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Cannabis and Cannabinoid Biology in Stroke: Controversies, Risks, and Promises

Authors:
1
Stroke is the fifth leading cause of death and affects 0.8
million Americans annually.1 The causes, duration, local-
ization, and injury severity, as well as the presence of comor-
bidity factors, impact the overall outcome and likelihood of
survival. The current therapeutical approach for acute ischemic
stroke includes thrombolysis and mechanical thrombectomy.
Reperfusion with intravenous alteplase (recombinant tissue
plasminogen activator; activase and actilyse) remains the
mainstay treatment for ischemic stroke, and a recent pooled
analysis of 9 clinical trials showed that this therapy is bene-
ficial regardless of patient age and stroke severity, as long as
it can be administered within 4.5 hours of onset.2 Although
alteplase increases the risk of early hemorrhage, the number
of patients with a good outcome exceeds the ones with a fatal
intracranial hemorrhage.2
Nevertheless, immediate reperfusion therapy does not di-
rectly address the secondary neurological sequelae that lead
to continued brain injury after stroke. Depending on injury se-
verity, complex cascades of biochemical events are activated,
generating deleterious responses, such as excitotoxicity, ox-
idative stress, and inflammation that affect both the central
nervous system and the overall stroke outcome. Homeostatic
cellular functions governing ATP-dependent ion gradients,
calcium influx, endoplasmic reticulum, and mitochondrial
function, membrane stability, redox balance, and blood-brain
barrier permeability all become dysfunctional after ischemic
stroke.3 Pharmacological interventions targeting 1 steps of
this cascade have led to the development of many neuropro-
tective drugs over the last 2 decades.4 While some of the drugs
produced encouraging results, particularly when combined
with alteplase therapy, many proved ineffective in clinical tri-
als.5 Consequently, no neuroprotective treatment options cur-
rently exist to improve neurological outcome after ischemic
stroke, making it imperative to conduct new research for novel
therapies.
Endocannabinoid System
In recent years, the endocannabinoid system (ECS) has be-
come the subject of great interest in neurobiology and neuro-
pharmacology, mainly because of its predominant distribution
in the central nervous system.6 The ECS is composed of
endocannabinoids, endogenous lipid-based retrograde neu-
rotransmitters that bind to the cannabinoid receptors CB1
and CB2, as well as cannabinoid receptor proteins expressed
throughout the central nervous system and peripheral nervous
system (Figure). Importantly, modulating the activity of the
ECS turned out to hold therapeutic promise in a wide range of
pathological conditions and neurological disorders.6
The ECS has emerged as a new therapeutic target in a
variety of neurological disorders with a robust neuroinflam-
matory component that leads to brain tissue injury.7 There
is convincing evidence that the components of the ECS are
altered during ischemic stroke in both animals and humans,
indicating that this system may contribute to the consequences
of ischemic stroke.8 Although numerous studies have exam-
ined the effects of cannabinoids and the role of the ECS in
experimental models of ischemic stroke, results have been
somewhat conflicting in support of either a beneficial or det-
rimental role. Nevertheless, a recent systematic review and
meta-analysis of the currently available preclinical studies
reported neuroprotective effects from a range of approaches
to use of cannabinoids.9 The main advantage of cannabinoids
in neuroprotection is their broad-spectrum activity at multiple
cellular and molecular mechanisms that involve not only the
ECS itself but also the immune system.10 Cannabinoids can
limit excitotoxicity, oxidative stress, and neuroinflammation,
and to enhance the trophic and metabolic support of neu-
rons by acting through either specific cannabinoid receptor–
mediated signaling pathways or via direct interactions with
transcription factors. There are no previous or current clin-
ical trials using cannabinoids in stroke, but their pleiotropic
effects on the ischemic penumbra and cerebral vasculature
after stroke, combined with their excellent tolerability, make
them promising candidates for future treatment development.
Neurological Benefits of Cannabis
and Cannabinoid Use
Cannabis (Cannabis sativa), also known as marijuana, has
been used for centuries as a medicinal and recreational drug.
It contains >120 different cannabinoids that have been identi-
fied, but the role and importance of most of them are yet to
be fully understood.11 Broadly, cannabinoids are defined as
phytocannabinoids, synthetic cannabinoids, and endogenous
cannabinoids. The 2 most notable and thoroughly investigated
phytocannabinoids are the 9-tetrahydrocannabinol (THC)
and cannabidiol (CBD). Studies of 9-THC and CBD led
From the Cerebral Microcirculation Section, Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke,
National Institutes of Health, Bethesda, MD (S.-H.C., Y.M., A.C.S.); and Department of Neurobiology, University of Pittsburgh, PA (S.-H.C., Y.M., A.C.S.).
Correspondence to Afonso C. Silva, PhD, Department of Neurobiology, University of Pittsburgh, 3501 Fifth Ave, 6065 Biomedical Science Tower 3,
Pittsburgh, PA 15261. Email afonso@pitt.edu
Cannabis and Cannabinoid Biology in Stroke
Controversies, Risks, and Promises
Sang-Ho Choi, PhD; Yongshan Mou, MD; Afonso C. Silva, PhD
(Stroke. 2019;50:00-00. DOI: 10.1161/STROKEAHA.118.023587.)
Section Editors: Anna M. Planas, PhD, and Midori A. Yenari, MD
© 2019 American Heart Association, Inc.
DOI: 10.1161/STROKEAHA.118.023587Stroke is available at https://www.ahajournals.org/journal/str
Stroke
Basic Science Advances for Clinicians
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2 Stroke September 2019
to the discovery of the 2 endogenous cannabinoid receptors
CB1R (cannabinoid receptor type 1) and CB2R (cannabinoid
receptor type 2).12,13 THC exerts its well-known psychoactive
effects, including relaxation, euphoria, dreaminess, feelings
of anxiety, and paranoia, through the CB1R. THC has also
been demonstrated to impair cognition and psychomotor per-
formance.14,15 However, recent studies have shown that THC
promotes hippocampal neurogenesis and restores memory
and cognitive function in aged animals.16,17 Despite the bene-
ficial effects of THC, its psychoactive effects have limited the
medical use of cannabis.
On the contrary, CBD is known as the main nonpsycho-
active component of cannabis and has shown anti-inflamma-
tory, immunosuppressive, analgesic, and anxiolytic effects.
In particular, CBD has a low affinity in the micromolar range
for the cannabinoid receptors and was found to be an anti-
convulsant in animal models and humans with epilepsy.18
Although cannabis is still listed by the US Drug Enforcement
Administration as a schedule I substance of the Controlled
Substances Act, the US Food and Drug Administration
has approved on June 25, 2018, the first prescription drug
derived from cannabis for treating 2 rare and severe forms
of epilepsy.19 The Epidiolex oral solution contains highly
purified plant-derived CBD. In September 2018, the Drug
Enforcement Administration classified Epidiolex as a
schedule V substance, clearing the final hurdle for its legal
prescription in the United States. Although Epidiolex is the
first Food and Drug Administration–approved drug directly
derived from the cannabis plant, it is not the first cannabi-
noid-based drug approved in the United States. The Food and
Drug Administration approved 3 synthetic cannabinoid-based
drugs: Marinol, Syndros, and Cesamet. Marinol and Syndros
include the active component dronabinol—a synthetic form
of THC. Cesamet includes the active ingredient nabilone,
which is synthetically derived and has a chemical structure
similar to THC. All 3 synthetic compounds are prescribed to
adults for the treatment of nausea and vomiting associated
with chemotherapy, while Marinol and Syndros are also in-
dicated for the treatment of anorexia associated with weight
loss in AIDS patients. Although Epidiolex is currently only
approved for 2 rare forms of epilepsy, this sets a precedent
that may benefit the world of cannabinoid research.
Figure. Overview of biosynthesis and degradation of endocannabinoids and its multiple cellular actions in the brain. The endocannabinoid system is com-
posed of cannabinoid receptors (CB1 [cannabinoid receptor type 1] and CB2 [cannabinoid receptor type 2]), endocannabinoids (2-arachidonoylglycerol
[2-AG] and N-arachidonoylethanolamine [AEA]), and its synthesizing (DAGL [diacylglycerol lipase] and NAPE-PLD [N-arachidonoyl phosphatidyl ethanol-
preferring phospholipase D]) and degrading enzymes (MAGL [monoacylglycerol lipase] and FAAH [fatty acid amide hydrolase]). CB1 receptors are abundant
in the central nervous system, particularly in the cortex, basal ganglia, hippocampus, hypothalamus, and cerebellum. CB2 receptors are primarily present in
microglia and immune system and are highly inducible after tissue injury or during neuroinflammation. As a lipid signaling molecule, 2-AG readily cross the
membrane and activate CB1 receptors located in the presynaptic neurons. Activated CB1 receptor inhibits neurotransmitter release through the suppression
of calcium influx and activates potassium (K+) channels, as well as induces the activation of AKT (protein kinase B) and MAPK (mitogen-activated protein
kinase) survival pathway. Although 2-AG mainly mediates retrograde endocannabinoid signaling, AEA also activates presynaptic CB1 receptors and intra-
cellular CB1 receptors as well. 2-AG functions as the primary cannabinoid receptor signaling molecule. 2-AG is also a significant precursor for arachidonic
acid (AA) and, therefore, plays a substantial role in proinflammatory pathways. 2-AG is synthesized from diacylglycerol by DAGL, whereas AEA is synthe-
sized from NAPE by NAPE-PLD. MAGL is the rate-limiting enzyme in the degradation of 2-AG. 2-AG also modulates the activity of microglia and astrocytes.
These glial cells also are a source for brain endocannabinoids. Increased number of microglia and astrocytes are typically found in the ischemic brain and
result in increased production of proinflammatory cytokines. This process leads to a change toward a more proinflammatory milieu in the brain. GABA indi-
cates gamma aminobutyric acid; NMDAR, N-methyl-D-aspartate receptor; PGs, prostaglandins; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol
4,5-bisphosphate; PLC, phospholipase C; and VGCC, voltage-gated calcium channel.
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Choi et al Cannabis and Cannabinoid Biology in Stroke 3
Accumulating preclinical studies suggest that cannabi-
noids have significant therapeutic value in stroke. A recent
systemic review and meta-analysis by England et al9 demon-
strated that all subclasses of cannabinoids, cannabis-derived,
synthetic, specific CB1R, and CB2R agonists, significantly
reduced infarct volume in transient and permanent ischemia
and improve both early and late functional outcome in exper-
imental stroke when given after stroke onset. CBD showed
trends to infarct reduction with delayed administration 6
hours after stroke onset.9 Repeated treatment with CBD from
day 1 or day 3 to day 14 improved functional outcome and
survival rates, which suggest that CBD may have neuroprotec-
tive effects not only at the early phase but also at the late time
point.20 Multiple targets have been proposed to mediate the
neuroprotective effects of CBD such as a combination of a po-
tent antioxidant, immunosuppression, and anti-inflammatory
actions.21 CBD also counteracts the cerebral hemodynamic
impairment and produces beneficial cardiac effects. Sultan et
al22 conducted a systemic review and meta-analysis with 25
studies and concluded that CBD is associated with changes in
hemodynamics in vivo. Acute and chronic administration of
CBD did not affect blood pressure or heart rate under control
conditions but reduced blood pressure and heart rate in stress-
ful conditions. Jadoon et al23 found that acute administration
of CBD reduced resting systolic blood pressure and blunted
the blood pressure response to stress in humans. In mouse and
piglet models of stroke, CBD significantly increased cerebral
blood flow.24,25
Moreover, CBD reduced brain edema and blood-brain
barrier permeability associated with ischemic condition.26
CBD has negligible activity on cannabinoid receptors but may
interfere with the ECS and directly or indirectly stimulate
5-hydroxytryptamine 1A receptors, adenosine receptors, tran-
sient receptor potential vanilloid subtype 1, and nuclear recep-
tors of the peroxisome proliferator-activated receptor family.21
THC also showed trends to infarct reduction with delayed ad-
ministration 4 hours.9 The neuroprotective effect of THC is
related to the CB1R-mediated inhibition of voltage-sensitive
calcium channels, which reduces calcium influx, excessive
glutamate release, hypothermia, and enhances cerebral blood
flow.27,28 Also, THC, when acting on the CB2R found in the
immune system, decreased the severity of stroke. Oral treat-
ment with a low dose of THC inhibited atherosclerosis pro-
gression in a murine model of established atherosclerosis,
through pleiotropic immunomodulatory effects on lymphoid
and myeloid cells. CBD was also effective in diabetic com-
plications and related atherosclerosis.29 Administration of the
CB1R agonist HU-210 significantly reduced motor disability
and infarct volume in a dose-dependent manner and was use-
ful 4 hours after stroke onset.30 This neuroprotection is associ-
ated with the indirect protective effects of hypothermia.
Despite a large number of preclinical studies, there are no
previous clinical trials using cannabinoids in stroke, although
relevant clinical trials using cannabinoids in other neurolog-
ical disorders already exist.31 THC/CBD oromucosal spray
(Sativex) is the first cannabis-based medicine to be licensed in
the United Kingdom and currently available in numerous coun-
tries worldwide for the treatment of multiple sclerosis-related
spasticities not responded adequately to other medication.32
Spasticity is common after stroke and other neurological con-
ditions and causes significant limitations on activities of daily
living.33 Importantly, a clinical trial investigating THC:CBD
oromucosal spray efficacy and safety for poststroke spasticity
has been registered.34 Also, another relevant clinical trial was
efficacy and safety evaluation of a single intravenous dose
of dexanabinol (HU-211)—a synthetic and nonpsychoactive
cannabinoid derivate—in patients experiencing severe trau-
matic brain injury.35 This phase III trial concluded that dex-
anabinol was safe but was not efficacious for the treatment of
traumatic brain injury.
Neurological Complications of Cannabis
and Cannabinoid Use
Cannabis is the most commonly produced and consumed il-
licit substance in the world, and the contents of THC and CBD
varied widely in street cannabis. Because THC is the primary
psychoactive component cannabinoid, cannabis users prefer
the strains of the plant with higher THC content. Potter et al36
carried out the potency of THC and CBD seized by police in
England in 2005 and found that the median content of THC
was significantly higher than the one recorded 10 years be-
fore. In contrast, CBD content was found to be extremely low
in more recent cannabis. Cascini et al37 also performed a meta-
analysis to assess the potency of THC from 1970 to 2009 and
reported a temporal trend of increasing potency worldwide.
These findings indicate that trends for preferring higher THC
content variants carry significant health risks, particularly to
those who are susceptible to its harmful effects.
The growing popularity of recreational consumption of
cannabis, especially among the young population, raises im-
mediate concerns regarding its safety. Recent case-control
studies and systemic reviews have shown that cannabis use
can significantly affect physical and mental health and lead to
substance dependence.38 Mainly, ischemic stroke is the most
commonly reported adverse neurovascular effect of cannabis
use in the young population. Kalla et al39 conducted a study
in patients aged 18 to 55 years and found that cannabis use
was independently associated with a 26% increase in the risk
of stroke after corrected for known risk factors, such as obe-
sity, hypertension, smoking, and alcohol use. This study drew
data from the Nationwide Inpatient Sample, which includes
the health records of patients admitted over 1000 hospitals
comprising about 20% of US medical centers.
Similarly, Jouanjus et al38 conducted a systemic review
with 116 cases published between January 2011 to March
2016 in patients aged 18 to 44 years and concluded that al-
though cannabis use is linked to several adverse cardiovas-
cular events, the evidence is the most persuasive for ischemic
stroke. Similar results were also reported from the US nation-
wide inpatient sample, showing that recreational use of can-
nabis was independently associated with a 2.25-fold increase
in the risk of acute ischemic stroke among people aged 25 to
34 years.40 On the contrary, a recent population-based cohort
and long-term follow-up study of 45 000 Swedish men per-
formed by Falkstedt et al41 analyzed the effects of cannabis,
tobacco, and alcohol use on the risk of early stroke. They
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4 Stroke September 2019
found no apparent association between cannabis use in young
adults and stroke, including strokes occurring before 45 years
of age. However, tobacco smoking showed a clear associa-
tion with stroke. Because most studies were based on hospital
discharge records, the findings may not be reflective of the
general population regarding cannabis use and early stroke.
Furthermore, epidemiological studies have not performed an
individual analysis of patients without other cardiovascular
risk factors, which may limit the estimation of the risk of
stroke associated with cannabis use alone. Nevertheless, there
are currently limited data, inadequate assessment of cannabis
use, and few population-based studies to confirm or reject the
hypothesis of the effects of cannabis use and early stroke.
It is critically important to identify all factors that may
play a role in the recent increase in the incidence of stroke
among the young population. One striking element reported
in the majority of the case studies was a temporal relation-
ship between cannabis use and the occurrence of stroke.
However, a temporal correlation does not mean causation,
and other factors may be involved. Currently, reversible ce-
rebral vasoconstriction triggered by cannabis use may be a
possible mechanism of stroke. Chronic cannabis use leads to
impairment in cerebrovascular function, which has been as-
sociated with an increased risk for stroke.42 Cannabis-related
angiopathy has also been linked with ischemic stroke in
heavy users.43 Another possible mechanism of acute ischemic
stroke due to cannabis use could be an increase in procoagu-
lant effects, as THC increases the expression of glycoprotein
IIb-IIIa and P-selectin on human platelets in a concentration-
dependent manner.44 Platelet aggregation is a significant risk
factor for acute ischemic stroke,45 and it is relatively more
important in younger than in older stroke patients.46 Earlier
research has indicated that THC induces tachycardia.47 It has
been suggested that CBD reduces THC-induced adverse car-
diovascular effects.48 Jamil et al49 reported a case of possible
concurrent use of cannabis and other drugs on the develop-
ment of stroke. Cannabis often precedes or is used along with
other substances.
Besides this vascular role of cannabis in the occurrence
of stroke, a cellular effect of cannabis on brain mitochon-
drial respiratory chain dysfunction and oxidative stress was
recently suggested as a potential mechanism involved in can-
nabis-related stroke.50 Indeed, despite the widespread use of
cannabis, the low frequency of neurovascular complications
after their use may be due to a genetic predisposition to neuro-
vascular toxicity in some individuals.
There is still debate about the possible behavioral and
pathological consequences of cannabis use. Because several
questions remain unsolved, further research is still needed to
assess the pathophysiological mechanisms involved in young
cannabis users with stroke.
New Approaches to Targeting the ECS With
Selective Inhibitors of Monoacylglycerol Lipase
In recent decades, multiple lines of research have provided
insights into the biochemical regulation, pathophysiological
roles, and therapeutic potential of the endogenous cannabi-
noid 2-arachidonoylglycerol (2-AG).51 2-AG is synthesized
on demand and acts as a full agonist of cannabinoid recep-
tors, but its rapid degradation by MAGL (monoacylglycerol
lipase) results in short-lived actions. Many physiological and
pathological processes involve 2-AG, which behaves as a ret-
rograde signaling lipid that inhibits neurotransmitter release
at both excitatory and inhibitory synapses. Several neurolog-
ical disorders with an inflammatory involvement, including
ischemic stroke, show elevated levels of 2-AG.52 Although
the exact role of 2-AG is not clear, the neuroprotection
exerted by exogenous 2-AG suggests that 2-AG contributes to
neuroprotection not only by reducing neuronal excitotoxicity
and inhibiting the production of proinflammatory cytokines
and reactive oxygen species but also by lowering cerebral
vasoconstriction.53
Inactivation of MAGL leads to the elevation of the level
of 2-AG, thus resulting in an enhancement of the endocan-
nabinoid signaling. Beyond this critical role, the study by
Nomura et al54 provides compelling evidence linking both
the endocannabinoid and eicosanoid signaling pathways
through MAGL, which hydrolyzes 2-AG to arachidonic acid.
Arachidonic acid is of particular interest as the precursor of
the eicosanoid family that includes proinflammatory prosta-
glandins and leukotrienes. It is possible that pharmacological
inhibition of MAGL might be a promising therapeutic target
not only by enhancing anti-inflammatory and neuroprotec-
tive 2-AG signaling through cannabinoid receptor–dependent
mechanisms but also by reducing proinflammatory eico-
sanoid production. Although early MAGL inhibitors had poor
selectivity and low potency, they contributed significantly
to advancing the understanding of the pathophysiological
roles of MAGL.55 Inhibition of MAGL activity with JZL184
reduced 2-AG hydrolysis by 85% in the mouse brain and
led to dramatic elevations in brain 2-AG levels. A single dose
of JZL184 was capable of inhibiting MAGL for 24 hours,
with a maximal 8-fold elevation of brain 2-AG levels for at
least 8 hours.55
Most importantly, acute MAGL blockade with JZL184
has been shown to exhibit a wide range of beneficial effects
in neurodegenerative diseases.54 Recent studies demonstrated
that the MAGL inhibitor JZL184 significantly reduces infarct
volume in both transient and permanent models of ischemic
stroke and improves the functional outcome when adminis-
tered it after stroke onset.56 CPD-4645—a newly character-
ized MAGL inhibitor—modified the transcription profile
of brain vasculature and restored its functional homeostasis
in the photothrombotic model of ischemic stroke.57 These
results highlight a bidirectional mechanism of action—
simultaneous enhancement of cannabinoid signaling through
elevation of 2-AG and reduction of arachidonic acid and
downstream eicosanoids—that can achieve therapeutic effi-
cacy through either cannabinoid receptor–dependent or inde-
pendent mechanisms.
Over the past decades, considerable efforts were made for
developing novel MAGL inhibitors with improved selectivity
and cross-species activity compared with JZL184. KML29—
an analog of JZL184—was the most selective for MAGL
over other serine hydrolase family of enzymes.58 MJN110—
another recently developed selective MAGL inhibitor—
showed markedly increased potency and no significant
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Choi et al Cannabis and Cannabinoid Biology in Stroke 5
cross-reactivity with fatty acid amide hydrolase.59 Interestingly,
those MAGL inhibitors do not cause cannabimimetic activity
such as catalepsy and hypothermia. Clinical research in the
field of MAGL inhibitors is still at early stages. During the
past 5 years, several academic groups and pharmaceutical
companies have patented about 20 MAGL inhibitors for a
large number of therapeutic uses, such as pain, inflammation,
metabolic, and neurodegenerative diseases, as well as the
treatment of cancer, anxiety, and epilepsy.60 Recently, a potent
human MAGL inhibitor ABX-1431 (Abide Therapeutics) has
completed a placebo-controlled phase I for safety and toler-
ability.61 ABX-1431 is currently subjected to phase II trials
in patients with Tourette Syndrome and neuropathic pain.
Although the translational potential of MAGL inhibitors still
needs basic and preclinical studies, the results of ongoing and
future clinical trials will hopefully unveil the MAGL inhibi-
tors as a new drug class for the treatment of human diseases,
including stroke.
Conclusions
Neurovascular complications, such as reversible cerebral vaso-
constriction syndrome, intracranial hemorrhages, and ischemic
strokes and their association with cannabis and cannabinoids
are an emerging area of research as more states legalize can-
nabis for medical and recreational use. However, several
questions remain unanswered about the pathophysiological
role of cannabis and cannabinoids in such complications.
Epidemiological studies must provide detailed information
concerning not only the quantity and the frequency of can-
nabis use but also the type of cannabis used. Longitudinal
studies are needed to clarify the impact of cannabis on the se-
vere consequences associated with their use. Despite the con-
troversy of cannabis use, the first cannabis-derived Epidiolex
received the US Food and Drug Administration approval as a
treatment for some types of epilepsy and opened new horizons
for medical use of cannabis. This approval highlights the im-
portance of critical benefit-risk analysis and careful evaluation
in the drug development process.
Acknowledgments
We acknowledge several relevant studies used to prepare this article
that could not be cited because of word count restrictions.
Sources of Funding
This research was supported by the Intramural Research Program of
the National Institute of Neurological Disorders and Stroke, National
Institutes of Health.
Disclosures
None.
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KEY WORDS: brain ischemia cannabidiol dronabinol humans nervous
system diseases
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... The mechanism of potential neurologic effects of marijuana remains largely obscure. Preliminary reports suggest that chronic habitual use of marijuana can lead to multifocal intracerebral vasospasm, multifocal intracranial stenosis, cardiac embolization, hypotension, altered vasomotor function, and other cerebrovascular dysfunctions, which could increase the stroke risk (3,6). ...
... We agree that nonsteroidal antiinflammatory drugs are generally to be avoided in patients with severe hemophilia, and that they have no role in the emergency management of bleeding. However, selective cyclooxygenase-2 inhibitors are safe in these patients, and are valuable in managing the inflammatory pain of chronic hemophilic arthropathy (6). ...
... Recent studies reported that heavy and chronic marijuana use can lead to multifocal intracerebral vasospasm, multifocal intracranial stenosis, cardiac embolization, systemic hypotension, altered vasomotor function, and other cerebrovascular dysfunctions, which can increase the stroke risk. 10,11 Increasing marijuana potency by higher tetrahydrocannabinol concentration poses a greater risk of neurological complications, mainly stroke due to its procoagulant effects on platelets. 10,11 Potential limitations of this study include its cross-sectional nature and retrospective review of the database. ...
... 10,11 Increasing marijuana potency by higher tetrahydrocannabinol concentration poses a greater risk of neurological complications, mainly stroke due to its procoagulant effects on platelets. 10,11 Potential limitations of this study include its cross-sectional nature and retrospective review of the database. Stroke episodes and marijuana use are self-reported, so may include self-reporting bias, and cross-sectional design may limit the causality between marijuana use and stroke. ...
Article
Background and Purpose- Amidst legalization of therapeutic and recreational use of marijuana/cannabis in the United States, cerebrovascular effects of marijuana use remain largely unknown, especially among young adults. We aimed to examine the association between marijuana use (18-44 years) among young adults and stroke events. Methods- The study analyzed pooled data from the Behavioral Risk Factor Surveillance System (2016-2017)-a nationally representative cross-sectional survey collected by the Centers for Disease Control and Prevention. Weighted logistic regression models were used to examine an association of recent marijuana use (within the last 30 days) and stroke in young adults (18-44 years) adjusting for patient demographics, risk behavior, and relevant comorbidities. Results- Overall, 13.6% of participants (n=43 860; weighted 35.5 million; 49.9% men) reported using marijuana recently (in the last month), with 63.3% of them being men. Compared with nonusers, marijuana users were often younger (18-34 years; 73.8% versus 61%), non-Hispanic white or black, and with some college education. Marijuana users were often physically active (81.8% versus 77.5%), heavy drinkers (16.8% versus 4.9%), current combustible cigarette users (37.9% versus 15%) hypertension, diabetes mellitus, and hyperlipidemia as compared with nonusers (P<0.01). Young adults with recent marijuana use showed 1.82× higher odds (adjusted odds ratio, 1.82 [95% CI, 1.08-3.10]) of stroke compared with nonusers, which further increased to 2.45× higher (adjusted odds ratio, 2.45 [95% CI, 1.31-4.60]) among frequent marijuana users (>10 days/month). Compared with nonusers, stroke odds were even higher among frequent marijuana users with concomitant combustible cigarette use (adjusted odds ratio, 3.12 [95% CI, 1.40-6.97]) and e-cigarette use (adjusted odds ratio, 2.63 [95% CI, 1.07-6.46]), respectively. Conclusions- There may be a significantly higher odds of stroke in young marijuana users (18-44 years) as compared with nonusers with even greater odds among frequent users (>10 days/month).
... A great deal of evidence supports the involvement of the endocannabinoid system (ECS) in the pathobiology of cerebral ischemia [1][2][3]. The ECS comprises endocannabinoids, i.e., endogenous lipid-based transmitters that bind to the cannabinoid receptors CB1 and CB2, related enzymes, and transport proteins. ...
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Both preclinical and clinical evidence supports the involvement of the endocannabinoid system in the pathobiology of cerebral ischemia. Selective cannabinoid-2 (CB2) receptor agonists exert significant neuroprotection in animal models of focal brain ischemia through a robust anti-inflammatory effect, involving both resident and peripheral immune cells. Nevertheless, no definitive studies demonstrating the relevance of CB2 receptors in human stroke exist. Using rtPCR and flow cytometry assays, we investigated CB2 receptor expression in circulating monocytes from 26 acute ischemic stroke patients and 16 age-matched healthy controls (CT). We also evaluated miR-665 expression, as potential CB2 receptor regulator. The median mRNA levels of CB2 were significantly (p < 0.0001) increased in total monocytes 24 h and 48 h after stroke as compared with CT. This was paralleled by elevation of miR-665 levels in monocytes collected from patients 24 h (p < 0.05 vs CT) and 48 h (p < 0.05 vs CT and p < 0.0001 vs 24 h) after ischemic stroke. Furthermore, an increased percentage of CB2+/CD16+ events, but not CB2+/CD14+ events, was found 24 h [20.17% (IQR, 17.22–23.58)] and 48 h [18.61% (IQR, 15.44–22.06)] after ischemic stroke when compared with CT [10.96% (IQR, 9.185–13.32)]. The percentage of CB2+/CD16+ events in monocytes was positively correlated with NIHSS score at entrance (r = 0.4327, p = 0.027). The potential beneficial functions of CD16+ intermediate and nonclassical monocytes in stroke and the elevated expression of CB2 receptor in these subsets strongly suggest that CB2 receptor agonists can be exploited for the treatment of ischemic stroke patients.
... Further, THC, when acting on the CB2R on immune cells, was found to decrease the severity of stroke. Low oral doses of THC modulated myeloid and lymphoid cells to improve ischemia in atherosclerosis model [173]. ...
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Cannabis-inspired medical products are garnering increasing attention from the scientific community, general public, and health policy makers. A plethora of scientific literature demonstrates intricate engagement of the endocannabinoid system with human immunology, psychology, developmental processes, neuronal plasticity, signal transduction, and metabolic regulation. Despite the therapeutic potential, the adverse psychoactive effects and historical stigma, cannabinoids have limited widespread clinical application. Therefore, it is plausible to weigh carefully the beneficial effects of cannabinoids against the potential adverse impacts for every individual. This is where the concept of “personalized medicine” as a promising approach for disease prediction and prevention may take into the account. The goal of this review is to provide an outline of the endocannabinoid system, including endocannabinoid metabolizing pathways, and will progress to a more in-depth discussion of the therapeutic interventions by endocannabinoids in various neurological disorders.
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Background: Cannabis is the most consumed recreational drug in the world. It is possible that cannabis has an association with an increased risk of vasospasm-related strokes and delayed cerebral ischemia (DCI), which are major causes of morbidity and mortality in aneurysmal subarachnoid hemorrhage (aSAH). Hence, this study aimed to explore the independent relationship between cannabis use and outcomes after aSAH using the 2016 United States Nationwide Inpatient Sample. Methods: This study was conducted using the 2016 National Inpatient Sample with ICD-10 codes. Multivariate logistic regression was used to examine the association between cannabis use, the primary (inpatient mortality) and secondary outcomes. Results: There were 42,394 patients identified with aSAH, of whom 925 were identified as cannabis users. Cannabis users and non-users were similar in terms of severity of aSAH. Although the unadjusted mortality rate was lower among cannabis users (16%) than non-users (22%), (p = 0.04), both the age-adjusted odds ratio (OR) (0.83, 95% confidence interval (CI): 0.56; 1.24) and the multivariate-adjusted OR (0.87, 95% CI: 0.54; 1.42) did not reach statistical significance. Secondary outcomes did not reach statistical significance. Conclusion: In this nationwide cohort, cannabis users with aSAH had similar outcomes compared to nonusers. However, these results are likely limited by underreporting of cannabis use. Future prospective studies are needed to elucidate the pathophysiology and association between cannabis and outcomes following aSAH.
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Background: Acute neurological insults caused by infection, systemic inflammation, ischemia, or traumatic injury are often associated with breakdown of the blood-brain barrier (BBB) followed by infiltration of peripheral immune cells, cytotoxic proteins, and water. BBB breakdown and extravasation of these peripheral components into the brain parenchyma result in inflammation, oxidative stress, edema, excitotoxicity, and neurodegeneration. These downstream consequences of BBB dysfunction can drive pathophysiological processes and play a substantial role in the morbidity and mortality of acute and chronic neurological insults, and contribute to long-term sequelae. Preserving or rescuing BBB integrity and homeostasis therefore represents a translational research area of high therapeutic potential. Methods: Induction of general and localized BBB disruption in mice was carried out using systemic administration of LPS and focal photothrombotic ischemic insult, respectively, in the presence and absence of the monoacylglycerol lipase (MAGL) inhibitor, CPD-4645. The effects of CPD-4645 treatment were assessed by gene expression analysis performed on neurovascular-enriched brain fractions, cytokine and inflammatory mediator measurement, and functional assessment of BBB permeability. The mechanism of action of CPD-4645 was studied pharmacologically using inverse agonists/antagonists of the cannabinoid receptors CB1 and CB2. Results: Here, we demonstrate that the neurovasculature exhibits a unique transcriptional signature following inflammatory insults, and pharmacological inhibition of MAGL using a newly characterized inhibitor rescues the transcriptional profile of brain vasculature and restores its functional homeostasis. This pronounced effect of MAGL inhibition on blood-brain barrier permeability is evident following both systemic inflammatory and localized ischemic insults. Mechanistically, the protective effects of the MAGL inhibitor are partially mediated by cannabinoid receptor signaling in the ischemic brain insult. Conclusions: Our results support considering MAGL inhibitors as potential therapeutics for BBB dysfunction and cerebral edema associated with inflammatory brain insults.
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2-Arachidonoylglycerol (2-AG) is a signaling lipid in the central nervous system that is a key regulator of neurotransmitter release. 2-AG is an endocannabinoid that activates the cannabinoid CB1 receptor. It is involved in a wide array of (patho)physiological functions, such as emotion, cognition, energy balance, pain sensation and neuroinflammation. In this review, we describe the biosynthetic and metabolic pathways of 2-AG and how chemical and genetic perturbation of these pathways has led to insight in the biological role of this signaling lipid. Finally, we discuss the potential therapeutic benefits of modulating 2-AG levels in the brain.
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Background and purpose: MAGL (monoacylglycerol lipase) is an enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol and regulates the production of arachidonic acid and prostaglandins-substances that mediate tissue inflammatory response. Here, we have studied the effects of the selective MAGL inhibitors JZL184 and MJN110 and their underlying molecular mechanisms on 3 different experimental models of focal cerebral ischemia. Methods: SHR (spontaneously hypertensive rats) and normotensive WKY (Wistar Kyoto) rats were subject to an intracortical injection of the potent vasoconstrictor endothelin-1, permanent occlusion of a distal segment of the middle cerebral artery via craniectomy, or transient occlusion of the middle cerebral artery by the intraluminal suture method. JZL184 or MJN110 was administered 60 minutes after focal cerebral ischemia. Infarct volumes, hemispheric swelling, and functional outcomes were assessed between days 1 to 28 by magnetic resonance imaging, histology, and behavioral tests. Results: Pharmacological inhibition of MAGL significantly attenuated infarct volume and hemispheric swelling. MAGL inhibition also ameliorated sensorimotor deficits, suppressed inflammatory response, and decreased the number of degenerating neurons. These beneficial effects of MAGL inhibition were not fully abrogated by selective antagonists of cannabinoid receptors, indicating that the anti-inflammatory effects are caused by inhibition of eicosanoid production rather than by activation of cannabinoid receptors. Conclusions: Our results suggest that MAGL may contribute to the pathophysiology of focal cerebral ischemia and is thus a promising therapeutic target for the treatment of ischemic stroke.
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Neurogenesis is influenced by various external factors such as enriched environments. Some researchers had postulated that neurogenesis has contributed to the hippocampal learning and memory. This project was designed to observe the effect of Delta-9-tetrahydrocannabinol (∆9-THC) in cognitive performance that influenced by the neurogenesis. Different doses of ∆9-THC were used for observing the neurogenesis mechanism occurs in the hippocampus of rats. The brains were stained with antibodies, namely BrdU, glial fibrillary acidic protein (GFAP), nestin, doublecortin (DCX) and class III β-tubulin (TuJ-1). The cognitive test was used novel-object discrimination test (NOD) while the proteins involved, DCX and brain-derived neurotrophic factor (BDNF), were measured. Throughout this study, ∆9-THC enhanced the markers involved in all stages of neurogenesis mechanism. Simultaneously, the cognitive behaviour of rat also showed improvement in learning and memory functions observed in behavioural test and molecular perspective. Administration of ∆9-THC was observed to enhance the neurogenesis in the brain, especially in hippocampus thus improved the cognitive function of rats.
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Harvard neurologist Elizabeth Thiele, MD, PhD, is only half-kidding about the surprising direction her research has taken.
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The serine hydrolase monoacylglycerol lipase (MGLL) converts the endogenous cannabinoid receptor agonist 2-arachidonoylglycerol (2-AG) and other monoacylglycerols into fatty acids and glycerol. Genetic or pharmacological inactivation of MGLL leads to elevation in 2-AG in the central nervous system and corresponding reductions in arachidonic acid and eicosanoids, producing anti-nociceptive, anxiolytic, and anti-neuroinflammatory effects without inducing the full spectrum of psychoactive effects of direct cannabinoid receptor agonists. Here, we report the optimization of hexafluoroisopropyl carbamate-based irreversible inhibitors of MGLL, culminating in a highly potent, selective, and orally available, CNS-penetrant MGLL inhibitor, 28 (ABX-1431). Activity-based protein profiling experiments verify the exquisite selectivity of 28 for MGLL versus other members of the serine hydrolase class. In vivo, 28 inhibits MGLL activity in rodent brain (ED50 = 0.5 – 1.4 mg/kg), increases brain 2-AG concentrations, and suppresses pain behavior in the rat formalin pain model. ABX-1431 (28) is currently under evaluation in human clinical trials.
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Background: Cannabis for medicinal and/or recreational purposes has been decriminalized in 28 states as of the 2016 election. In the remaining states, cannabis remains the most commonly used illicit drug. Cardiovascular effects of cannabis use are not well established due to a limited number of studies. We therefore utilized a large national database to examine the prevalence of cardiovascular risk factors and events amongst patients with cannabis use. Methods: Patients aged 18-55 years with cannabis use were identified in the National Inpatient Sample 2009-2010 database using the Ninth Revision of International Classification of Disease code 304.3. Demographics, risk factors, and cardiovascular event rates were collected on these patients and compared with general population data. Results: Prevalence of heart failure, cerebrovascular accident (CVA), coronary artery disease, sudden cardiac death, and hypertension were significantly higher in patients with cannabis use. After multivariate regression adjusting for age, sex, hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, tobacco use, and alcohol use, cannabis use remained an independent predictor of both heart failure (odds ratio = 1.1, 1.03-1.18, P < 0.01) and CVA (odds ratio = 1.24, 1.14-1.34, P < 0.001). Conclusion: Cannabis use independently predicted the risks of heart failure and CVA in individuals 18-55 years old. With continued legalization of cannabis, potential cardiovascular effects and their underlying mechanisms need to be further investigated.
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Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together in a single document the most up-to-date statistics related to heart disease, stroke, and the cardiovascular risk factors listed in the AHA's My Life Check - Life's Simple 7 (Figure¹), which include core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure [BP], and glucose control) that contribute to cardiovascular health. The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, healthcare administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions. Cardiovascular disease (CVD) and stroke produce immense health and economic burdens in the United States and globally. The Update also presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease [CHD], heart failure [HF], valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). Since 2007, the annual versions of the Statistical Update have been cited >20 000 times in the literature. From January to July 2017 alone, the 2017 Statistical Update was accessed >106 500 times. Each annual version of the Statistical Update undergoes revisions to include the newest nationally representative data, add additional relevant published scientific findings, remove older information, add new sections or chapters, and increase the number of ways to access and use the assembled information. This year-long process, which begins as soon as the previous Statistical Update is published, is performed by the AHA Statistics Committee faculty volunteers and staff and government agency partners. This year's edition includes new data on the monitoring and benefits of cardiovascular health in the population, new metrics to assess and monitor healthy diets, new information on stroke in young adults, an enhanced focus on underserved and minority populations, a substantively expanded focus on the global burden of CVD, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the AHA's 2020 Impact Goals. Below are a few highlights from this year's Update.
Article
Background: Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. Methods: In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690. Findings: Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment. Interpretation: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial. Funding: GW Pharmaceuticals.
Article
Introduction: Monoacylglycerol lipase is a serine hydrolase that plays a major role in the degradation of the endocannabinoid 2-arachidonoylglycerol. Because of this key role, selective inactivation of MAGL represents an interesting approach to obtain desirable effects in several diseases. Furthermore, MAGL is upregulated in cancer cells and primary tumors and its inhibition in aggressive breast, ovarian, and melanoma cancer cells impairs cell migration, invasiveness, and tumorigenicity. Areas covered: This review covers patent literature on MAGL inhibitors and their applications published from 2013 to 2017. Expert opinion: MAGL inhibition has gained considerable importance in many therapeutic fields and one compound has been subjected to Phase I studies. Even if a reasonable number of patents have been recently reported, novel MAGL inhibitors are still required, especially novel chemical classes displaying a reversible mechanism of action.