment Murikinati et al. Another study demonstrated that CB2 receptor plays a major role in driving neuroblast migrations as well as subsequent neurogenesis in the peri-infarct cortex after experimental stroke in mice which positively impact stroke outcome. It was also suggested that, endocannabinoid tone is essential for this process by promoting migration of neuroblasts toward the injured brain tissue which leads to increased number of new cortical neurons.
As a result, motor functional recovery is increased which is beneficial for improving the outcome of aged patients as well as reducing their disabilities after chronic stroke Bravo-Ferrer et al.
Even though these preclinical studies suggest a neuroprotective action of cannabinoids and cannabinoid receptors on stoke outcome, the matter is far from being set. In fact, conflicting results remain Rivers-Auty et al. Rivers-Auty et al. Another study conducted by Garberg HT et al. Finally, most of the neuroprotective effect of cannabinoids related preclinical studies did not evaluate stroke outcomes with behavioral studies however, behavioral studies are integral part of stroke outcome research Alamri et al.
Investigators tried to correlate stroke outcomes with histological scores. Since histological improvement does not confirm long term post stroke benefits Clarkson et al.
Furthermore, there are no human studies to confirm or refute these in data and properly assess the post-stroke effects of cannabinoids as neuroprotectant. Cannabis based medications for instance nabiximols and THC have therapeutic potential against some symptoms associated with neurological diseases such as multiple sclerosis, chronic pain Cohen et al.
Exogenous cannabinoids such as CBD and nabilone are also found to have therapeutic activity in psychiatric disorders including schizophrenia, posttraumatic stress disorder PTSD and general and social anxiety Cohen et al. Although cannabinoid-based drugs have shown some therapeutic activities against neurological and psychiatric disorders the effect of cannabis on the neurological system cannot be denied.
It has been demonstrated from various in vivo studies that THC is responsible for inducing dose-dependent toxicity as well as causing structural changes in those parts of brain which are rich in CB1 receptors.
These receptors are located primarily in cerebellum, hippocampus, amygdala, prefrontal cortex, and striatum Lawston et al. However, studies conducted on human brains assessing the long term cannabis use and related brain structural changes do not fully confirm these findings although changes in the density of gray or white matter have been reported in different regions of frontal and parietal lobes Matochik et al.
This disconnect between in vivo and human studies might be due to the different sample characteristics, inter-individual variabilities related to past history of drug use, consumption rate, psychological problems, and differences in the experimental methodology Batalla et al. These regions of the brain control motivation, emotion, and affective processing Battistella et al. Various studies reported that, adolescents can experience persistent deficiency in different cognitive functions including attention, memory, and processing speed due to chronic cannabis use Chadwick et al.
It has been found from neuropsychological tests and advanced imaging techniques that, learning process of adolescents can be affected by cannabinoid use as well Rivera-Olmos and Parra-Bernal, Additionally, fatal brain development can also be affected by cannabis exposure during pregnancy which may ultimately result in impaired vision and coordination, larger intermittent attention, as well as behavioral problems in children at later phase Wu et al.
Also, different psychiatric diseases Table 3 including schizophrenia, bipolar disorder, social anxiety, and suicidal thought are found to be higher in cannabis users compared to non-users Mental Health, These detrimental effects of cannabinoid may vary from person to person because of genetic variability. Besides, these detrimental effects can also depend on the age of the user.
For instance, the exposure of adolescents to cannabinoids leads to severe memory impairment compared to adult Jouroukhin et al. Several studies have demonstrated the potential role of gene variation on the development of psychosis due to cannabis use NIDA, a.
It has been found that risk of psychosis among the daily cannabis users carrying a specific variant of AK21 gene is seven times higher compared with those who use it infrequently or never used Di Forti et al. Another study revealed an increased risk of psychosis among adults who carry a specific variant of the gene for catechol-O-methyltransferase COMT enzyme and used cannabis during adolescence. This enzyme can degrade different neurotransmitters for instance, dopamine and norepinephrine Caspi et al.
Interestingly, cannabis use has also been shown to worsen the condition of schizophrenic patients. Cannabis can cause an acute psychotic reaction at high doses, in non-schizophrenic people who are cannabis users, although this fades as the drug effects wears off NIDA, a.
Although the mechanism behind THC induced cognitive and behavioral dysfunction is yet to be established, recent studies conducted on mice model have demonstrated that these detrimental effects are facilitated by astrocyte CNR1 Han et al.
Interestingly, all the cannabis users do not experience cognitive impairment which clearly suggests the impact of genetic vulnerability on detrimental effects of cannabis Blanco et al. This activation results in excessive glutamate secretion and decreased immunoreactivity of parvalbumin-positive presynaptic boutons around pyramidal neurons of the CA3 area of the hippocampus as well as impaired memory. It has been suggested from this research that, COX-2 inhibitors can prevent these cognitive deficits which may act as a potential target for future studies Jouroukhin et al.
It is well established that oxidative stress OS is associated with vascular endothelial dysfunction in a causative and dose dependent manner. Current scientific opinion considers the exposure to reactive oxygen species ROS; e.
At the cerebrovascular level OS promotes oxidative damage and BBB breakdown via tight junction TJ modification as well as activation of proinflammatory pathways Pun et al. Activation of the Nuclear factor erythroid 2-related factor NRF2 , a redox-sensitive transcription factor which, in turn, promotes the activation of several biological systems encompassing anti-inflammatory molecules, antioxidants, drug metabolizing enzymes including cytochrome Ps , and free radical scavengers, also plays a critical protecting role against OS However, chronic exposure to OS stimuli [such as that to tobacco smoke Prasad et al.
From the point of view of oxidative stress, several studies suggest that smoking marijuana is not much different than smoking tobacco. Sarafian et al. In addition, other investigators found that THC, the main psychoactive component in the cannabis, acts as a potent promoter of OS and inflammation, thus appearing as a risk factor for the onset of ischemic stroke Wolff et al. On the other hand, there are also evidences that non-psychoactive CBDs, can have neuroprotective effects by reducing the reactivity of microglial cells, and transmigration of leukocytes through downregulation of chemokines, interleukin-1, and vascular cell adhesion molecule-1 Mecha et al.
In vitro studies using amyloid-beta-stimulate PC12 neurons CBD could inhibit the activity of inducible nitric oxide synthase, thus preventing the production of nitric oxide and reducing OS Esposito et al.
By contrast, in vivo studies to assess the protective effect of cannabis treatment against OS development and nigrostriatal cell injury induced by intrastriatal injection of rotenone did not produce any significant result Omar, Unfortunately, there are contrasting results concerning the oxidative and antioxidative property of cannabinoids.
Some of these controversial results could be attributed to the length of exposure such as acute vs. As for the overall pro-oxidative effect of smoking marijuana, it is very likely that ROS are generated as a byproduct of combustion rather than a direct effect of cannabinoids. Similarly to tobacco smoke where most of the oxidative stress is generated by the combustion of tobacco rather than exposure to nicotine which can also promotes OS but to a much lower extent Naik et al.
Cannabis or marijuana is the most widely used recreational drug and around million people use it around the world 2. Now-a-days cannabis use among young people especially teenagers has been increased drastically as a recreational element. National Institute of Drug Abuse reported that, It has also been found that, cannabis use among college students in US remains at the highest level in last three decades.
This data clearly indicates the widespread use of cannabis among youth and it is the high time to elucidate the consequence of cannabis use in human. Although the direct effect of cannabis exposure and health consequences is still unknown, numerous case reports, population-based studies as well as animal studies demonstrated the potential link between cannabis use and neurovascular as well as neurological diseases.
It is evident from various studies that, recreational use of cannabinoids is related to both cardio and cerebrovascular events such as ischemic and hemorrhagic stroke Goyal et al. Unfortunately, both cerebrovascular and neurological disorders are found to be higher in young population as they are the main consumer. Although the underlying mechanism behind cannabis use and occurrence of cerebrovascular diseases has not been elucidated yet, the handful of case reports and preclinical studies on animal model highlighted provide some plausible insights.
These includes but not limited to reversible cerebral vasoconstriction Wolff et al. A very recent report showed that, genetic modifications as well as age of consumers play a pivotal role in developing neurological disorders Jouroukhin et al. However, additional and more specific studies will be necessary to determine their relevant contribution to the onset of cerebrovascular and neurological disorders.
To the best of our knowledge, a very few studies have been performed to understand the mechanism of detrimental effect of cannabis on both neurology and the BBB. Since the BBB restricts the communication between blood and brain parenchyma and maintains cerebral homeostasis, damage of BBB results in neuronal dysregulation and degeneration. Therefore, it is evident the studying the effects of cannabis and particularly chronic exposure to it, should be considered a major target for future studies.
SA conceived the study and prepared the drafting of the manuscript. LC assisted with the drafting of the manuscript and preparation of the figures.
LC also oversaw the entire project and provided funding support. All authors reviewed the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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You have to be open-minded in an area that is continuing to evolve. What is the truth of the positive health benefits? I would prefer that we use FDA-approved medications when possible. They are much safer, and you can be sure of the purity and potency. But there is evidence to support the use of cannabis and cannabinoids for a handful of medical conditions. That is dwarfed by the number of conditions for which people are actually using it, but the evidence of benefit is not zero.
Just by having that conversation, you could do a lot of good. HILL: In , we had two FDA-approved cannabinoids, dronabinol and nabilone, for nausea and vomiting associated with cancer chemotherapy, and for appetite stimulation in wasting conditions. Last year they added cannabidiol — only one version is FDA-approved — and it is for a couple of pediatric epilepsy conditions. Beyond the FDA-approved indications, the best evidence is for three things: chronic pain, neuropathic pain — which is a burning sensation in your nerves — and muscle spasticity associated with multiple sclerosis.
There are more than six randomized control trials for each of those three conditions. There are problems associated with some of those trials — sample sizes are small and the follow-up periods are not as long as we would like them to be.
HILL: Schedule 1 really means two things. Number one, does it have addictive potential? Cannabis does, clearly. But it also means that there is no medical value. Funding is a bigger barrier. There are permanent crowd-control ropes in the parking lot and a police detail. A lot of people are profiting from cannabis while neglecting to contribute to the scientific evidence base. HILL: Over 22 million Americans used cannabis last year, and the literature says about 10 percent of those are using medicinally.
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