Who is affected by cannabis use

Skip directly to site content Skip directly to page options Skip directly to A-Z link. Marijuana and Public Health. Section Navigation. Facebook Twitter LinkedIn Syndicate. Moreover, the hemorrhagic stroke occurrence has been rarely reported in different studies Goyal et al.

Several neurological disorders such as cognitive dysfunction, behavioral problems, memory, attention deficiency, structural, and functional changes in brain have been observed in different studies related to cannabis exposure Chadwick et al.

Increased use of cannabis or cannabinoids is associated with several complications related to different organs including the neurological and cerebrovascular system in human body. Due to this, exhaustive studies need to be performed to establish the possible link between cannabis inhalation and neurological and cerebrovascular effect. Keeping the popularity of cannabis use in mind, the aim of this review article is to list the neurological and cerebrovascular effects of marijuana inhalation including the probable mechanisms related to these effects.

Case reports based on cannabis inhalation and cerebrovascular diseases were also searched and evaluated for inclusion in this review. Peer-reviewed articles presenting results of experimental studies in animal models and population-based studies were analyzed and presented in this review paper.

Cannabinoids CBs are a group of chemical compounds which have varying affinity to cannabinoid receptors. Generally, cannabinoids can be classified into three groups namely, phytocannabinoids isolated from natural source, C. Although cannabinoids can be extracted naturally from the plants, it can also be cultivated indoors using hydroponic and artificial lighting system nowadays. It was first cultivated in Central Asia however gradually it was brought to cultivate all over the world Singh et al.

Generally, it is collected from three strains of cannabis plant named C. THC was isolated as one of the first phytocannabionoids Gaoni and Mechoulam, In the plant C. Usually, the buds and the leaves of the cannabis plants contain the highest amount of psychoactive ingredient, THC.

This THC can be taken up from dried buds and leaves by smoking as well as it can be taken in other forms for instance edibles, waxes, oils, liquid incense, or vapor for both medical and recreational uses. For medical purpose, cannabis has been used to treat nausea and vomiting due to chemotherapy, neuropathic pain related to cancer and advanced neurological disorders Singh et al. However, the popularity of cannabis use lies in its recreational purposes.

Therefore, in spite of being listed as a schedule 1 substance according to the Section of the Controlled Substances Act of by Drug Enforcement Administration of USA, the use of cannabis has been legalized or decriminalized in different states of USA Singh et al.

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.

Besides natural sources, THC compounds can be synthesized for both medical and recreational uses. Since , two synthetic THC compounds named dronabinol and nabilone have been using in USA in capsule forms for treating nausea, vomiting, and weight loss related to chemotherapy and acquired immunodeficiency syndrome. Besides, highly potent cannabinoids and cannabimimetics can be synthesized illegally by altering the structure of THC in numerous ways for recreational purposes which have already gained popularity among the users due to its potency, longer duration, and the failure of conventional drug screening tests to recognize the compounds Gurney et al.

More than chemicals are present in C. During cannabis smoking, over 2, compounds including hydrocarbon, nitrogenous compounds, amino acids, fatty acid, sugar etc. Smoking a to 1, mg cannabis cigarette provides a THC dose of 0. THC is absorbed and reaches high blood concentration rapidly after inhalation through lungs Vandevenne et al. Due to extensive lipid solubility and large volume of distribution, THC has a long biological half-life 18 h to 4 days Adams and Martin, ; Ashton, and gets distributed in adipose tissue, liver, lung, and spleen Chiarotti and Costamagna, ; Sharma et al.

On the other hand, systemic absorption of THC is relatively slow after oral ingestion compared to inhalation. Regular cannabis use can be defined as taking cannabinoids 10 to 19 times monthly, whereas heavy use can be termed as using 20 times in a month. However, both regular and heavy use of cannabis are related to several chronic health problems including anxiety, depression, and neurocognitive alterations Hall and Degenhardt, Cannabinoids interact directly with our body through a complex system named endocannabinoid system which helps to maintain homeostasis of body by regulating metabolism, intercellular communication, appetite, and memory, immune, and pain responses.

CB receptors mainly belong to the G-protein coupled receptor GPCR family, having inhibitory function on the cyclic adenosine monophosphate cAMP pathway through intracellular signal transduction Richter et al. Although CB1 receptors are scattered all over the body, these are present predominantly in anatomical regions of the brain Grotenhermen, related to memory, anxiety, cognition, pain sensory, motor coordination, endocrine function Herkenham et al.

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.

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. On the other hand, CB2 receptors are located in peripheral nervous system and immune system and the primary function of this receptor is anti-inflammatory activity through initiating an immune response to reduce inflammation as well as tissue damage Turcotte et al. Also, it plays a pivotal role in the immune suppressive action of the cannabinoids Sharma et al.

The psychoactive agent of cannabis, THC binds with the cannabinoid 1 CB1 receptor in the brain and the non-psychoactive component, CBD is the most likely to interact with cannabinoid 2 CB2 receptor and exert their activities. Therefore, cannabis is used in medical purposes to reduce inflammation, relieve pain, and decrease seizures Rivera-Olmos and Parra-Bernal, ; Perucca, Thus, the cerebrovascular system refers to the blood vessels through which blood is carried out to and from the brain.

The cerebrovascular anatomy has an endocranial and exocranial component that can be further divided into the anterior and posterior circulation based on the contribution of blood flow through the internal carotid arteries ICAs and vertebral arteries, respectively Hendricks et al. It transports essential nutrients which are required for the normal metabolism of the brain cells Sivandzade and Cucullo, The BBB is primarily composed of endothelial cells, pericytes, and astrocytes restricting the communication between blood and the brain parenchyma Abbott et al.

As a result, the BBB plays a pivotal role in restraining the entry of neurotoxic plasma components, xenobiotics, blood cells, and pathogens in the brain Winkler et al. On contrary, the BBB also limits drug delivery into the brain to treat different neurological diseases Abbott, ; Kaisar et al.

Abbott et al. Breakdown of BBB has been observed in many functional imaging of human patients and postmortem brain samples in various neurological diseases. This breakdown not only causes edema and disrupts ionic homeostasis but also results in altered signaling and immune infiltration. As a consequence, BBB breakdown leads to neuronal dysregulation and ultimately to neuronal degeneration Daneman and Prat, Studies on acute neurovascular events related to cannabis use have appeared as early as Mohan and Sood, Stroke is the fifth leading cause of death in USA Vijayan et al.

To examine the effect of cannabinoids on blood circulation as well as reactive vasodilation or vasoconstriction, particularly focusing on the cerebral vascular bed, several studies on rat, mouse, rabbit, cat, and pig models were performed Richter et al.

On the other hand, all perfused cerebral vessels reacted with wall relaxation in case of large mammals Richter et al. Additionally, three studies on rat models Bloom et al. Other studies involving rat and pig models have demonstrated the cerebrovascular dilation due to cannabinoids perfusion Hillard et al.

No study reported any possible mechanism underlying vasoconstrictive effect due to cannabis. It has also been suggested that, vasodilating effect could be beneficial or detrimental depending on the time of vasodilation after CNS insult.

As vasodilation reduces the peripheral resistance and increases CBF, this may serve as a protective mechanism and increase oxygen supply in case of a cerebral insult. This protective mechanism may be beneficial in early stages of ischemia. However, if it happens in a later stage, it might augment the recuperation of cerebral function Richter et al. As these studies were conducted in different variety of animal models involving different experimental setup, cannabinoid molecules, and their respective doses, it is difficult to draw any conclusion Richter et al.

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.

Brain health: Marijuana can cause permanent IQ loss of as much as 8 points when people start using it at a young age. These IQ points do not come back, even after quitting marijuana. Mental health: Studies link marijuana use to depression, anxiety, suicide planning, and psychotic episodes. It is not known, however, if marijuana use is the cause of these conditions. Athletic Performance: Research shows that marijuana affects timing, movement, and coordination, which can harm athletic performance.

Driving: People who drive under the influence of marijuana can experience dangerous effects: slower reactions, lane weaving, decreased coordination, and difficulty reacting to signals and sounds on the road. Daily life: Using marijuana can affect performance and how well people do in life. Research shows that people who use marijuana are more likely to have relationship problems, worse educational outcomes, lower career achievement, and reduced life satisfaction.

Over the past few decades, the amount of THC in marijuana has steadily climbed; today's marijuana has three times the concentration of THC compared to 25 years ago. The higher the THC amount, the stronger the effects on the brain—likely contributing to increased rates of marijuana-related emergency room visits.

While there is no research yet on how higher potency affects the long-term risks of marijuana use, more THC is likely to lead to higher rates of dependency and addiction. Marijuana refers to the dried leaves, flowers, stems, and seeds from the Cannabis sativa or Cannabis indica plant.

Marijuana is a psychoactive drug that contains close to chemicals, including THC, a mind-altering compound that causes harmful health effects. National Institutes of Health. Drug Topics. More Drug Topics. Quick Links.