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Neurological
disorders
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Muller-Vahl
KR, Kolbe H, Schneider U, Emrich HM. Cannabis
in movement disorders. Forsch Komplementarmed.
1999 Oct;6 Suppl 3:23-7. |
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Central cannabinoid receptors are densely located
in the output nuclei of the basal ganglia (globus
pallidus, substantia nigra pars reticulata),
suggesting their involvement in the regulation
of motor activity. Furthermore, there is evidence
that endogenous cannabinoid transmission plays
a role in the manipulation of other transmitter
systems within the basal ganglia by increasing
GABAergic transmission, inhibiting glutamate
release and affecting dopaminergic uptake. Most
hyperkinetic and hypokinetic movement disorders
are caused by a dysfunction of basal ganglia-thalamo-cortical
loops. It has been suggested that an endogenous
cannabinoid tone participates in the control
of movements and, therefore, the central cannabinoid
system might play a role in the pathophysiology
of these diseases. During the last years in
humans a limited number of clinical trials demonstrated
that cannabinoids might be useful in the treatment
of movement disorders. Despite the lack of controlled
studies there is evidence that cannabinoids
are of therapeutic value in the treatment of
tics in Tourette syndrome, the reduction of
levodopa-induced dyskinesia in Parkinson s disease
and some forms of tremor and dystonia. It can
be speculated that cannabinoid antagonists might
be useful in the treatment of chorea in Huntington
s disease and hypokinetic parkinsonian syndromes.
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Romero
J, Lastres-Becker I, de Miguel R, Berrendero
F, Ramos JA, Fernandez-Ruiz J. The endogenous
cannabinoid system and the basal ganglia.
biochemical, pharmacological, and therapeutic
aspects. Pharmacol Ther. 2002 Aug;95(2):137-52.
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New data strengthen the idea of a prominent
role for endocannabinoids in the modulation
of a wide variety of neurobiological functions.
Among these, one of the most important is the
control of movement. This finding is supported
by 3 lines of evidence: (1) the demonstration
of a powerful action, mostly inhibitory in nature,
of synthetic and plant-derived cannabinoids
and, more recently, of endocannabinoids on motor
activity; (2) the presence of the cannabinoid
CB(1) receptor subtype and the recent description
of endocannabinoids in the basal ganglia and
the cerebellum, the areas that control movement;
and (3) the fact that CB(1) receptor binding
was altered in the basal ganglia of humans affected
by several neurological diseases and also of
rodents with experimentally induced motor disorders.
Based on this evidence, it has been suggested
that new synthetic compounds that act at key
steps of endocannabinoid activity (i.e., more-stable
analogs of endocannabinoids, inhibitors of endocannabinoid
reuptake or metabolism, antagonists of CB(1)
receptors) might be of interest for their potential
use as therapeutic agents in a variety of pathologies
affecting extrapyramidal structures, such as
Parkinson's and Huntington's diseases. Currently,
only a few data exist in the literature studying
such relationships in humans, but an increasing
number of journal articles are revealing the
importance of this new neuromodulatory system
and arguing in favour of the funding of more
extensive research in this field. The present
article will review the current knowledge of
this neuromodulatory system, trying to establish
the future lines for research on the therapeutic
potential of the endocannabinoid system in motor
disorders.
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| PARKINSON |
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Sieradzan
KA, Fox SH, Hill M, Dick JPR et al, Cannabinoids
reduce levodopa-induced dyskinesia in Parkinson’s
disease: a pilot study. Neurology 57 Dec
2001: 2108-2111 |
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The lateral segment of the globus pallidus (GPl)
is thought to be overactive in levodopa-induced
dyskinesia in PD. Stimulation of cannabinoid
receptors in the GPl reduces gamma-aminobutyric
acid (GABA) reuptake and enhances GABA transmission
and may thus alleviate dyskinesia. In a randomized,
double-blind, placebo-controlled, crossover
trial (n = 7), the authors demonstrate that
the cannabinoid receptor agonist nabilone significantly
reduces levodopa-induced dyskinesia in PD.
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| NEUROPROTECTION/
BRAIN INJURY |
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Mechoulam
R, Panikashvili D, Shohami E. Cannabinoids
and brain injury: therapeutic implications.
Trends Mol Med. 2002 Feb;8(2):58-61. |
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Mounting in vitro and in vivo data suggest that
the endocannabinoids anandamide and 2-arachidonoyl
glycerol, as well as some plant and synthetic
cannabinoids, have neuroprotective effects following
brain injury. Cannabinoid receptor agonists
inhibit glutamatergic synaptic transmission
and reduce the production of tumour necrosis
factor-alpha and reactive oxygen intermediates,
which are factors in causing neuronal damage.
The formation of the endocannabinoids anandamide
and 2-arachidonoyl glycerol is strongly enhanced
after brain injury, and there is evidence that
these compounds reduce the secondary damage
incurred. Some plant and synthetic cannabinoids,
which do not bind to the cannabinoid receptors,
have also been shown to be neuroprotective,
possibly through their direct effect on the
excitatory glutamate system and/or as antioxidants.
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Grundy
RI. The therapeutic potential of the cannabinoids
in neuroprotection. Expert Opin Investig
Drugs. 2002 Oct;11(10):1365-74. |
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After thousands of years of interest the last
few decades have seen a huge increase in our
knowledge of the cannabinoids and their mode
of action. Their potential as medical therapeutics
has long been known. However, very real concerns
over their safety and efficacy have lead to
caution and suspicion when applying the legislature
of modern medicine to these compounds. The ability
of this diverse family of compounds to modulate
neurotransmission and act as anti-inflammatory
and antioxidative agents has prompted researchers
to investigate their potential as neuroprotective
agents. Indeed, various cannabinoids rescue
dying neurones in experimental forms of acute
neuronal injury, such as cerebral ischaemia
and traumatic brain injury. Cannabinoids also
provide symptomatic relief in experimental models
of chronic neurodegenerative diseases, such
as multiple sclerosis and Huntington's disease.
This preclinical evidence has provided the impetus
for the launch of a number of clinical trials
in various conditions of neurodegeneration and
neuronal injury using compounds derived from
the cannabis plant. Our understanding of cannabinoid
neurobiology, however, must improve if we are
to effectively exploit this system and take
advantage of the numerous characteristics that
make this group of compounds potential neuroprotective
agents.
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Grundy
R.I., Rabuffetti M., Beltramo M. Cannabinoids
and Neuroprotection. Molecular Neurobiology
2001; 24:29-51. |
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Cannabinoid compounds are endowed with pharmacological
properties that make them interesting candidates
for therapeutic development. These properties
have been known since antiquity. However, in
the last decade extremely important advances
in the understanding of the physiology, pharmacology,
and molecular biology of the cannabinoid system
have given this field of research fresh impetus
and have renewed the interest in the possible
clinical exploitation of these compounds. In
the present review we summarize the effects
elicited, at the cellular level, by cannabinoids
acting through receptor-dependent and receptor-independent
mechanisms. These data suggest different ways
by which cannabinoids may act as neuroprotective
agents (prevention of excitotoxicity by inhibition
of glutamate release, antioxidant effects, anti-inflammatory
actions, etc.). The experimental evidence supporting
these hypotheses are presented and discussed
with regard to both preclinical and clinical
studies in disease states such as cerebral ischemia,
brain trauma, and Multiple Sclerosis.
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| DYSTONIA |
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Fox
SH, Kellett M, Moore AP, Crossman AR, Brotchie
JM. Randomised, double-blind, placebo-controlled
trial to assess the potential of cannabinoid
receptor stimulation in the treatment of
dystonia. Mov Disord. 2002 Jan;17(1):145-9.
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Cannabis may have medicinal uses in a variety
of diseases. The neural mechanisms underlying
dystonia involve abnormalities within the basal
ganglia-in particular, overactivity of the lateral
globus pallidus (GPl). Cannabinoid receptors
are located presynaptically on GABA terminals
within the GPi, where their activation reduces
GABA reuptake. Cannabinoid receptor stimulation
may thus reduce overactivity of the GPl and
thereby reduce dystonia. A double-blind, randomised,
placebo-controlled, crossover study using the
synthetic cannabinoid receptor agonist nabilone
in patients with generalised and segmental primary
dystonia showed no significant reduction in
dystonia following treatment with nabilone.
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| HUNTINGTON’S
DISEASE |
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Müller-Vahl
KR et al. Nabilone increases Choreatic Movements
in Huntington’s Disease. Movement
Disorders 1999; 14 (6): 1038-1040 |
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No abstract found
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Consroe
P, Laguna J, et al: Controlled clinical
trial of cannabidiol in Huntington's disease.
Pharmacol Biochem Behav. 1991 Nov;40(3):701-8.
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Based on encouraging preliminary findings, cannabidiol
(CBD), a major nonpsychotropic constituent of
Cannabis, was evaluated for symptomatic efficacy
and safety in 15 neuroleptic-free patients with
Huntington's Disease (HD). The effects of oral
CBD (10 mg/kg/day for 6 weeks) and placebo (sesame
oil for 6 weeks) were ascertained weekly under
a double-blind, randomized cross-over design.
A comparison of the effects of CBD and placebo
on chorea severity and other therapeutic outcome
variables, and on a Cannabis side effect inventory,
clinical lab tests and other safety outcome
variables, indicated no significant (p greater
than 0.05) or clinically important differences.
Correspondingly, plasma levels of CBD were assayed
by GC/MS, and the weekly levels (mean range
of 5.9 to 11.2 ng/ml) did not differ significantly
over the 6 weeks of CBD administration. In summary,
CBD, at an average daily dose of about 700 mg/day
for 6 weeks, was neither symptomatically effective
nor toxic, relative to placebo, in neuroleptic-free
patients with HD.
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| TOURETTE
SYNDROME |
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Muller-Vahl
KR, Schneider U, Prevedel H, Theloe K, Kolbe
H, Daldrup T, Emrich HM. Delta 9-tetrahydrocannabinol
(THC) is effective in the treatment of tics
in Tourette syndrome: a 6-week randomized
trial. J Clin Psychiatry. 2003 Apr;64(4):459-65.
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BACKGROUND: Preliminary studies
suggested that delta-9-tetrahydrocannabinol
(THC), the major psychoactive ingredient of
Cannabis sativa L., might be effective in the
treatment of Tourette syndrome (TS). This study
was performed to investigate for the first time
under controlled conditions, over a longer-term
treatment period, whether THC is effective and
safe in reducing tics in TS.
METHOD: In this randomized,
double-blind, placebo-controlled study, 24 patients
with TS, according to DSM-III-R criteria, were
treated over a 6-week period with up to 10 mg/day
of THC. Tics were rated at 6 visits (visit 1,
baseline; visits 2-4, during treatment period;
visits 5-6, after withdrawal of medication)
using the Tourette Syndrome Clinical Global
Impressions scale (TS-CGI), the Shapiro Tourette-Syndrome
Severity Scale (STSSS), the Yale Global Tic
Severity Scale (YGTSS), the self-rated Tourette
Syndrome Symptom List (TSSL), and a videotape-based
rating scale.
RESULTS: Seven patients dropped
out of the study or had to be excluded, but
only 1 due to side effects. Using the TS-CGI,
STSSS, YGTSS, and video rating scale, we found
a significant difference (p <.05) or a trend
toward a significant difference (p <.10)
between THC and placebo groups at visits 2,
3, and/or 4. Using the TSSL at 10 treatment
days (between days 16 and 41) there was a significant
difference (p <.05) between both groups.
ANOVA as well demonstrated a significant difference
(p =.037). No serious adverse effects occurred.
CONCLUSION: Our results provide
more evidence that THC is effective and safe
in the treatment of tics. It, therefore, can
be hypothesized that the central cannabinoid
receptor system might play a role in TS pathology.
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Muller-Vahl
KR, Prevedel H, Theloe K, Kolbe H, Emrich
HM, Schneider U. Treatment of Tourette syndrome
with delta-9-tetrahydrocannabinol (delta
9-THC): no influence on neuropsychological
performance. Neuropsychopharmacology. 2003
Feb;28(2):384-8. |
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Previous studies provide evidence that marihuana
(Cannabis sativa) and delta-9-tetrahydrocannabinol
(Delta(9)-THC), the major psychoactive ingredient
of marihuana, respectively, are effective in
the treatment of tics and behavioral problems
in Tourette syndrome (TS). It, therefore, has
been speculated that the central cannabinoid
receptor system might be involved in TS pathology.
However, in healthy marihuana users there is
an ongoing debate as to whether the use of cannabis
causes acute and/or long-term cognitive deficits.
In this randomized double-blind placebo-controlled
study, we investigated the effect of a treatment
with up to 10 mg Delta(9)-THC over a 6-week
period on neuropsychological performance in
24 patients suffering from TS. During medication
and immediately as well as 5-6 weeks after withdrawal
of Delta(9)-THC treatment, no detrimental effect
was seen on learning curve, interference, recall
and recognition of word lists, immediate visual
memory span, and divided attention. Measuring
immediate verbal memory span, we even found
a trend towards a significant improvement during
and after treatment. Results from this study
corroborate previous data suggesting that in
patients suffering from TS, treatment with Delta(9)-THC
causes neither acute nor long-term cognitive
deficits. Larger and longer-duration controlled
studies are recommended to provide more information
on the adverse effect profile of THC in patients
suffering from TS.
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Muller-Vahl
KR, Kolbe H, Schneider U, Emrich HM. Cannabinoids:
possible role in patho-physiology and therapy
of Gilles de la Tourette syndrome. Acta
Psychiatr Scand. 1998 Dec;98(6):502-6. |
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High densities of cannabinoid receptors were
found in the basal ganglia and hippocampus,
indicating a putative functional role of cannabinoids
in movement and behaviour. Anecdotal reports
suggested beneficial effects of marihuana in
Tourette's syndrome (TS). We therefore interviewed
64 TS patients with regard to use of marihuana
and its influence on TS symptomatology. Of 17
patients (27%) who reported prior use of marihuana,
14 subjects (82%) experienced a reduction or
complete remission of motor and vocal tics and
an amelioration of premonitory urges and obsessive-compulsive
symptoms. Our results provide more evidence
that marihuana improves tics and behavioural
disorders in TS. It can be speculated that cannabinoids
might act through specific receptors, and that
the cannabinoid system might play a major role
in TS pathology.
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