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Cannabis and Amyotrophic Lateral Sclerosis: Hypothetical and Practical Applications, and a Call for Clinical Trials

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Abstract

Significant advances have increased our understanding of the molecular mechanisms of amyotrophic lateral sclerosis (ALS), yet this has not translated into any greatly effective therapies. It appears that a number of abnormal physiological processes occur simultaneously in this devastating disease. Ideally, a multidrug regimen, including glutamate antagonists, antioxidants, a centrally acting anti-inflammatory agent, microglial cell modulators (including tumor necrosis factor alpha [TNF-alpha] inhibitors), an antiapoptotic agent, 1 or more neurotrophic growth factors, and a mitochondrial function-enhancing agent would be required to comprehensively address the known pathophysiology of ALS. Remarkably, cannabis appears to have activity in all of those areas. Preclinical data indicate that cannabis has powerful antioxidative, anti-inflammatory, and neuroprotective effects. In the G93A-SOD1 ALS mouse, this has translated to prolonged neuronal cell survival, delayed onset, and slower progression of the disease. Cannabis also has properties applicable to symptom management of ALS, including analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. With respect to the treatment of ALS, from both a disease modifying and symptom management viewpoint, clinical trials with cannabis are the next logical step. Based on the currently available scientific data, it is reasonable to think that cannabis might significantly slow the progression of ALS, potentially extending life expectancy and substantially reducing the overall burden of the disease.
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American Journal of Hospice and Palliative
http://ajh.sagepub.com/content/27/5/347
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DOI: 10.1177/1049909110369531
2010 27: 347 originally published online 3 May 2010AM J HOSP PALLIAT CARE
Gregory T. Carter, Mary E. Abood, Sunil K. Aggarwal and Michael D. Weiss
Clinical Trials
Cannabis and Amyotrophic Lateral Sclerosis: Hypothetical and Practical Applications, and a Call for
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Rehabilitation Medicine and Palliative Care
Cannabis and Amyotrophic Lateral Sclerosis:
Hypothetical and Practical Applications, and
a Call for Clinical Trials
Gregory T. Carter, MD, MS
1
, Mary E. Abood, PhD
2
,
Sunil K. Aggarwal, PhD
3
, and Michael D. Weiss, MD
1,4,5
Abstract
Significant advances have increased our understanding of the molecular mechanisms of amyotrophic lateral sclerosis (ALS), yet
this has not translated into any greatly effective therapies. It appears that a number of abnormal physiological processes occur
simultaneously in this devastating disease. Ideally, a multidrug regimen, including glutamate antagonists, antioxidants, a centrally
acting anti-inflammatory agent, microglial cell modulators (including tumor necrosis factor alpha [TNF-a] inhibitors), an antiapop-
totic agent, 1 or more neurotrophic growth factors, and a mitochondrial function-enhancing agent would be required to com-
prehensively address the known pathophysiology of ALS. Remarkably, cannabis appears to have activity in all of those areas.
Preclinical data indicate that cannabis has powerful antioxidative, anti-inflammatory, and neuroprotective effects. In the G93A-
SOD1 ALS mouse, this has translated to prolonged neuronal cell survival, delayed onset, and slower progression of the disease.
Cannabis also has properties applicable to symptom management of ALS, including analgesia, muscle relaxation, bronchodilation,
saliva reduction, appetite stimulation, and sleep induction. With respect to the treatment of ALS, from both a disease modifying
and symptom management viewpoint, clinical trials with cannabis are the next logical step. Based on the currently available sci-
entific data, it is reasonable to think that cannabis might significantly slow the progression of ALS, potentially extending life expec-
tancy and substantially reducing the overall burden of the disease.
Keywords
cannabis, endocannabinoids, amyotrophic lateral sclerosis, clinical trials, motor neuron disease
Introduction
Amyotrophic lateral sclerosis (ALS), with an incident rate of
5 to 7 per 100 000 population, is the most common form of
adult motor neuron disease.
1
Amyotrophic lateral sclerosis is
a rapidly progressive neuromuscular disease that destroys both
upper and lower motor neurons, resulting in weakness, spasti-
city, and ultimately death from respiratory failure. The vast
majority of ALS cases are acquired and occur sporadically.
Emerging evidence suggests that increased oxidative stress
from free radical toxicity and/or excessive glutamate activity
is what leads to motor neuron cell death in the brain and spinal
cord.
2-5
Inherited forms of the disease, which occur in approx-
imately 5%to 10%of all patients with ALS, are largely
because of mutations in the superoxide dismutase gene, pre-
sumably producing a marked increase in oxidative stress. Pre-
sentations of familial ALS have more variability than in
sporadic ALS and are mutation specific with the most aggres-
sive form because of the A4V mutation.
5
Recent results have
established that ALS also involves other nonneuronal cells
including astroglia and microglia.
6,7
Other putative mechan-
isms involved in motor neuron degeneration in ALS include
mitochondrial dysfunction, neuroinflammation, growth factor
deficiency, and glutamate excitotoxicity.
2,3
Significant advances have been made regarding our under-
standing of the molecular mechanisms of ALS.
8-12
However,
this has not yet translated into an effective therapeutic treat-
ments. To date, the only food and drug administration- (FDA)
approved therapy available for ALS is the antiglutamatergic
agent Riluzole, which has limited therapeutic efficacy.
10
Given
1
Muscular Dystrophy Association/Amyotrophic Lateral Sclerosis Center,
University of Washington Medical Center, Seattle, WA, USA
2
Anatomy and Cell Biology and Center for Substance Abuse Research, Temple
University, Philadelphia, PA, USA
3
Medical Scientist Training Program, School of Medicine, University of
Washington, Seattle, WA, USA
4
Neuromuscular Disease Division, Department of Neurology, University of
Washington Medical Center, Seattle, WA, USA
5
Electrodiagnostic Laboratory, University of Washington Medical Center,
Seattle, WA, USA
Corresponding Author:
Gregory T. Carter, 1800 Cooks Hill Road, Suite E, Centralia, WA 98531, USA
Email: gtcarter@uw.edu
American Journal of Hospice
& Palliative Medicine
®
27(5) 347-356
ªThe Author(s) 2010
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this perspective, there remains an ongoing search for novel
therapeutic approaches. There is increasing evidence that can-
nabinoids and manipulation of the endocannabinoid system
may have beneficial disease-modifying potential in ALS.
13-21
Moreover, the clinical effects of cannabis, the principal
cannabinoid-producing botanical agent, have been reported to
be useful in managing the symptomatology in ALS, as well
as many other neurodegenerative disorders.
22-34
Thus, signifi-
cant efforts are now being directed at evaluating the role of the
endocannabinoid system in the pathophysiology of ALS. In
addition, there is an emerging body of science that points to
a role of exogenous cannabinoids in both clinical symptom
management and a positive disease-modifying effect.
13-21
The Physiology and Pharmacology of
Cannabinoids
Prior to the last decade, there was little known about the spe-
cific pharmacological and molecular effects of cannabis. How-
ever, important advances have taken place recently, which have
greatly increased the understanding of the receptors and ligands
composing the endogenous cannabinoid system.
35-54
Research
has shown that 2 major cannabinoid receptor subtypes exist,
including the cannabinoid receptor, type 1 (CB1) subtype,
which is predominantly expressed in the brain, and the canna-
binoid receptor, type 2 (CB2) subtype, which is primarily found
on the cells of the immune system.
35,49,50
A variety of ligands
for these receptors based on the cannabinoid structure have
been synthesized and studied. Experiments performed with
several types of neural cells that endogenously express the
CB1 receptor suggest that activation of protein kinases may
be responsible for some of the cellular responses elicited by
these receptors.
51
The discovery of the endocannabinoids, that
is, endogenous metabolites capable of activating the cannabi-
noid receptors, and the understanding of the molecular
mechanisms leading to their biosynthesis, release, and inactiva-
tion, have created a new area in research on the pharmaceutical
applications of cannabinoid-based medicines.
52
The character-
ization of endocannabinoids such as anandamide and the detec-
tion of widespread cannabinoid receptors in the brain and
peripheral tissues suggest that the cannabinoid system repre-
sents a previously unrecognized ubiquitous network in the ner-
vous system.
Cannabinoid receptors are G protein-coupled, 7-segment
transmembrane proteins, similar to the receptors of other neu-
rotransmitters such as dopamine, serotonin, and norepinephr-
ine.
51,52
Dense receptor concentrations are found in the
cerebellum, basal ganglia, and hippocampus, likely accounting
for the effect of exogenously administered cannabinoids on
motor tone and coordination as well as mood state.
53-55
Low
concentrations are found in the brain stem, accounting for the
low potential for lethal overdose with cannabinoid-based med-
icines.
56-59
A growing number of strategies for separating
sought-after therapeutic effects of cannabinoid receptor ago-
nists from the unwanted consequences of CB1 receptor activa-
tion are emerging. Recently, ligands have been developed that
are potent and selective agonists for CB1 and CB2 receptors, as
well as potent CB1—selective antagonists and inhibitors of
endocannabinoid uptake or metabolism.
60
In addition, varieties
of cannabis are known to contain a mix of partial cannabinoid
agonists and antagonists, which can be rationally used. This
knowledge may lead to the design of synthetic cannabinoid
agonists and antagonists as well as cannabis strains with high
therapeutic potential. The fact that both CB1 and CB2 receptors
have been found on immune cells suggests that cannabinoids
play an important role in the regulation of the immune system.
Recent studies show that cannabinoids downregulate cytokine
and chemokine production, both mechanisms that suppress
inflammatory responses.
61-64
Manipulation of endocannabi-
noids (ie, via the use of exogenous cannabis) has great potential
treatment viability against inflammatory disorders, including
the inflammation seen in the central nervous system (CNS)
of the patients with ALS. The potential use of cannabinoids
as a novel class of anti-inflammatory agents may become one
of the predominant indications, as that includes not only neuro-
modulation but pain as well.
65,66
Indeed, any number of inflam-
matory processes that are at least partially triggered by
activated T cells or other cellular immune components could
be treated with cannabis and other cannabinoid-based medicines.
Cannabinoids are chemically classified as terpenes. These
are lipid-soluble hydrocarbons that function as major biosyn-
thetic cellular messengers in many forms of life. Terpenes are
widespread in plants and most species of animals as well,
including humans. Any compound that resembles the basic ter-
penes structure, yet may be modified chemically via oxidation
or other processes, is termed a terpenoid. Many hormones,
including estrogens, are terpenoids, and share the same basic
organic chemical structure as cannabinoids.
53,54
All terpenes
are organic, readily penetrate the highly lipophilic CNS.
Interestingly, tamoxifen, which is an antagonist of the estro-
gen receptor in breast tissue, is terpenoid and chemically
resembles cannabinoids. Tamoxifen’s primary use is as a
FDA-approved drug for the treatment of breast cancer.
67-69
However, phase II clinical trials of tamoxifen in ALS have now
demonstrated preliminary efficacy and safety.
68
A phase 2B
study demonstrated increased survival after 2 years in patients
with ALS taking higher doses of tamoxifen, with no effect seen
in 2 lower dose groups.
68
The 3 higher dose groups experienced
a 4- to 6-month prolongation of survival over a 24-month trial,
with no significant side effects observed.
68
Interestingly, gluta-
mate uptake in cultured retinal cells is inhibited by tamoxifen,
thus this mechanism may be part of a possible beneficial effect
in ALS.
67
The chemical similarity between cannabinoids and
tamoxifen points to a possible shared mechanism of action for
neural protection.
69
The cannabis plant is a remarkably complex plant, with sev-
eral phenotypes, each containing over 400 distinct chemical
moieties.
70-73
Approximately 70 of these are chemically unique
and classified as cannabinoids.
70-73
Delta-9 tetrahydrocannabi-
nol (THC) and delta-8 THC appear to produce the majority of
the psychoactive effects of cannabis.
74,75
Delta-9 THC, the
active ingredient in dronabinol (Marinol), is the most abundant
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cannabinoid in the plant, which historically led researchers to
erroneously hypothesize that it was the main source of the
drug’s impact. It is now known that other major plant cannabi-
noids, including cannabidiol and cannabinol, modify the phar-
macology of THC and have distinct effects of their own.
Cannabidiol is the second most prevalent of cannabis’s active
ingredients and may produce most of its therapeutic effects.
Cannabidiol becomes THC as the plant matures and this THC
over time breaks down into cannabinol. Up to 40%of the can-
nabis resin in some strains is cannabidiol.
72
The amount varies
according to plant. Some varieties of Cannabis sativa have
been found to have no cannabidiol.
72
Cannabidiol breaks down
to cannabinol as the plant matures. Much less is known about
cannabinol, although it appears to have distinct pharmacologi-
cal properties that are quite different from cannabidiol. Canna-
binol has significant anticonvulsant, sedative, and other
pharmacological activities likely to interact with the effects
of THC.
75-78
Cannabinol may induce sleep and may provide
some protection against seizures for epileptics.
78
Hypothetical Applications
Preclinical Studies of the Endocannabinoid System in ALS
The primary murine model for human ALS is the G93A-SOD1
mutant mouse, which is genetically engineered to replicate
familial ALS.
4
There is strong evidence in the G93A-SOD1
mouse model of ALS that the endocannabinoid system is
involved, both directly and indirectly, in the pathophysiology
of the disease. Several recent studies have highlighted this.
Rossi et al
17
investigated both excitatory and inhibitory synap-
tic transmission in the striatum of symptomatic G93A-SOD1
ALS mice, along with the sensitivity of these synapses to
CB1 receptor stimulation. They reported a reduced frequency
of glutamate-mediated spontaneous excitatory postsynaptic
currents and increased frequency of GABA-mediated sponta-
neous inhibitory postsynaptic currents in recordings from stria-
tal neurons in ALS mice. This is likely due to some presynaptic
defects in transmitter release. The sensitivity of CB1 receptors
in controlling both glutamate and GABA transmission was
potentiated in ALS mice. This provides good evidence that
adaptations of the endocannabinoid system might be involved
in the pathophysiology of ALS. This is not inconsistent with
current theories on pathophysiological mechanisms of ALS,
which still remain largely a pathophysiologic enigma.
79-83
Bilsland et al
18
showed that treatment of postsymptomatic,
90-day-old SOD1G93A mice with a synthetic cannabinoid,
WIN55,212-2, significantly delayed disease progression.
Furthermore, genetic ablation of the fatty acid amide hydrolase
(FAAH) enzyme, which results in raised levels of the endocan-
nabinoid anandamide by preventing its breakdown, prevented
the appearance of disease signs in 90-day-old SOD1G93A
mice. Surprisingly, elevation of cannabinoid levels with either
WIN55,212-2 or FAAH ablation had no effect on life span.
Ablation of the CB1 receptor, in contrast, had no effect on dis-
ease onset in SOD1G93A mice but significantly extended life
span. Together, these results indicate that cannabinoids have
significant neuroprotective and disease-modifying effects in
this model of ALS and suggest that these beneficial effects may
be mediated by non-CB1 receptor-based mechanisms.
It is now known that during active neurodegeneration from
disease or trauma in the CNS, the concentration of tumor
necrosis factor alpha (TNF-a) rises well above normal levels
during the inflammatory response. Addition of exogenous
TNF-a, both in vitro and in vivo, to neurons has been shown
to significantly potentiate glutamatergic excitotoxicity. Thus,
the discovery of drug targets reducing excess TNF-aexpres-
sion may help protect neurons after injury. Zhao et al
84
inves-
tigated the neuroprotective role of the CB1 receptor after
TNF-aexposure in the presence or absence of CB1 agonists.
They demonstrated that CB1 activation blocks the TNF-a-
induced increase in inflammation, thus protecting the neurons
from damage. Thus, neuroprotective strategies which increase
CB1 activity may help to reduce damage to motor neurons in
ALS that are mediated by CNS inflammation.
Additionally, CB2 receptors are dramatically upregulated in
inflamed neural tissues associated with CNS disorders, includ-
ing ALS.
85
In G93A-SOD1 mutant mice, endogenous cannabi-
noids are elevated in spinal cords of symptomatic mice.
21
Furthermore, treatment with nonselective cannabinoid partial
agonists prior to, or on, symptom appearance minimally delays
disease onset and prolongs survival through undefined mechan-
isms. Shoemaker et al
14
demonstrated that messenger RNA
(mRNA) levels, receptor binding, and function of CB2, but not
CB1, receptors are dramatically and selectively upregulated in
spinal cords of G93A-SOD1 mice in a temporal pattern paral-
leling disease progression. Daily injections of the selective
CB2 agonist AM-1241, initiated at symptom onset, increased
the survival interval after disease onset by 56%.
14
Disease-Modifying Treatment of ALS
Clinical trials for ALS have been largely based on preclinical
work using the G93A-SOD1 mouse. Unfortunately, translation
of therapeutic success in mice to humans has proven quite dif-
ficult and a cure for ALS is not yet known. Many factors have
been implicated in explaining the predominantly negative
results of numerous randomized clinical trials in ALS, includ-
ing methodological problems in the use of animal-drug screen-
ing, the lack of assessment of pharmacokinetic profile of the
drugs, and methodological pitfalls of clinical trials in patients
with ALS. Riluzole is currently the only agent approved by the
FDA for the treatment of ALS.
10
This drug inhibits the presy-
naptic release of glutamate and reduces neuronal damage in
experimental models of ALS. Four controlled trials of a total
of 974 riluzole-treated and 503 placebo-treated patients
showed that it prolonged survival opposed to placebo, although
the benefit was fairly modest.
10
Because oxidative stress is one
of the proposed pathogenic factors in ALS, antioxidants have
been extensively tested, including vitamin E, vitamin C, coen-
zyme Q, B-carotene, N-acetylcysteine, and creatine, an amino
acid naturally found in skeletal.
11
To date, trials of
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neurotrophic factors, antioxidants, glutamate antagonists, and
creatine have all failed to show any significant benefit in
humans, although most had significant benefit shown in
mice.
11
It is currently felt that a cocktail approach may be the
ideal treatment strategy, including glutamate antagonists, anti-
oxidants, and neurotrophic factors.
68
Recently, the kynurenine
pathway (KP) has emerged as a potential target for ALS treat-
ment.
8
The KP is a major route for the metabolism of trypto-
phan, generating neuroactive intermediates in the process.
These catabolites include the excitotoxic N-methyl-D-aspartate
(NMDA) receptor agonist, quinolinic acid (QUIN), and the
neuroprotective NMDA receptor antagonist, kynurenic acid
(KYNA). These catabolites appear to play a key role in the
communication between the nervous and immune systems and
also in modulating cell proliferation and tissue function. Tar-
geting the KP, hence, could offer a new therapeutic option to
improve ALS treatment, and several drugs that block the KP
are already under investigation.
Although other potential neuroprotective agents have been
evaluated in randomized clinical trials, none have shown
unequivocal benefit for the treatment of ALS. Thus, there
remains an enormous need for more trials to test other putative
disease-modifying therapies. As the effectiveness of such drugs
can only be definitively established by large, costly, phase III
randomized controlled studies, it is imperative that researchers
target compounds that have potential benefit based on demon-
strated pharmacological and physiological mechanisms.
There remains the possibility that ALS could represent a
state of clinical endocannabinoid deficiency (CED).
28,31
The
endocannabinoid anandamide demonstrates dopamine-
blocking and anti-inflammatory effects and is also tonically
active in the periaqueductal gray matter.
81
Endocannabinoids
also modulate glutamatergic neurotransmission indirectly via
NMDA receptors, and these pathways can be modulated to pro-
duce a clinical effect, such as reduction in motor tone, seizure
threshold, and perception of pain and mood state.
82-93
These
clinical, biochemical, and pathophysiological patterns could
reflect an underlying abnormality in the endocannabinoid sys-
tem in ALS that could be potentially treated with exogenous
cannabinoids, that is, via clinical use of cannabis or some deri-
vative thereof.
Practical Applications
Symptom Management in ALS
As discussed previously, animal studies strongly suggest that
the endocannabinoid system is implicated in the pathophysiol-
ogy of ALS, either directly as part of the underlying disease
mechanisms, or indirectly, inasmuch as this system plays a role
in the homeostatic functioning of the neuromuscular system.
Irrespective, it is clear that cannabinoids are able to slow down
the progression of ALS in mice, likely by acting as an antiox-
idant, among other mechanisms.
15-18
In addition to the neuro-
protective effect, patients report that cannabis helps in
treating symptoms of the disease, including alleviating pain
and muscle spasms, improving appetite, diminishing depres-
sion, and helping to manage sialorrhea (excessive drooling)
by drying up saliva in the mouth.
24
Indeed, in a large survey
it was noted that patients with ALS who were able to obtain
cannabis found it preferable to prescription medication in man-
aging their symptoms. However, this study also noted that the
biggest reason patients with ALS were not using cannabis was
their inability to obtain it, due to legal or financial reasons or
lack of safe access.
24,26
There are many other clinical problems faced by patients
with ALS that could be helped by cannabis. The majority of
patients with ALS experience significant pain.
24
The pain is
largely due to immobility, which can cause adhesive capsulitis,
mechanical back pain, pressure areas on the skin, and more
rarely, neuropathic pain.
24,31
Pain in ALS is a frequent symp-
tom especially in the later stages of disease and can have a pro-
nounced influence on quality of life and suffering.
94-98
Treatment of pain, therefore, should be recognized as an impor-
tant aspect of palliative care in ALS. A recent Cochrane review
of the evidence for the efficacy of drug therapy in relieving
pain in ALS revealed no randomized or quasi-randomized con-
trolled trials showing significant benefit. Despite the major
pain problems encountered by patients with ALS, there are
no clear guidelines and few randomized clinical trials about
how to manage pain in ALS. However, as noted previously, the
cannabinoids have been shown to produce an anti-
inflammatory effect by inhibiting the production and action
of TNF and other acute phase cytokines.
35
Additionally, canna-
bis may reduce pain sensation, likely through a brain stem cir-
cuit that also contributes to the pain-suppressing effects of
morphine.
99
Cannabinoids produce analgesia by modulating
rostral ventromedial medulla neuronal activity in a manner
similar to, but pharmacologically distinct from, that of mor-
phine.
100,101
This analgesic effect is also exerted by some endo-
genous cannabinoids (anandamide) and synthetic cannabinoids
(methanandamide) and may be prevented by the use of selec-
tive antagonists.
102-104
Thus, cannabinoids are centrally acting
analgesics with a different mechanism of action than opioids,
although the analgesia produced by cannabinoids and opioids
may involve similar pathways at the brain stem level.
103-105
There are now multiple, well-controlled clinical studies
using cannabis to treat pain, showing ample evidence of
analgesic efficacy.
106
A recent systematic review and meta-
analysis of double-blind randomized controlled trials that com-
pared any cannabis preparation to placebo among participants
with chronic pain showed a total of 18 completed trials. The
studies indicate that cannabis is moderately efficacious for the
treatment of chronic pain.
106
In the setting of ALS, the medica-
tions should be titrated to the point of comfort. Concomitant
use of narcotics may also be beneficial because, as noted above,
the opioid receptor system is distinct from the cannabinoid
system. In that regard, the antiemetic effect of cannabis may
help with the nausea sometimes associated with narcotic
medications.
In addition to pain, spasticity is also a major problem for
patients with ALS. Spasticity in ALS is induced both at the
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motor cortex and at the spinal cord level through the loss of
motor neuron inhibition.
107-110
Cannabis has an inhibitory
effect via augmentation of g-amino-butyric acid (GABA) path-
ways in the CNS.
111
This produces motor neuron inhibition at
spinal levels in mice. Several past studies have suggested that
cannabinoid therapy provide at least a subjective reduction of
spasticity, although virtually all of the studies have been done
in patients with multiple sclerosis (MS).
29,112
A survey study
has shown that patients with ALS do subjectively report that
cannabis helps alleviate symptoms of spasticity.
24
In addition to pain and spasticity, there are other pharmaco-
logical effects of cannabis that may be useful for patients with
ALS. Patients with ALS and bulbar symptoms also usually
have difficulty controlling and swallowing the saliva that is
normally present in the oral cavity.
113
Cannabis is a potent anti-
salivatory compound that swiftly dries the oral cavity and
upper airway, potentially reducing the risk of aspiration pneu-
monia and increasing patient comfort.
22,24
Cannabis also increases appetite and may help prevent ‘‘ALS
cachexia,’’ a phenomenon experienced by some patients where
weight loss occurs in excess of that caused by muscle atrophy
and reduced caloric intake.
114-116
In addition to improving appe-
tite, cannabis appears to also help with mood state and sleep.
Patients with ALS previously have reported that cannabis is at
least moderately effective at reducing symptoms of pain, spasti-
city, drooling, appetite loss, and depression.
24
Cannabinoids will vaporize at temperatures in the range of
200F and can be inhaled via a hot mist.
117-119
This delivers the
cannabinoids rapidly, allowing for ease of titration and letting
patients with ALS having severe dysarthria rapid access to the
drug’s effects. Vaporizing also helps dry up oral secretions.
24
Cannabis may also be ingested orally or through a feeding tube,
although absorption is much slower. Cannabis can be titrated to
desired effect, with individual, patient-specific dosing.
120-122
In terms of clinical trials for disease-modifying effects, dosing
paradigm would be more complex. Fortunately, the low toxi-
city of cannabis would allow for trail and error. Based on the
available studies, a typical dosing range for clinical effects
would likely be 1 to 2 g/d of cannabis, with an average THC
content of 20%by weight.
122
A Call for Clinical Trials
In terms of symptoms management, cannabis is a substance
with many pharmacological properties that are directly applica-
ble to the clinical care of patients with ALS. These include
analgesia, muscle relaxation, bronchodilation, saliva reduction,
appetite stimulation, sleep induction, and mood elevation.
24
From a pharmacological perspective, cannabis is remarkably
safe with realistically no possibility of overdose or frank phys-
ical addiction. There is a valid, logical, scientifically grounded
rationale to support the use of cannabis in the pharmacological
management of ALS. Indeed, cannabis, as a single compound,
could potentially replace and provide the benefits of multiple
standard medications, including analgesics, antispasmodics,
anxiolytics, antidepressants, appetite stimulants, and agents
used to dry the mouth (typically anticholinergic medications).
There is ample clinical evidence to warrant the empiric use
of cannabis to manage the symptoms of ALS.
From an experimental, disease-modifying perspective, it is
not likely that a single mechanism agent would treat all of the
abnormal physiological processes occurring simultaneously in
this devastating disease.
123-127
Thus, some experts are now
advocating for a combination drug approach to slowing the pro-
gression of ALS.
80
Based on what is known about the patho-
physiology of ALS, a multidrug regimen would include
glutamate antagonists, antioxidants, a CNS anti-inflammatory
agent, a microglial cell modulators, including TNF-ainhibi-
tors, an antiapoptotic agent, 1 or more neurotrophic growth fac-
tors, and a mitochondrial function-enhancing agent.
127,128
Remarkably, cannabinoids appear to have at least some activity
in all of those categories.
129-131
Moreover, there is a particu-
larly strong, growing, body of preclinical data indicating that
cannabis has powerful antioxidative, anti-inflammatory, and
protective neuromodulatory effects.
132-135
In the G93ASOD1
ALS mouse, this has translated to prolonged neuronal cell
survival.
15,16,18,43
There is an overwhelming amount of preclinical and clinical
evidence to warrant initiating a multicenter randomized,
double-blind, placebo-controlled trial of cannabis as a
disease-modifying compound in ALS. Secondary outcome
measures could include clinical management, with end points
such as pain scores, quality-of-life measures, and so on. Devel-
oping a multicenter clinical research trial using cannabis would
pose many unique barriers that would have to be overcome.
Inasmuch as there is no commercial manufacturer of cannabis,
the study would have to be funded either by the federal govern-
ment or privately. Presumably, there would be no industry
funding. Obtaining the trial drug would require the investiga-
tors to gain access to a large, reliable supply of cannabis that
is legal for medical research. At present, the only source of can-
nabis that can be legally used in research in the United States is
through the National Institute on Drug Abuse (NIDA). National
Institute on Drug Abuse provides low-potency material and
makes the cannabis available only to projects it approves.
National Institute on Drug Abuse supplies cannabis with a THC
content, by weight, of 2%to 4%typically, although it has sup-
plied cannabis with an 8%by weight THC content on occa-
sion.
136,137
The average THC content of cannabis at
randomly surveyed medical cooperatives in California is
approximately 15%to 20%.
26,117,121
Thus, an independent
source of cannabis would be needed to ensure a consistently
high cannabinoid content that may be strong enough to possibly
alter the disease progression. An independent cannabis source
would also allow investigators to avoid NIDA’s arbitrary and
lengthy review process that it mandates before providing any
cannabis for research. Historically, NIDA has derailed clinical
trial plans by refusing to supply cannabis, even after the
research protocols were approved by the FDA.
117
Nonetheless,
it is possible, with coordinated effort, to effectively do double-
blind, randomized, placebo-controlled clinical trials with can-
nabis.
138-141
To properly evaluate both subjective and objective
Carter et al 351
351
at UNIV WASHINGTON LIBRARIES on April 4, 2011ajh.sagepub.comDownloaded from
effects, cannabinoid blood levels should be followed as well, to
further ensure adequate data for a doseresponse curve.
Clinical trials with cannabis would also address the issue of
single versus multiple drug clinical trials. Arguable, multiple
drug trials would increase the chances of success but also expo-
nentially increase the difficulty of completing the trial and ana-
lyzing the data. Cannabis, as a single agent, in essence provides
the advantages of a multiple drug trial due to its multiple
mechanisms of action. Cannabis is a unique compound that
possesses significant internal therapeutic synergy. The search
for the underlying cause of ALS continues.
142,143
With respect
to treatment, from both a symptom management and disease
modifying viewpoint, the logical next step, based on the avail-
able science, would be clinical trials with cannabis. Although
not expected to be necessarily curative, it is not unreasonable
to think that cannabis might significantly slow the progression
of ALS, potentially extending life expectancy and substantially
reducing the overall burden of the disease.
Declaration of Conflicting Interests
The authors declared no conflicts of interest with respect to the author-
ship and/or publication of this article.
Funding
The authors received no financial support for the research and/or
authorship of this article.
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... Preclinical studies that were initiated in 2004 explored the role of cannabinoids and have identified that these compounds as a promising disease-modifying therapy to be confirmed in clinical trials with ALS patients (Bilsland & Greensmith, 2008;Carter et al., 2010;de Lago et al., 2015;. These preclinical studies were conducted mainly in the G93A transgenic mouse that overexpresses a mutated form of SOD1 and confirmed the potential of different cannabinoids able to reduce (i) excitotoxicity (effects that depend on targeting CB 1 receptors); (ii) microglial activation and neuroinflammation (effects mediated by the activation of the CB 2 receptor and/or by modulating PPAR-γ/NF-κB signalling or the GPR55 orphan receptor) and (iii) oxidative injury (effects that are receptor independent and/or related to PPAR-γ/Nrf2 signalling) . ...
... The possibility that certain cannabinoids may provide benefits in ALS has been also studied at the clinical level, although the number of clinical trials carried out are still too small to get any significant and reliable findings from, thus stressing the urgent need of additional clinical investigation (Carter et al., 2010). The first studies were exclusively observational (e.g. ...
... cramps, spasticity and drooling; see Amtmann et al., 2004), but also searching for more general effects that cannabis may provide to ALS patients (e.g. analgesia, bronchodilation, saliva reduction, appetite stimulation and sleep induction; see Carter et al., 2010;Chiò et al., 2017). These observational studies have derived in a few number of controlled clinical trials. ...
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Cannabinoids form a singular group of plant‐derived compounds, endogenous lipids and synthetic derivatives with multiple therapeutic effects exerted by targeting different elements of the so‐called endocannabinoid system. One of their therapeutic applications is the preservation of neuronal integrity exerted by attenuating the multiple neurotoxic events that kill neurons in neurodegenerative disorders. In this review, we will address the potential of cannabinoids as neuroprotective agents in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder characterized by muscle denervation, atrophy and paralysis, and progressive deterioration in upper and/or lower motor neurons. The emphasis will be paid on the cannabinoid receptor type‐2 (CB2), whose activation limits glial reactivity, but the potential of additional endocannabinoid‐related targets will be also addressed. The evidence accumulated so far at the preclinical level supports the need to move soon towards the patients and initiate clinical trials to confirm the potential of cannabinoid‐based medicines as disease modifiers in ALS.
... Exogenous cannabinoids play a pleiotropic activity mostly through two cannabinoid receptors: CB1 is predominantly expressed in the brain, and CB2 is primarily found in the cells of the immune system (Lucas et al., 2018). Since the pathophysiology of motor neuron degeneration in ALS may involve mitochondrial dysfunction, excessive glutamate activity, oxidative stress, neuroinflammation, and growth factor deficiency, cannabis could be effective in modulating these processes (Bilsland and Greensmith, 2008;Carter et al., 2010;Papadimitriou et al., 2010;Appel et al., 2011). To support these hypotheses, a recent metaanalysis of preclinical studies in murine ALS models conducted by Urbi and colleagues suggests that cannabinoid receptor agonists may improve survival time (Urbi et al., 2019b). ...
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Medical use of cannabis has been receiving growing attention over the last few decades in modern medicine. As we know that the endocannabinoid system is largely involved in neurological disorders, we focused on the scientific rationale of medical cannabis in three neurological disorders: amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease through pharmacological plausibility, clinical studies, and patients’ view. Clinical studies (randomized controlled trials, open-label studies, cohorts, and case reports) exploring medical cannabis in these disorders show different results depending on the methods and outcomes. Some show benefits on motor symptoms and others on non-motor symptoms and quality of life. Concerning patients’ view, several web surveys were collected, highlighting the real use of cannabis to relieve symptoms of neurological disorders, mostly outside a medical pathway. This anarchic use keeps questioning particularly in terms of risks: consumption of street cannabis, drug–drug interactions with usual medical treatment, consideration of medical history, and adverse reactions (psychiatric, respiratory, cardiovascular disorders, etc.), underlining the importance of a medical supervision. To date, most scientific data support the therapeutic potential of cannabis in neurological disorders. As far as patients and patients’ associations are calling for it, there is an urgent need to manage clinical studies to provide stronger evidence and secure medical cannabis use.
... On the other hand, a decline in TNF-α levels may be an efficacy marker of antiviral therapy (ART) (Aukrust et al. 1999;Cervia et al. 2010;Malherbe et al. 2014). Preclinical research has also demonstrated that both cannabinoid administration and cannabinoid receptor stimulation inhibit the production and inflammatory action of TNF-α and, in turn, mitigate neuronal damage (Abood 2005;Carter et al. 2010;Zhao et al. 2010). Taken together, such evidence suggests that TNF-α is likely a critical mediator of neuroinflammatory-induced cognitive alterations and thus, may be a mechanism by which HIV and CB modulate brain function. ...
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Chronic inflammation in the central nervous system is one mechanism through which human immunodeficiency virus (HIV) may lead to progressive cognitive decline. Given cannabis’s (CB’s) anti-inflammatory properties, use prevalence among people living with HIV (PLWH), and evidence implicating the insula in both, we examined independent and interactive effects of HIV and CB on insular circuitry, cognition, and immune function. We assessed resting-state functional connectivity (rsFC) of three insula subregions among 106 participants across four groups (co-occurring: HIV+/CB+; HIV–only: HIV+/CB−; CB–only: HIV−/CB+; controls: HIV−/CB−). Participants completed a neurocognitive battery assessing functioning across multiple domains and self-reported somatic complaints. Blood samples quantified immune function (T-cell counts) and inflammation (tumor necrosis factor alpha [TNF–α]). We observed interactive HIV × CB effects on rsFC strength between two anterior insula (aI) subregions and sensorimotor cortices such that, CB appeared to normalize altered rsFC among non-using PLWH. Specifically, compared to controls, HIV–only and CB–only groups displayed decreased dorsal anterior insula (DI) – postcentral gyrus rsFC and increased ventral anterior insula (VI) – supplementary motor area rsFC, whereas the co-occurring group displayed DI and VI rsFC more akin to that of controls. Altered DI – postcentral rsFC correlated with decreased processing speed and somatic complaints, but did not significantly correlate with inflammation (TNF–α). These outcomes implicate insula – sensorimotor neurocircuitries in HIV and CB and are consistent with prior work suggesting that CB use may normalize insula functioning among PLWH. Graphical Abstract
... A series of preclinical studies initiated in 2004 have investigated different cannabinoids for their neuroprotective effects in ALS [reviewed in (18)(19)(20)(21)(22)]. Most of these studies were carried out in the classic mutant SOD-1 mouse model (23). ...
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The activation of the cannabinoid receptor type‐2 (CB2) afforded neuroprotection in amyotrophic lateral sclerosis (ALS) models. The objective of this study was to further investigate the relevance of the CB2 receptor through investigating the consequences of its inactivation. TDP‐43(A315T) transgenic mice were crossed with CB2 receptor knock‐out mice to generate double mutants. Temporal and qualitative aspects of the pathological phenotype of the double mutants were compared to TDP‐43 transgenic mice expressing the CB2 receptor. The double mutants exhibited significantly accelerated neurological decline, such that deteriorated rotarod performance was visible at 7 weeks, whereas rotarod performance was normal up to 11 weeks in transgenic mice with intact expression of the CB2 receptor. A morphological analysis of spinal cords confirmed an earlier death (visible at 65 days) of motor neurons labelled with Nissl staining and ChAT immunofluorescence in double mutants compared to TDP‐43 transgenic mice expressing the CB2 receptor. Evidence of glial reactivity, measured using GFAP and Iba‐1 immunostaining, was seen in double mutants at 65 days, but not in TDP‐43 transgenic mice expressing the CB2 receptor. However, at 90 days, both genotypes exhibited similar changes for all these markers, although surviving motor neurons of transgenic mice presented some morphological abnormalities in absence of the CB2 receptor that were not as evident in the presence of this receptor. This faster deterioration seen in double mutants led to premature mortality compared with TDP‐43 transgenic mice expressing the CB2 receptor. We also investigated the consequences of a pharmacological inactivation of the CB2 receptor using the selective antagonist AM630 in TDP‐43 transgenic mice, but results showed only subtle trends towards a greater deterioration. In summary, our results confirmed the potential of the CB2 receptor agonists as a neuroprotective therapy in ALS and strongly support the need to progress towards an evaluation of this potential in patients.
... Opioids may be used for both neuropathic and nociceptive pain in advanced disease states or when pain is poorly controlled yet there is a scarcity of reliable data (Brettschneider et al., 2013). Studies have shown that cannabis might be effective in reducing both neuropathic and nociceptive pain and may act synergistically with opioids (Amtmann et al., 2004;Carter et al., 2010). Mexiletine may effectively reduce the frequency of muscle cramps (Weiss et al., 2016) while quinine may reduce muscle cramp intensity (El-Tawil et al., 2010). ...
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For patients diagnosed with a rare musculoskeletal or neuromuscular disease, pain may transition from acute to chronic; the latter yielding additional challenges for both patients and care providers. We assessed the present understanding of pain across a set of ten rare, noninfectious, noncancerous disorders; Osteogenesis Imperfecta, Ehlers-Danlos Syndrome, Achondroplasia, Fibrodysplasia Ossificans Progressiva, Fibrous Dysplasia/McCune-Albright Syndrome, Complex Regional Pain Syndrome, Duchenne Muscular Dystrophy, Infantile- and Late-Onset Pompe disease, Charcot-Marie-Tooth Disease, and Amyotrophic Lateral Sclerosis. Through the integration of natural history, cross-sectional, retrospective, clinical trials, & case studies we described pathologic and genetic factors, pain sources, phenotypes, and lastly, existing therapeutic approaches. We highlight that while rare diseases possess distinct core pathologic features, there are a number of shared pain phenotypes and mechanisms that may be prospectively examined and therapeutically targeted in a parallel manner. Finally, we describe clinical and research approaches that may facilitate more accurate diagnosis, monitoring, and treatment of pain as well as elucidation of the evolving nature of pain phenotypes in rare musculoskeletal or neuromuscular illnesses.
... CB2 receptors were up-regulated in G93A-SOD1 mutant mice, a mouse model of ALS [167]. This is in line with a previous study whereby CB1 and CB2 receptors were determined in transactive response TAR DNA binding protein-43 mice (43 kDa TDP-43) [168]; thus, these mice were used as an animal model for ALS [169], and these deposits have been found in ALS patient's brains indicative of toxicity and ultimately cell death [170]. Fortunately, CB2 receptors were upregulated in both male and female TDP-43 mice [168]. ...
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Background Cannabis and its extracts are now being explored due to their huge health benefits. Although, the effect it elicits whether in humans or rodents may vary based on the age of the animal/subject and or the time in which the extract is administered. However, several debates exist concerning the various medical applications of these compounds. Nonetheless, their applicability as therapeutics should not be clouded based on their perceived negative biological actions. Methodology Articles from reliable databases such as Science Direct, PubMed, Google scholar, Scopus and Ovid were searched. Specific search methods were employed using multiple keywords: ‘‘Medicinal Cannabis; endocannabinoid system; cannabinoids receptors; cannabinoids and cognition; brain disorders; neurodegenerative diseases’’. For the inclusion/exclusion criteria, only relevant articles related to medicinal cannabis and its various compounds were considered. Result and conclusion The current review highlights the role, effects and involvement of cannabis; cannabinoids and endocannabinoids in preventing selected neurodegenerative diseases and possible amelioration of cognitive impairments. Also, cannabis utilization in many disease conditions such as Alzheimer’s and Parkinson’s disease among others. In conclusion, the usage of cannabis should be further explored as accumulating evidence suggests that it could be effective and somewhat safe especially when recommended dosage is adhered to. Furthermore, an in-depth studies should be conducted in order to unravel the specific mechanism underpinning the involvement of cannabinoids at the cellular level and their therapeutic applications.
... Recent pharmacological studies have indicated that Cannabis has a variety of properties, such as analgesic [6], antibacterial [7], anti-inflammatory [8], anti-allergic [9], anti-hypertensive and anti-thrombotic effects [10]. Clinically, unofficially approved cannabis has been widely used for neurological diseases and antitumour applications [11,12]. ...
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Cannabinoids' usefulness in the treatment of neurological disorders (epilepsy, and various neurodegenerative diseases, such as Multiple Sclerosis and Alzheimer's Disease) has been demonstrated in a growing number of studies. Of the 11 known general types of natural cannabinoids, the focus has been mainly directed at cannabidiol (CBD) due to its specificity in stimulating cannabinoid receptors and the low rate of side effects, as well as on Δ (9)-tetrahydrocannabinol (Δ9-THC). The natural and synthetic analogs of CBD have been described as a potential treatment in neurological diseases, as they showed their therapeutic benefits in reducing the seizures from epilepsy and their neuroprotectivity in neurodegenerative diseases. First and foremost, CBD's neuroprotective properties are due to its capacity to act as an endogenous cannabinoid receptor agonist. Second, CBD enhances neuroprotection by interacting with many signal transduction pathways mediated indirectly through cannabinoid receptors. CBD also reduces the hyperphosphorylation of glycogen synthetase kinase 3 (GSK-3) induced by the buildup of Amyloid β in the physiopathology of Alzheimer's disease.
Chapter
Neurologic conditions represent some of the most confusing, challenging, and frustrating cases to treat. Because of this, it is not surprising that many pet owners turn to alternative therapies, including cannabis, to treat their pets. This chapter provides information on the use of cannabinoid compounds for the treatment or management of common neurologic diseases and disorders of dogs and cats.
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The endocannabinoid system (ECS) is a lipid signalling system, comprising of the endogenous cannabis-like ligands (endocannabinoids) anandamide (AEA) and 2-arachidonoylglycerol (2-AG), which derive from arachidonic acid. These bind to a family of G-protein-coupled receptors, called CB1 and CB2. The cannabinoid receptor 1 (CB1R) is distributed in brain areas associated with motor control, emotional responses, motivated behaviour and energy homeostasis. In the periphery, the same receptor is expressed in the adipose tissue, pancreas, liver, GI tract, skeletal muscles, heart and the reproduction system. The CB2R is mainly expressed in the immune system regulating its functions. Endo cannabinoids are synthesized and released upon demand in a receptor-dependent way. They act as retrograde signalling messengers in GABAergic and glutamatergic synapses and as modulators of postsynaptic transmission, interacting with other neurotransmitters. Endocannabinoids are transported into cells by a specific uptake system and degraded by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The ECS is involved in various pathophysiological conditions in central and peripheral tissues. It is implicated in the hormonal regulation of food intake, cardiovascular, gastrointestinal, immune, behavioral, antiproliferative and mammalian reproduction functions. Recent advances have correlated the ECS with drug addiction and alcoholism. The growing number of preclinical and clinical data on ECS modulators is bound to result in novel therapeutic approaches for a number of diseases currently treated inadequately. The ECS dysregulation has been correlated to obesity and metabolic syndrome pathogenesis. Rimonabant is the first CB1 blocker launched to treat cardiometabolic risk factors in obese and overweight patients. Phase III clinical trials showed the drug's ability to regulate intra-abdominal fat tissue levels, lipidemic, glycemic and inflammatory parameters. However, safety conerns have led to its withdrawal. The role of endocannabinoids in mammalian reproduction is an emerging research area given their implication in fertilization, preimplantation embryo and spermatogenesis. The relevant preclinical data on endocannabinoid signalling open up new perspectives as a target to improve infertility and reproductive health in humans.
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OBJECTIVES: This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis. METHODS: Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources. RESULTS: Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging. CONCLUSION: Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.
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There is now convincing evidence for the existence of at least two types of cannabinoid receptor, CB1 and CB2, both coupled to G proteins. CB1 receptors are present in the central nervous system and in certain peripheral tissues where at least some are located at autonomic nerve terminals. CB2 receptors are found only outside the brain, mainly in cells of the immune system. The existence of endogenous ligands for cannabinoid receptors, both centrally and peripherally, is also generally accepted. These recent discoveries have prompted the development of cannabinoid receptor antagonists and of selective cannabinoid CB1 and CB2 receptor agonists. These compounds are important experimental tools that will help to establish the physiological roles of cannabinoid receptors and their endogenous ligands. The availability of such compounds should also facilitate the discovery of novel therapeutic uses for cannabinoid receptor agonists and antagonists.
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Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetra hydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetra hydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
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Cannabis (marijuana) has been proposed as treatment for a widening spectrum of medical conditions and has many properties that may be applicable to the management of amyotrophic lateral sclerosis (ALS). This study is the first, anonymous survey of persons with ALS regarding the use of cannabis. There were 131 respondents, 13 of whom reported using cannabis in the last 12 months. Although the small number of people with ALS that reported using cannabis limits the interpretation of the survey findings, the results indicate that cannabis may be moderately effective at reducing symptoms of appetite loss, depression, pain, spasticity, and drooling. Cannabis was reported ineffective in reducing difficulties with speech and swallowing, and sexual dysfunction. The longest relief was reported for depression (approximately two to three hours).
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Historically, the evidence for cannabinoids acting as analgesics has been mostly anecdotal. Recently, studies utilizing animal models have indicated that cannabinoids produce antinociception and antihyperalgesia by acting at peripheral, spinal, and supraspinal sites to inhibit mast cell degranulation, primary afferent activity, and responses of nociceptive neurons. Additionally, a number of studies indicate that the cannabinoid system tonically regulates nociceptive thresholds, raising the possibility that hypoactivity of the cannabinoid system produces or prolongs hyperalgesia and chronic pain. Other studies have indicated that inactive doses of cannabinoids potentiate the antinociceptive effects of opioids. Collectively, these studies suggest that administration of peripherally selective cannabinoids, enhancement of endogenous cannabinoid activity, and coadministration of inactive doses of cannabinoids with other analgesics, such as morphine, may prove therapeutically beneficial and may also provide ways to separate the analgesic effects of cannabinoids from their side effects.