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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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