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Abstract

Neurodegenerative diseases represent, nowadays, one of the main causes of death in the industrialized country. They are characterized by a loss of neurons in particular regions of the nervous system. It is believed that this nerve cell loss underlies the subsequent decline in cognitive and motor function that patients experience in these diseases. A range of mutant genes and environmental toxins have been implicated in the cause of neurodegenerative disorders but the mechanism remains largely unknown. At present, inflammation, a common denominator among the diverse list of neurodegenerative diseases, has been implicated as a critical mechanism that is responsible for the progressive nature of neurodegeneration. Since, at present, there are few therapies for the wide range of neurodegenerative diseases, scientists are still in search of new therapeutic approaches to the problem. An early contribution of neuroprotective and antiinflammatory strategies for these disorders seems particularly desirable because isolated treatments cannot be effective. In this contest, marijuana derivatives have attracted special interest, although these compounds have always raised several practical and ethical problems for their potential abuse. Nevertheless, among Cannabis compounds, cannabidiol (CBD), which lacks any unwanted psychotropic effect, may represent a very promising agent with the highest prospect for therapeutic use.
REVIEW
Cannabidiol: A Promising Drug for Neurodegenerative Disorders?
Teresa Iuvone1,
, Giuseppe Esposito2, Daniele De Filippis1,
, Caterina Scuderi2& Luca Steardo2
1 Department of Experimental Pharmacology, Faculty of Pharmacy, University of Naples “Federico II,” Naples, Italy
2 Department of Physiology and Pharmacology “V. Erspamer,” University of Rome “La Sapienza”, Piazzale Aldo Moro, Rome, Italy
Endocannabinoid Research Group
Keywords
Alzheimer disease; Cannabinoid; Movement
disorders; Multiple sclerosis; Parkinson disease.
Correspondence
Prof. Teresa Iuvone, Department of
Experimental Pharmacology, Faculty of
Pharmacy, University of Naples “Federico II,”
Via D. Montesano, 49 80131 Naples, Italy.
Tel.: +39-081-678429;
Fax: +39-081-678403;
E-mail: iuvone@unina.it
doi: 10.1111/j.1755-5949.2008.00065.x
Neurodegenerative diseases represent, nowadays, one of the main causes of
death in the industrialized country. They are characterized by a loss of neurons
in particular regions of the nervous system. It is believed that this nerve cell loss
underlies the subsequent decline in cognitive and motor function that patients
experience in these diseases. A range of mutant genes and environmental tox-
ins have been implicated in the cause of neurodegenerative disorders but the
mechanism remains largely unknown. At present, inflammation, a common
denominator among the diverse list of neurodegenerative diseases, has been
implicated as a critical mechanism that is responsible for the progressive na-
ture of neurodegeneration. Since, at present, there are few therapies for the
wide range of neurodegenerative diseases, scientists are still in search of new
therapeutic approaches to the problem. An early contribution of neuropro-
tective and antiinflammatory strategies for these disorders seems particularly
desirable because isolated treatments cannot be effective. In this contest, mar-
ijuana derivatives have attracted special interest, although these compounds
have always raised several practical and ethical problems for their potential
abuse. Nevertheless, among Cannabis compounds, cannabidiol (CBD), which
lacks any unwanted psychotropic effect, may represent a very promising agent
with the highest prospect for therapeutic use.
Introduction
In the present article, the current literature regarding
CBD use in preclinical and clinical studies has been re-
vised, underlying the potential of CBD in the prevention
of the main neurodegenerative disorders and the clini-
cal management of symptoms related to these patholo-
gies. Although the range of its clinical effect is impressive;
however, to date, the molecular mechanisms through
which CBD exerts its action remain elusive. As a result,
this phytocannabinoid may represent a lead compound
for the development of therapeutics that are able to exert
neuroprotection as well as to operate against neuroinfla-
mmatory component of neurodegenerative disorders.
Neurodegenerative Disorders
Neurodegenerative diseases, from Greek vευρo-, n´
euro-
, “nerval” and Latin d¯
egener¯
are, “to decline”, are char-
acterized by a slow progressive neuronal loss in specific
brain areas, which leads to the observed clinical man-
ifestations [1]. Although they have different etiologies,
most of them share similar histomorphological features,
such as neuronal loss, gliosis, and the presence of aggre-
gates of misfolded or aberrant proteins [2,3]. Neurode-
generative diseases are characterized by cognitive, motor,
and/or behavioral dysfunctions. This clinical heterogene-
ity is in large part attributable to pathological variability
and the characteristic topographic pattern of central ner-
vous system (CNS) involvement, displayed by each par-
ticular disease entity, the latter being determined by the
selective vulnerability of brain cells to the disease pro-
cess. Neurodegenerative diseases may be crudely divided
into two major groups according to phenotypic features:
conditions causing problems with movements, or condi-
tions affecting memory and related to dementia [2]. Neu-
rodegenerative disorders usually extend over a decade.
Neurodegeneration begins long before patients experi-
ence any symptoms, which are noticed only when many
cells are irreversibly damaged and cease to function, so
CNS Neuroscience & Therapeutics 15 (2009) 65–75 c
2009 Blackwell Publishing Ltd 65
Cannabidiol and Neurodegeneration T. Iuvone et al.
that the actual onset of disease precedes clinical manifes-
tations by many years.
The mechanism that drives chronic progression of neu-
rodegenerative diseases remains elusive. Clearly, if a driv-
ing force persists actively, therapeutic strategies aimed
at neurorescue, replacement, or regeneration might un-
derperform. Recently, neuroinflammation, a prominent
feature shared by various neurodegenerative diseases,
has been increasingly implicated in the mechanisms that
are responsible for such disorders, so that it is now re-
garded as a double-edged sword [4]. In fact, without
neuroinflammation, removal of offending materials and
recovery from injuries become impossible, whereas an
uncontrolled neuroinflammation can become devastat-
ing, since overactivated microglia and astrocytes produce
a myriad of neurotoxic substances that are responsible
for a vicious self-propagating cycle that drives to chronic
progression of neurodegenerative diseases [5,6]. The clas-
sical division between degenerative and inflammatory
CNS disorders is vanishing, as accumulating evidence
shows that inflammatory processes are important in the
pathophysiology of primarily degenerative disorders, and
neurodegeneration complicates primarily inflammatory
diseases of the brain and spinal cord. In fact, Alzheimer
disease (AD), Parkinson disease (PD), and amyotrophic
lateral sclerosis (ALS) are among the best examples of
neurodegenerative disorders that are precociously asso-
ciated with intense inflammation, whereas multiple scle-
rosis (MS) is an inflammatory disease in which neurode-
generation may occur as a very early event [7,8]
Such evidence imposes reconsideration of the per-
ceived relationship between neuroinflammation and
neurodegeneration, suggesting that one is not simply
a culmination of the other, since they may occur in
parallel. On the basis of these considerations, an early
combination of antiinflammatory and neuroprotective
strategies, irrespective of the nature of the primary in-
sult, appears as a rationale and desirable approach, since
focusing on only one process might also worsen the
other. Therefore, in view of the emerging role of the ac-
tivated glia in contributing to neurodegeneration, in re-
cent years, the importance to finely tune a protracted glial
overactivation as a novel disease-modifying approach to
counteract neurodegenerative disorders has been high-
lighted and it offers hope for a successful therapy.
Because of the vicious cycle and the disappointing fail-
ure of the present treatments, drugs with multiple ac-
tions, addressed at both inflammatory and noninflam-
matory mechanisms, may represent the most promising
therapeutic strategies for neurodegenerative diseases.
Along this line, a unique opportunity to improve neu-
roinflammation and neurodegeneration simultaneously
could be offered by pharmacological agents affecting the
endocannabinoids system (ECS) [9,10]. In the last few
years, Cannabis derivatives have attracted much atten-
tion.
Cannabinoids or, Even Better,
Cannabidiol?
The anecdotal use of Cannabis for therapeutical aim dates
back to about 5000 years, although the introduction of
its derivatives in the Western medicine belongs to the
nineteenth century, reaching a peak of interest in 1960s,
when 9- tetrahydrocannabinol (9-THC), the main psy-
chotropic component of marijuana, was identified and
synthesized [11].
At present, “cannabinoids” (CBs) can be separated
into three different groups: endogenous (endocannabi-
noids), synthetic, and phytocannabinoids. The latter
group includes terpenophenolic substances extracted
from Cannabis sativa,suchas9-THC and cannabidiol
(CBD). Two membrane receptors for CBs, both coupled to
Giprotein, and named CB1and CB2,have been identified
so far [12]. It is now commonly accepted that CB1recep-
tors are located primarily in the central and peripheral
neurons, whereas CB2receptors are most abundant in
cells of the immune system [13]. However, CB1receptors
are also expressed by some nonneuronal cells, including
immune cells, whereas CB2has been recognized on some
neuronal cells, either within or outside the brain, even
if its role remains to be better clarified [14,15]. More-
over, two orphan G protein-coupled receptors, GPR119
and GPR55, possibly activated by multiple different CB
ligands, have been recently proposed as novel CB recep-
tors [16].
Cannabis pharmacology is constantly growing up, and
therapeutic properties of CB receptor agonists and an-
tagonists have been suggested for the treatment of dif-
ferent human disorders by preclinical and clinical obser-
vations in which interactions at CB1and/or CB2sites
appear to affect molecular mechanisms that are respon-
sible for disease onset or progression [17]. Along this
line, a particular interest was raised by the discovery that
these agents may be protective in some CNS disorders.
In fact, CB receptors are present in the senile plaques
from postmortem human brain, together with markers
of microglial activation, as well as in AD patients, al-
though the number of CB1-positive neurons has been
found to be drastically reduced [18]. Moreover, it has
been reported that CB1agonism was able to prevent tau
hyperphosphorylation in cultured neurons [19] and an-
tagonize cellular changes and behavioral consequences
in β-amyloid-induced rodents [18,20]. On the contrary,
CB2antagonists resulted to be protective in in vivo ex-
periments by downregulating reactive gliosis occurring in
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T. Iuvone et al.Cannabidiol and Neurodegeneration
β-amyloid-injected animals [21]. The protective role of
CBs has been recognized not only in AD models but also
in other experimental paradigms of neurodegenerative
disorders, such as 1-Methyl 4-Phenil 1,2,3,6 Tetrahydro-
Piridine (MPTP) and HIV-1/Tat protein neurotoxicity
[22,23]. Finally, there are growing evidence that CB1,
and possibly CB2, receptor interactions could affect neu-
ropathology and disease progression in rodent model of
both MS [24] and ALS [25,26].
Despite the emerging evidence regarding putative ther-
apeutical activities of CBs, their effective introduction in
the clinical use is still controversial and strongly limited
by unavoidable psychotropic effects, exhibited by many
of them. In this scenario, CBD, which constitutes up to
40% of the Cannabis extract, may represent the most
promising candidate for clinical utilization due to its re-
markable lack of any cognitive and psychoactive actions,
in addition to its excellent tolerability profile in humans
[27].
Because of its very low toxicity in humans, a large
number of trials have been performed to assess the clini-
cal efficacy of CBD in different pathologies. Most of these
trials have been executed utilizing Sativex R(GW Phar-
maceuticals, Salisbury, UK), the only commercially avail-
able preparation containing CBD/9-THC. Four different
formulations of Sativex Rare currently under investiga-
tion: high THC extract (Tetranabinex R; GW Pharmaceu-
ticals), THC:CBD (narrow ratio), THC:CBD (broad ratio),
and high CBD extract (Nabidiolex R; GW Pharmaceuti-
cals) [28]. Three Sativex Rdelivery systems exist: oro-
mucosal spray, sublingual tablets, and inhalated (but not
smoked) dosage forms.
In 2005, the oromucosal spray administration of
Sativex Rhas been agreed to for MS symptoms treatment
[29].
It has been established that coadministration of CBD
and 9-THC may modify the pharmacological effect of
the latter, potentiating some of its reputed benefits,
whereas attenuating some of its negative effects [30–
32].
CBD Pharmacology
CBD is a natural compound isolated across the 1930s
and 1940s from marijuana, but its structure and absolute
configuration were fully elucidated only in the 1960s by
Mechoulam et al. [33].
()CBD isomer is the major nonpsychotropic con-
stituent naturally present in Cannabis sativa. Molecular
pharmacology of CDB is not well defined, and little is
known about a possible CBD-dependent signaling path-
way. At first glance, at the chemical structure, it is easy to
recognize CBD antioxidant properties due to the presence
of two hydroxilic groups [33]. Since its antioxidant prop-
erties cannot account for the wide spectrum of biological
effects displayed in both preclinical and clinical investi-
gations, several studies have been carried on in order to
identify other mechanisms through which CBD exerts its
actions. Up to date, no evidence has been provided that,
at least, the natural isomer fully binds to any known re-
ceptor site, so that such an interaction might be regarded
as responsible for some or all the biological effects ob-
served. In fact, CBD, even if it belongs to the CB “fam-
ily”, exhibits only a weak ability to remove 3[H]CP55940,
a not selective ligand for CB receptors from both CB1and
CB2receptor sites, being required for this effect concen-
trations in the micromolar range [34,35]. However, re-
cently, evidence has emerged pointing out that, despite
its low affinity for CB receptors, CBD could work as an in-
verse agonist at CB2receptor, at concentration values in
low nanomolar range, in both mouse whole-brain mem-
branes and membranes from CHO cells transfected with
hCB2receptors [36]. In any case, even if the relevance
of CBD interactions at CB receptors still remains con-
troversial, its influence on the endocannabinoid signal-
ing system appears convincingly demonstrated. Indeed,
although CBD does not seems to clearly operate at CB re-
ceptors; however, it has been observed that it is able to
potentiate the endocannabinoid signaling system, work-
ing at different levels. Indeed, CBD increases anandamide
(AEA, the first endocannabinoid identified) levels by in-
hibiting its reuptake and degradation, blunting both the
expression and the activity of fatty acid amide hydrolase
(FAAH) [37,38], the enzyme involved in the breakdown
of AEA. It should be noted, however, that the concentra-
tions of CBD required for the inhibition of AEA reuptake
and hydrolysis are quite high (>20 μM) [37]. Moreover,
further interactions between CBD and ECS have been
reported to occur in the hippocampal tissue. Indeed, by
enhancing the levels of endocannabinoids, either by ex-
ogenous application or by a stimulated upregulation,
CBD-induced calcium responses appeared strongly de-
creased. In this case, CBD responses, observed both in the
neurons and in the glia, were not dependent on classical
CB receptor [39] but potentially mediated through an un-
characterized postsynaptic CB-like receptor coupled to a
Gq/11 protein.
Moreover, CBD and its (+) enantiomer interact with
the transient potential vanilloid receptor type-1 (TPVR-
1),withanEC
50 estimated between 3.2 and 3.5 μMand
a maximal effect similar to that exhibited by the natural
agonist capsaicin, both in vitro [37] and in a rat model
of acute inflammation [40]. Looking for sites possibly re-
sponsible for CBD activity, it has been reported the ability
of CBD to interact at the 5-HT1A serotonin receptor [41],
CNS Neuroscience & Therapeutics 15 (2009) 65–75 c
2009 Blackwell Publishing Ltd 67
Cannabidiol and Neurodegeneration T. Iuvone et al.
as well as to allosterically modulate μand δopioid recep-
tors in rat cerebral cortex membrane homogenates [42].
Finally, CBD has been observed to significantly antago-
nize the orphan receptor GPR55 [16].
To date, although CBD pharmacodynamic remains, in
many aspects, still unclear, yet, its pharmacokinetics ap-
pears better defined. Once orally given, in consequence
of a marked first-pass effect, CBD bioavailability ranges
between values of 13 and 19%, making for this reason
the intravenous administration preferable [43]. Once in-
jected, CBD is rapidly distributed and easily passes the
blood–brain barrier (BBB), considering its lipophilicity,
which in turn provides CBD a prolonged elimination
[43].
Metabolism of CBD showed biotransformation routes
typically observed for phytocannabinoids [44,45]. Al-
though different metabolic pathways have been observed
in different animal species, including human, overall
CBD metabolism displays common features. Indeed, CBD
undergoes multiple hydroxylations, oxidations to car-
boxylic acids, beta-oxidation, conjugation, and epoxida-
tion [45,46]. Finally, CBD is preferentially excreted from
urine, both in the free state and as its glucuronide, with a
half-life of 9 h [47].
Encouraged by the lack of any unwanted psychotropic
effects, and in view of its potential therapeutic use, ef-
forts have been made to delineate its toxicological profile.
In this regard, CBD has been found to exert a very low
toxicity, both in human and in other species, exhibiting
an LD50 of 212 mg/kg when intravenously injected into
rhesus monkey [48]. Moreover, CBD does not display
teratogenic as well as mutagenic activities [49]. How-
ever, CBD appears to impair hepatic drug metabolism
of same drugs in different animal species [50] through
the inactivation of specific cytochrome P450s belonging
to the 2C and 3A subfamilies. These interactions de-
serve to be taken into the right account in case of CBD
coadministration.
CBD: Mechanism of Cell Protection
and Antiischemic Effect
CBD exhibits a wide spectrum of interesting biological ef-
fects either in vitro or in vivo. A special attention merits
the ability of CBD to regulate both cell cycle and cell sur-
vival fate. The antiproliferative effects of CBD, described
in leukemia, breast cancer, and glioma [51,52], together
with its property to induce tumor regression and inhibi-
tion of glioma cell invasion observed in rats [53], support
a key role of CBD in the control of tumor development
and progression.
A similar proapoptotic potential was also exhibited by
CBD in primary cells of the immune system [54]. All this,
in concert with a strong inhibition of neutrophil chemo-
taxis and proliferation [55], would be considered, at least
in part, as the basis of its great efficacy as an antiin-
flammatory drug, described both in models of acute and
chronic inflammation [56].
Further effects of CBD on immune cells include the
modulation of tumour necrosis factor (TNF)-α,inter-
leukin (IL)-1, and interferon (IFN)-γby mononuclear
cells [57,58] and the suppression of chemokine produc-
tion by human B cells [59].
The antiinflammatory effects of CBD have not been re-
stricted to the control of the peripheral inflammatory pro-
cess since interesting results have also been observed in
the prevention of the neuroinflammation [60], an effect
that may justify the emerging role, described for CBD, as
a potential neuroprotective agent.
The nonpsychoactive marijuana-constituent CBD was
found to prevent both glutamate neurotoxicity and
radical oxygen species (ROS)-induced cell death. Neu-
roprotection was unaffected by CB receptor antag-
onism, suggesting CBD as a useful therapeutic ef-
fect, independent of psychoactive effects mediated
by receptor interactions. CBD was able to antago-
nize glutamate toxicity in cortical neurons with po-
tency, regardless of whether the insult was operated
through N-methyl-D-aspartate (NMDA), 2-amino-3-(4-
butyl-3-hydroxyisoxazol-5-yl)propionic acid (AMPA), or
kainate receptors, pointing out that CBD antagonizes
all three receptors with similar affinity or, more likely,
that its site of action remains downstream of initial re-
ceptor activation [61]. In an in vitro model of neu-
rodegeneration, the neuroprotective effect of CBD in-
volved the attenuation of the excessive production of
peroxynitrites induced by glutamate, thus preventing
apoptosis [62]. In addition, CBD was found to possess
antioxidant properties, since it attenuated ROS-induced
neurotoxicity, being more protective than either ascor-
bate or α-tocopherol [61,63].
Pre- and posttreatments with CBD were reported to
significantly diminish the infarct size in a mouse model
of brain ischemia. This effect was not inhibited by CB re-
ceptor antagonism. CBD also suppressed the decrease in
cerebral blood flow (CBF) due to the failure of cerebral
microcirculation after reperfusion, as well as it blunted
metalloperoxidase activity after reperfusion for up to
3 days, showing potent and long-lasting neuroprotec-
tant and antiiflammatory effects mediated through a CB-
independent mechanism [64,65].
Interestingly, these CBD neuroprotective effects were
inhibited by the 5-HT1A antagonist, W100135, but not
by the TPVR-1 antagonist, capszepine. Furthermore, the
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2009 Blackwell Publishing Ltd
T. Iuvone et al.Cannabidiol and Neurodegeneration
increased CBF induced by CBD was in part decreased by
5-HT1A antagonism, pointing out that CBD may exert a
neuroprotective effect toward brain ischemia, at least in
part, via 5-HT1A receptor [66].
Finally, in order to identify the mechanisms involved
in CBD neuroprotective actions, it cannot be excluded
that this phytocannabinoid operates its beneficial effects
also through the uncloned postsynaptic CB-like receptor
coupled to Gq/11, since mice deficient in this site were
found to display an impaired ability to activate neuropro-
tective mechanisms [67].
CBD and Experimental Model of ADs
The substantial and well-documented antioxidant, an-
tiinflammatory, and neuroprotective properties of CBD
have prompted researchers to test its effects in models
of neurotoxicity and neurodegenerative disorders. In this
context, very promising results have been achieved in
the control of β-amyloid-induced toxicity. Although, to
date, it is not fully elucidated if β-amyloid plaque deposi-
tion and the neurofibrillary tangles, found in postmortem
brain of AD patients, are the cause or the consequence of
the disease; however, the pivotal role of β-amyloid in in-
ducing neuronal damage and mediating neuroinflamma-
tion is evident. In investigations aimed at exploring CBD
effects on β-amyloid-induced neurotoxicity, this phyto-
cannabinoid was found to be able to protect differenti-
ated PC12 neuronal cells from the detrimental action in-
duced by peptide exposure through a combination of its
antioxidant, antiinflammatory, and antiapoptotic proper-
ties [64,68,69]. Indeed, CBD antioxidant effects account
mainly for the survival of cultured neurons, with a po-
tency higher than that exhibited by α-tocopherol [63],
also attenuating β-amyloid-induced molecular changes
possibly through additional mechanisms that are not dis-
played by classical antioxidants [69]. In fact, CBD resulted
in being able to weaken β-amyloid-induced GSK-3βacti-
vation, the key enzyme of wingless gene (WNT)/β-catenin
pathway, thus preventing tau protein hyperphosphoryla-
tion and the consequent neurofibrillary tangle formation
[69].
It has also been demonstrated that CBD decreased
phosphorylation of the stress-activated protein kinase,
P38 mitogen activated protein kinase (MAPK), thus pre-
venting the translocation of nuclear factor (NF)-κBinto
the nucleus and the subsequent transcription of impor-
tant proinflammatory genes, including those encoding for
inducible nitric oxide synthase (iNOS) protein [68].
The beneficial effects of CBD were also confirmed in a
mouse model of AD-related neuroinflammation induced
by the intrahippocampal injection of the human Aβ
(1–42) fragment, where CBD inhibited reactive gliosis
by attenuating glial cell activation and proinflammatory
mediator release in a dose-dependent manner [70].
These encouraging results emphasize the relevance of
CBD as a novel, very promising pharmacological tool ca-
pable of mitigating β-amyloid-evoked neuroinflamma-
tory and neurodegenerative responses.
CBD and Control of Movement
Disorders: ALS and Parkinson
and Huntington Disease
Anecdotal evidence has supported the notion that CBD
can exert beneficial role, alone or in combination with
9-THC, in different neurodegenerative disease, such as
PD and Huntington’s disease (HD), two chronic disorders
provoked by degenerative processes implicating specific
nuclei of the basal ganglia, responsible for abnormal reg-
ulation of movements. Both disorders have been scantly
investigated from the clinical point of view, whereas, at
preclinical level, accumulated findings appear more ex-
haustive and convincing for a possible medical utiliza-
tion of CBD to improve symptoms and/or delay dis-
ease progression. According to recent preclinical find-
ings, plant-derived CBs were able to prevent neuronal
damage induced by 6-hydroxydopamine unilateral injec-
tion into the nigra pars compacta [71]. This effect ap-
peared to not involve CB receptor mediation, whereas,
more likely, it might implicate the antioxidant activ-
ity, possibly combined with the capability to modulate
glial responses, relevant to neural survival. In rodents
with hemiparkinsonism, induced by the intranigral ad-
ministration of 6-hydroxydopamine, neuroprotective ef-
fects exerted by CBD antagonized dopaminergic transmis-
sion impairment by attenuating dopaminergic cell death,
rather than by increasing the functional turnover of the
surviving neurons [71]. Early human reports showed a
dose-related improvement (ranging from 20 to 50%) in
parkinsonian patients treated with oral doses of CBD
(100–600 mg/day over a 6-week period) [72]. On the
contrary, in a more recent controlled trial, a mixture
of 9-THC/CBD (2.5 mg/1.25 mg per capsule) failed to
exhibit any beneficial effect either on parkinsonism or
on levodopa-induced dyskinesias [73]. Unfortunately, no
subsequent trials were performed to elucidate such con-
troversial findings. Certainly, in comparison to the rele-
vance of rodent results, the limited clinical evidence sug-
gests performance of human studies to verify for good the
possible future clinical use of CBD in PD.
Similarly, founded on anecdotal accounts and results
of preliminary clinical reports, CBD was regarded as
a compound with therapeutical potential also against
hyperkinetic disorders. Indeed, CBD was found to
CNS Neuroscience & Therapeutics 15 (2009) 65–75 c
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Cannabidiol and Neurodegeneration T. Iuvone et al.
reduce apomorphine-induced turning behavior in 6-
hydroxydopamine-injected rats, an animal model of hy-
perkinetic movement disorders, whereas, on the con-
trary, it was able to potentiate hypokinesia generated by
tetrabenazine [74]. More recently, it was demonstrated
that CBD prevents in striatal neurons the toxicity of 3-
nitropropionic acid, a mitochondrial toxin that is able to
induce some biochemical alterations similar to those oc-
curring in HD [75].
CBD was investigated to prove its efficacy in HD, alone
or as an add-on drug to the approved therapy with
neuroleptics [76]. CBD, at an average daily dose of 10
mg/kg/day for 6 weeks, was neither symptomatically ef-
fective nor toxic compared with placebo in neuroleptic-
free patients with HD. Considering the negative results
on both the therapeutic and the safety measures, there is
a question about the dose as well as the duration of the
trial. Since such findings cannot be considered conclu-
sive, further clinical investigations, utilizing CBD alone
or in combination with 9-THC, have to be carried out
to estimate the actual antihyperkinetic value of these
molecules in a clinical setting.
ALS is a fatal neurodegenerative disease that is charac-
terized by selective loss, implicating motoneurons in the
cortex, brainstem, and spinal cord. Since recent studies
substantiate the relevance of neuroinflammation and ox-
idative stress in the pathophysiology of ALS [77], then it
is possible to suggest that CBD, because of its antiinflam-
matory and antioxidative properties, could be a promis-
ing tool to treat disturbances and prolong survival in ALS
patients. This is strongly supported by the report that 9-
THC was able to slow progression and prolong survival in
a mouse transgenic model of ALS, and that similar results
were obtained when cannabinol was utilized [78]. Fur-
thermore, these results have to be weighed up with the
anecdotal reports that recreational smoking of marijuana
does ameliorate symptomatology in ALS subjects.
CBD and MS
MS is considered the leading cause of neurological disabil-
ity among young and middle-aged people in the north-
ern industrialized countries. MS is considered to be an
autoimmune, demyelinating disease that has a complex
pathophysiology [79]. There is now clear evidence that:
(i) The immune response drives lesion formation and
relapsing-remitting clinical attacks. (ii) The progressive
stages of MS result from neurodegenerative processes,
which do not appear to respond to immunotherapy [80–
83]. (iii) These, distinct but related, disease elements both
produce nerve/loss that results in altered neurotransmis-
sion which leads to the development of a number of signs
of the disease, such as spasticity, pain, and bladder dys-
function [79]. The inability of available medicines to con-
trol such symptoms has prompted people with MS to self-
medicate and perceive benefit by taking Cannabis [84].
They also perceived an effect on relapsing disease sugges-
tive of immunosuppressive capabilities [84]. This latter
aspect is hard to predict, and disease activity may natu-
rally slow down at a time when residual symptoms are
becoming increasingly apparent and people may be tak-
ing Cannabis for symptom control [79,82]. Although the
ability of some CBs to exhibit immunosuppressive poten-
tial has been shown by several studies in MS models [85–
88], current Cannabis trials in MS for symptom control
have, so far, failed to demonstrate a significant reduction
of relapse, indicative of immunosuppressive properties in
humans [89]. Recently, accumulating evidence from pre-
clinical observations supports the notion that CBs may be
of more relevance in neuroprotection that in immuno-
suppression [90], and this is currently being investigated
in trials of a long-term administration of THC/CBD in pro-
gressive MS. Conversely, CBs have been reported to exert
a marked symptom control in MS.
Cannabis has long been proposed as a muscle relaxant
drug, with the first report of chronic motor handicaps
remarkably improved following marijuana smoking de-
scribed almost 30 years ago [91].
Since then, extensive preclinical findings have rein-
forced the notion deduced from the anecdotal observa-
tions that Cannabis derivatives may have a role in reliev-
ing symptoms in MS subjects. [92], offering the rationale
for performing randomized, controlled trials of Cannabis-
based medicine in MS-associated symptomatology.
The clinical trials focused on Sativex Refficacy in the
treatment of symptoms of MS, notably spasticity and neu-
ropathic pain. Beneficial results in placebo-controlled tri-
als were obtained when Sativex Rwas administered as
an add-on therapy in these indications, supporting the
view that Sativex Ris efficacious and well tolerated in the
treatment of these symptoms [93]. Additional trials con-
firmed that the CBD/THC combination is able to reduce
pain and sleep disturbance in patients with MS-related
central neuropathic pain and that this treatment is mostly
well tolerated [94].
Finally, a recent meta-analysis of Cannabis-based treat-
ment for neuropathic pain has concluded that the
CBD/THC buccal spray (Sativex R) was effective in alle-
viating MS-related pain [95].
For bladder dysfunctions occurring in MS patients,
anecdotal reports have suggested that Cannabis deriva-
tives may mitigate lower urinary tract symptoms. More
specifically, the results of a pilot study, utilizing THC/CBD
combination, have demonstrated a significant decrease
in urinary urgency and a reduction in the number and
volume of incontinence episodes, as well as a reduction
70 CNS Neuroscience & Therapeutics 15 (2009) 65–75 c
2009 Blackwell Publishing Ltd
T. Iuvone et al.Cannabidiol and Neurodegeneration
in the frequency of nocturia. The daily total voided
and catheterized volume and urinary incontinence pad
weights were also significantly decreased, whereas pa-
tients reported significant improvements in spasticity,
the quality of sleep, and the level of pain (measured
by patient self-assessment) [96]. Large, multicenter,
randomized, placebo-controlled trials are underway, al-
though no results are available at the moment. All these
data taken together suggest that although, until few years
ago, there was little consensus in the scientific literature
regarding phytocannabinoid utilization in current neuro-
logical therapy, presently, the majority of studies focus-
ing on this topic are oriented to suggest CBD, alone or in
combination, as a useful option in the treatment of MS,
at least in a subset of individuals.
CBD and Prion Diseases
Prion diseases are transmissible neurodegenerative disor-
ders that are characterized by the accumulation in the
CNS of the protease-resistant prion protein (PrPres), a
structurally misfolded isoform of its physiological coun-
terpart PrPsen. Both neuropathogenesis and prion infec-
tivity are related to PrPres formation [97]. CBD inhibited
PrPres accumulation in both mouse and sheep scrapie-
infected cells. Moreover, after intraperitoneal infection
with murine scrapie, peripheral injection of CBD lim-
ited cerebral accumulation of PrPres and significantly in-
creased the survival time of the infected mice. CBD inhib-
ited the neurotoxic effects of PrPres and affected PrPres-
induced microglial cell migration in a concentration-
dependent manner [97]. Therefore, CBD may protect
neurons against the multiple molecular and cellular fac-
tors involved in the different steps of the neurodegener-
ative process, which takes place during prion infection.
This evidence, together with CBD’s ability to specifically
target the brain and its lack of toxic side effects, makes
CBD a promising drug, also to be used in Prion diseases,
although the high concentration of CBD needed to ob-
tain the survival effect and the absence of an effect if CBD
is administered after infection have to be taken into the
right account, considering, at the moment, the lack of an
early diagnosis of this diseases in humans.
Conclusions
The present review summarized a growing number of ev-
idences, indicating an emerging role for CBD in the pre-
vention and management of the main neurodegenerative
disorders. CBD, in fact, resulted in being able to protect
neuronal and nonneural cells against several detrimen-
tal insults, such as β-amyloid or 6-hydroxydopamine and
glutamate [62,70,71], which are considered to be the ba-
sis of disorders such as AD and PD. The protective effects
of CBD have been, moreover, evidenced in several animal
models of neurodegeneration, and very interestingly, im-
portant clinical trials have confirmed the potential phar-
macological activity of CBD in the management of clin-
ical symptoms and the slow-down of the progression of
a variety of pathologies, including AD, MS, PD, and ASL.
Unfortunately, despite CBD promising therapeutic value,
the actual mechanism responsible for its action still re-
mains to be fully elucidated. In fact, although its antiox-
idant structure is evident, if truth be told, it would be
limited to restrict all CBD actions to a simple antioxidant
mechanism, since CBD has revealed to possess not only
an effectiveness higher than that of the classical antiox-
idant compounds but also some special activity unfamil-
iar to them [98]. In fact, in almost all the clinical stud-
ies performed, CBD has strongly enhanced the effects of
THC, underlining that at least some biological and clini-
cal action is stoutly linked to the enhancement of endo-
cannabinoid and endovanilloid signaling system.
Until now, the best results with CBD were reached by
the use of Sativex R, a combination of THC and CBD,
thanks to the mutual benefit capitalized by one from the
other active marijuana components. The medical litera-
ture on the topic seems to reinforce the view that CBD
achieves synergy with THC [99,100], consisting of poten-
tiation of benefits, antagonism of adverse effects, sum-
mation (entourage effects), and pharmacokinetics advan-
tages (CBD suppression of 11-hydroxylation of THC).
The great therapeutic value of CBD, either given alone
or in association with THC, derives from the considera-
tion that it represents a rare, if not unique, compound
that is capable of affording neuroprotection by the com-
bination of different types of properties (e.g., antigluta-
matergic effects, antiinflammatory action, and antioxi-
dant effects) that almost cover all spectra of neurotoxic
mechanisms that operate in neurodegenerative disor-
ders (excitotoxicity, inflammatory events, oxidative in-
jury, etc.).
The reported data here, taken together with the evi-
dence of the CBD’s almost absolute absence of side ef-
fects, including psychotropicity, suggest its great efficacy
and open new horizons for the treatment of the main
neurodegenerative disorders. However, in the near fu-
ture, further clinical trials, well designed, carefully exe-
cuted, and powered for efficacy, are crucial to definitively
assess the clinical values of CBD, alone or in combina-
tion, in the management of neurodegenerative diseases,
also in comparison to the other therapeutic approaches.
This will allow the promising expectations to move from
the present promising, although limited, results toward
incontrovertible evidence.
CNS Neuroscience & Therapeutics 15 (2009) 65–75 c
2009 Blackwell Publishing Ltd 71
Cannabidiol and Neurodegeneration T. Iuvone et al.
Acknowledgments
This work was supported by FIRB 2006.
Conflict of Interest
All authors disclose any potential conflicts of interest, in-
cluding all relevant financial interests (e.g. employment,
significant share ownership, patent rights, consultancy,
research funding) in any company or institution that
might benefit from the publication.
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... THC inhibits acetylcholinesterase activity and prevents aggregation of Aβ-plaques in vitro (Eubanks et al., 2006). On the other hand, CBD might have antioxidant activities that could affect the metabolism of anandamide, although the underlying mechanism and receptor remain unclear (Campillo and Paez, 2009;Iuvone et al., 2009;Iuvone et al., 2009). Aβ-induced neurotoxicity was protected by CBD in vitro. ...
... THC inhibits acetylcholinesterase activity and prevents aggregation of Aβ-plaques in vitro (Eubanks et al., 2006). On the other hand, CBD might have antioxidant activities that could affect the metabolism of anandamide, although the underlying mechanism and receptor remain unclear (Campillo and Paez, 2009;Iuvone et al., 2009;Iuvone et al., 2009). Aβ-induced neurotoxicity was protected by CBD in vitro. ...
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... Cannabinoids have been shown to exert anti-inflammatory activities in various in vivo and in vitro models and have demonstrated the ability to ameliorate various inflammatory degenerative diseases [11,12]. However, the mechanisms of these effects are not completely understood but may be the result of interaction with the cannabinoid receptor 2 (CB2) resulting in decreased adenosine signaling [13][14][15]. The COVID-19 infection results in Severe Acute Respiratory Syndrome (SARS-CoV-2) in a small percentage of cases. ...
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... Cannabinoids have also garnered attention due to their interaction with the endocannabinoid system [16]. Specifically, CBD is considered a leading compound for the development of treatment for neurodegenerative diseases due to its neuroprotective effects and efficacy without psychotropic symptoms [17]. Furthermore, a study implicated that phytochemicals of Med Cannabis Cannabinoids 2022;5:85-94 DOI: 10.1159/000524086 C. sativa, including several cannabinoids, are inhibitors of AChE, which is supported by data obtained from computational modeling studies [18]. ...
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... In addition, a significant advantage of the authors' HNPs is the CBD therapeutic encapsulation within the lipid layer. The therapeutic value of CBD is its capacity to provide neuroprotection against a spectrum of neurotoxic mechanisms that operate in neurodegenerative disorders (excitotoxicity, inflammatory events, oxidative injury) [43]. ...
... Cannabidiol (CBD), the non-intoxicating component of the cannabis sativa plant (Russo, 2017), does not alter subjective experience in the same way as ∆ 9tetrahydrocannabinol (THC). Data suggest that CBD can reduce inflammation, mitigate seizure frequency, prevent neural degeneration, and decrease other concerns in both clinical and preclinical studies (Devinsky et al., 2016;Gu et al., 2019;Iuvone et al., 2009;Karl et al., 2017;Ribeiro et al., 2015;Scuderi et al., 2009). CBD also shows potential effectiveness against psychosis, depression, and anxiety, at least in murine models (Crippa et al., , 2018De Mello Schier et al., 2012, 2014Khan et al., 2020). ...
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... Cannabinediol (CBD; (Figure 4B) non-psychoactive compound extracted from Cannabis sativa L., is an open pyran ring analogue. CBD has anti-inflammatory, antioxidant and anti-apoptotic effects (Iuvone et al., 2009). In addition, it has immunomodulatory properties (Mechoulam and Hanus 2002). ...
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Rationale Cannabidiol (CBD) and cannabidiolic acid (CBDA) are non-psychoactive components of the cannabis plant. CBD has been well characterised to have anxiolytic and anticonvulsant activity, whereas the behavioural effects of CBDA are less clear. Preclinical and clinical data suggests that CBD has antipsychotic properties and reduces methamphetamine self-administration in rats. An animal model that is commonly used to mimic the neurochemical changes underlying psychosis and drug dependence is methamphetamine (METH) sensitisation, where repeated administration of the psychostimulant progressively increases the locomotor effects of METH. Objective The aim of this study was to determine whether CBD or CBDA attenuate METH-induced sensitisation of locomotor hyperactivity in rats. Methods Eighty-six male Sprague Dawley rats underwent METH sensitisation protocol where they were subjected to daily METH (1 mg/kg on days 2 and 8, 5 mg/kg on days 3–7; i.p.) injections for 7 days. After 21 days of withdrawal, rats were given a prior injection of CBD (0, 40 and 80 mg/kg; i.p.) or CBDA (0, 0.1, 10 and 1000 µg/kg; i.p.) and challenged with acute METH (1 mg/kg; i.p.). Locomotor activity was then measured for 60 min. Results Rats displayed robust METH sensitisation as evidenced by increased locomotor activity to METH challenge in METH-pretreated versus SAL-pretreated rats. CBD (40 and 80 mg/kg) reduced METH-induced sensitisation. There was no effect of any CBDA doses on METH sensitisation or acute METH-induced hyperactivity. Conclusion These results demonstrate that CBD, but not CBDA, reduces METH sensitisation of locomotor activity in rats at pharmacologically effective doses, thus reinforcing evidence that CBD has anti-addiction and antipsychotic properties.
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Chapter
Ageratum houstonianum leaves are a common poisonous weeds found on the vast valley of Kangra in Palampur, Himachal Pradesh State, India. Freshly harvested leaves sample of Ageratum houstonionum were dried under shade and powdered. Leaf sample of A. houstonionum was extracted by process of hydrodistillation using a Clevenger-type apparatus for the preparation of essential oil. Extract from A. houstonianum was prepared by dissolving 5 μL of the essential oil in 10 mL methanol. All the sample was filtered through a Whatman (Maidstone, England) stainless steel syringe assembly using a 0.22 μm Durapore (Millipore: Milford, USA) membrane filter. Purification processes via column chromatography, thin layer chromatography and preparative thin layer chromatography were done. Reverse phase HPLC analysis was carried out via a Waters HPLC system consisting of model 510 and 515 pumps, a Rheodyne injector, a Novapak C18 column (250 x 4.6 mm i.d.; 4 μm), a model 490E multi-channel detector and Millennium 2010 sata manager. The mobile phase constituents were filtered using a Durapore 0.22 μm membrane filter. The elution was carried out with a linear gradient of acetonitrile: water (40:60) to pure acetonitrile in 60 min at a flow rate of 1 mL/min. detection was at 210, 240, 280 and 320 nm. The precocene was eluted within 25 min, the peak areas showed good reproducibility (average relative standard deviation were 0.78%), and the calibration curves (i.e. mass of precocene standard injected vs. peak area detected at 210 nm) were linear over the range of 0.05- 10 μg (for precocene I, y = 6654454 x + 176626, r2 = 0.99 and for precocene II, y = 4618457 x + 133472, r2 = 0.99). Standard sample containing precocene I (1 mg/mL) and precocene II (1 mg/mL) obtained from Sigma (St Louis, MO, USA) were prepared in methanol. Identified precocene I was screened against Trypanosoma evansi for trypanocidal activity on Vero cells grown in Dulbecco's Modified Eagle Medium (DMEM) and supplemented with foetal calf serum (FCS) 20-40% at appropriate conditions. In vitro cytotoxicity test of precocene I at concentrations (1.56-100 μg ml-1) was done on Vero cells but without FCS. In vitro trypanocidal activity varied from immobilization, reduction and to the killing of trypanosomes in corresponding ELISA plate wells. At 250 μg ml-1of purified precocene I, there was drastic reduction of average mean trypanosomes count to complete killing of trypanosomes (40.±0.0 to 0.00±0.00) at 9 h of incubation, which was statistically the same as diminazine aceturate (50 μg ml-1) at 4 h. Trypanosomes counts decreased in concentration and time –dependent manner with significant difference (P ≤ 0.05 to 0. 01)). During in vitro cytotoxicity test, Purified precocene I and diminazine aceturate standard drug, were cytotoxic to Vero cells at all concentrations except at concentrations of 6.25-1.56 μg ml-1 and 1.56 μg ml-1, respectively. Precocene I was responsible for higher anti-trypanosomal activity. Precocene I could be near futurtrypanocidal compound for a new trypanocide. To attest its full and firm trypanocidal activity potential, in vivo test need to be conducted alongside the in vitro method.
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Neurodegenerative diseases as diverse as Alzheimer's, Parkinson's, and Creutzfeldt-Jakob disease share a common pathogenetic mech- anism involving aggregation and deposition of misfolded proteins, which leads to progressive central nervous system disease. Although the type of aggregated protein and the regional and cellular distribu- tion of deposition vary from disease to disease, these disorders may all be linked by similar pathways of protein aggregation with fibril formation and amyloid deposition. This perspective on pathogene- sis suggests that a wide variety of neurodegenerative diseases can be grouped mechanistically as brain amyloidoses, an outlook that yields novel insights into potential therapeutic approaches that may be ap- plicable across the broad spectrum of neurodegenerative disease.
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GW Pharmaceuticals is undertaking a major research programme in the UK to develop and market distinct cannabis-based prescription medicines [THC:CBD, High THC, High CBD] in a range of medical conditions. The cannabis for this programme is grown in a secret location in the UK.It is expected that the product will be marketed in the US in late 2003. GW's cannabis-based products include selected phytocannabinoids from cannabis plants, including D9 tetrahydrocannabinol (THC) and cannabidiol (CBD). The company is investigating their use in three delivery systems, including sublingual spray, sublingual tablet and inhaled (but not smoked) dosage forms. The technology is protected by patent applications. Four different formulations are currently being investigated, including High THC, THC:CBD (narrow ratio), THC:CBD (broad ratio) and High CBD. GW is also developing a specialist security technology that will be incorporated in all its drug delivery systems. This technology allows for the recording and remote monitoring of patient usage to prevent any potential abuse of its cannabis-based medicines.GW plans to enter into agreements with other companies following phase III development, to secure the best commercialisation terms for its cannabis-based medicines. In June 2003, GW announced that exclusive commercialisation rights for the drug in the UK had been licensed to Bayer AG. The drug will be marketed under the Sativex® brand name. This agreement also provides Bayer with an option to expand their license to include the European Union and certain world markets. GW was granted a clinical trial exemption certificate by the Medicines Control Agency to conduct clinical studies with cannabis-based medicines in the UK. The exemption includes investigations in the relief of pain of neurological origin and defects of neurological function in the following indications: multiple sclerosis (MS), spinal cord injury, peripheral nerve injury, central nervous system damage, neuroinvasive cancer, dystonias, cerebral vascular accident and spina bifida, as well as for the relief of pain and inflammation in rheumatoid arthritis and also pain relief in brachial plexus injury. The UK Government stated that it would be willing to amend the Misuse of Drugs Act 1971 to permit the introduction of a cannabis-based medicine.GW stated in its 2002 Annual Report that it was currently conducting five phase III trials of its cannabis derivatives, including a double-blind, placebo-controlled trial with a sublingual spray containing High THC in more than 100 patients with cancer pain in the UK. Also included is a phase III trial of THC:CBD (narrow ratio) being conducted in patients with severe pain due to brachial plexus injury, as are two more phase III trials of THC:CBD (narrow ratio) targeting spasticity and bladder dysfunction in multiple sclerosis patients. Another phase III trial of THC:CBD (narrow ratio) in patients with spinal cord injury is also being conducted. Results from the trials are expected during 2003.Three additional trials are also in the early stages of planning. These trials include a phase I trial of THC:CBD (broad ratio) in patients with inflammatory bowel disease, a phase I trial of High CBD in patients with psychotic disorders such as schizophrenia, and a preclinical trial of High CBD in various CNS disorders (including epilepsy, stroke and head injury).GW Pharmaceuticals submitted an application for approval of cannabis-based medicines to UK regulatory authorities in March 2003. Originally GW hoped to market cannabis-based prescription medicines by 2004, but is now planning for a launch in the UK towards the end of 2003.Several trials for GW's cannabis derivatives have also been completed, including four randomised, double-blind, placebo-controlled phase III clinical trials conducted in the UK. The trials were initiated by GW in April 2002, to investigate the use of a sublingual spray containing THC:CBD (narrow ratio) in the following medical conditions: pain in spinal cord injury, pain and sleep in MS and spinal cord injury, neuropathic pain in MS and general neuropathic pain (presented as allodynia). Results from these trials show that THC:CBD (narrow ratio) caused statistically significant reductions in neuropathic pain in patients with MS and other conditions. In addition, improvements in other MS symptoms were observed as well.Phase II studies of THC:CBD (narrow ratio) have also been completed in patients with MS, spinal cord injury, neuropathic pain and a small number of patients with peripheral neuropathy secondary to diabetes mellitus or AIDS. A phase II trial of THC:CBD (broad ratio) has also been completed in a small number of patients with rheumatoid arthritis, as has a trial of High CBD in patients with neurogenic symptoms. A phase II trial has also been evaluated with High THC in small numbers of