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Medical marijuana in
neurology
Expert Rev. Neurother. 14(12), 1453–1465 (2014)
Selim R Benbadis*
1
,
Juan Sanchez-Ramos
1
,
Ali Bozorg
1
,
Melissa Giarratano
1
,
Kavita Kalidas
1
,
Lara Katzin
1
,
Derrick Robertson
1
,
Tuan Vu
1
,
Amanda Smith
2
and
Theresa Zesiewicz
1
1
Department of Neurology, University
of South Florida, Tampa, FL, USA
2
USF Health Byrd Alzheimer’s Institute,
Tampa, FL 33613, USA
*Author for correspondence:
sbenbadi@health.usf.edu
Constituents of the Cannabis plant, cannabinoids, may be of therapeutic value in neurologic
diseases. The most abundant cannabinoids are D
9
-tetrahydrocannabinol, which possesses
psychoactive properties, and cannabidiol, which has no intrinsic psychoactive effects, but
exhibits neuroprotective properties in preclinical studies. A small number of high-quality clinical
trials support the safety and efficacy of cannabinoids for treatment of spasticity of multiple
sclerosis, pain refractory to opioids, glaucoma, nausea and vomiting. Lower level clinical
evidence indicates that cannabinoids may be useful for dystonia, tics, tremors, epilepsy,
migraine and weight loss. Data are also limited in regards to adverse events and safety.
Common nonspecific adverse events are similar to those of other CNS ‘depressants’and
include weakness, mood changes and dizziness. Cannabinoids can have cardiovascular adverse
events and, when smoked chronically, may affect pulmonary function. Fatalities are rare even
with recreational use. There is a concern about psychological dependence, but physical
dependence is less well documented. Cannabis preparations may presently offer an option for
compassionate use in severe neurologic diseases, but at this point, only when standard-of-care
therapy is ineffective. As more high-quality clinical data are gathered, the therapeutic
application of cannabinoids will likely expand.
KEYWORDS:CBD • epilepsy • headaches • marijuana • multiple sclerosis • neurology
Cannabis preparations have been used as medi-
cations since the 19
th
century in Europe and
much longer as a traditional medicine in other
cultures. In 1999, the Institute of Medicine
published a comprehensive review of the litera-
ture [1] and concluded that although there are
risks, medical cannabis may be helpful for nau-
sea and vomiting, weight loss, pain, anxiety,
glaucoma, spasticity, multiple sclerosis (MS),
seizures and movement disorders. The American
Academy of Neurology (AAN) recently pub-
lished a position statement [2] and concluded
that medical marijuana is ‘probably effective’for
some symptoms of MS (spasticity, central pain,
painful spasms and urinary dysfunction),
‘probably ineffective’for levodopa-induced dys-
kinesias of Parkinson’s disease, and of ‘unknown
efficacy’in non-chorea symptoms of
Huntington’s disease, Tourette’s syndrome
(TS), cervical dystonia and epilepsy. Unfortu-
nately, quality clinical research on cannabis
preparations has been limited by the legal status
of marijuana. Legal restrictions on the use of
marijuana were formalized in 1970 when the
Controlled Substance Act included marijuana in
the list of Schedule I drugs. Substances in this
group have been deemed by the US FDA and
Drug Enforcement Administration (DEA) to
have ‘no currently accepted medical use in the
USA, a lack of accepted safety for use under
medical supervision and a high potential for
abuse’. Schedule I drugs include heroin, LSD,
methaqualone (Quaalude) and 3,4-methylene-
dioxymethamphetamine (MDMA or ‘Ecstasy’)
among others.
The situation in regards to marijuana
legalization is continuously evolving as the
issue is being addressed by the legislation in
each state. Currently, 23 states and the Dis-
trict of Columbia have enacted laws that
allow people to use marijuana as a medica-
tion with a doctor’s recommendation. Four
of those states have also legalized marijuana
for recreational use in adults. Marijuana is
stillillegalunderfederallaw,buttheJustice
Department is not challenging state laws as
long as they do not violate other federal
enforcement priorities, such as selling to
minors or trafficking the drug with gangs
and cartels. Marijuana is still a DEA Sched-
ule I drug, but given the above, its potential
role for medical use is a timely topic. Here
informahealthcare.com 10.1586/14737175.2014.985209 2014 Informa UK Ltd ISSN 1473-7175 1453
Review
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For personal use only.
the authors will review the potential utility of cannabinoids
for treatment of neurologic diseases.
Basic pharmacology
Marijuana describes preparations derived from the dried leaves
and flowers of the Cannabis plant. Synthetic cannabinoids are
pharmaceutical agents that are approved as prescription drugs
in several countries. These include dronabinol (Marinol) and
nabilone (Cesamet), two oral agents that are FDA approved for
use in the USA. Nabiximols (SativexTM) is an oromucosal spray
prepared from the extracts of the Cannabis plant, legalized in
several other countries but not in the USA [3,4].
The genus Cannabis includes two species that produce
useful amounts of psychoactive cannabinoids: Cannabis sativa
and C. indica. A third strain, C. ruderalis,hasfewpsychoac-
tive properties. Cannabis contains many compounds; it is
postulated that the C. sativa plant contains over 400 com-
pounds, approximately 60 of which are active [5–7].The
active compounds are collectively known as cannabinoids,
and their potency is variable depending on the species and
extraction process. There are three compounds that have
been isolated and identified as the most potent: D
9
-tetrahy-
drocannabinol (THC), cannabidiol (CBD) and cannibinol.
In the 1960s, THC was established as the cannabinoid pri-
marily responsible for the psychoactive properties of
marijuana and the one responsible for most, though not all,
of the pharmacologic effects of cannabis [3,4,8,9].
Cannabis is one of the first plants to have been used medici-
nally, and the therapeutic properties of marijuana have been
known for over 5000 years [7]. However, only recently has
its mechanism of action become understood better. In the
1990s, two types of cannabinoid receptors were identified: the
cannabinoid-1 (CB1) and cannabinoid-2 (CB2) receptors.
CB1 receptors are located primarily throughout the CNS and,
to a lesser extent, in the peripheral tissue [3,4,8,9]. The
CB1 receptors are spread throughout the brain and are found
in high densities in the neuron terminals of the basal ganglia,
cerebellum, hippocampus, neocortex, hypothalamus and limbic
cortex. The periaqueductal gray, dorsal horn and immune cells
also contain CB1 receptors, but to a lesser extent. A number of
neurotransmitters are affected by CB1, including acetylcholine,
norepinephrine, dopamine, serotonin, GABA, glutamate and
D-aspartate [5]. These interactions account for many of mar-
ijuana’s effects on pleasure, memory, thought, concentration,
sensory and time perception, and coordination. The
CB2 receptors are present mainly on immune cells and periph-
eral tissues and can have inflammatory, immunosuppressive
and antinociceptive activities [5,10]. The definitive pharmacologic
actions of CB2 receptor binding have yet to be determined,
but recently, CB2 receptors were identified in microglia [3].
As mentioned previously, there are multiple cannabinoid
compounds in medical cannabis, with varying effects on the
receptors (FIGURE 1) [3]. THC is the most potent of the com-
pounds and is considered a partial agonist at the CB1 receptor.
CBD is non-psychotropic and its mechanism of action is not
completely understood [3,4]. It is thought that CBD may be an
inverse agonist since it has been found to, in fact, counteract
the psychotropic activity of THC [8,9]. Anandamide is one of
several endogenous cannabinoids that have been identified and
widely studied [5,10]. These neurotransmitters, known collec-
tively as endocannabinoids, are synthesized on demand to act
on the CB receptors and then, in turn, are hydrolyzed as
needed to maintain homeostasis.
Cannabis preparations are available in a number of dosage
forms, all with vastly different concentrations of the various
cannabinoid compounds. Cannabis can be administered in
many ways. The plant material can be smoked in cigarettes or
pipes, inhaled through a vaporizer, extracts can be applied topi-
cally as oils or balms and various formulations can be ingested
in food or drinks. The systemic bioavailability of THC and
CBD depends on the concentration within the product as well
as the dosage form [3]. After inhalation, both THC and CBD
are absorbed rapidly (within minutes). Bioavailability ranges
from 10 to 45% and depends on how much is lost by heat or
by exhalation [3,4,11]. Vaporizing cannabis is becoming increas-
ingly popular as it allows for rapid absorption with minimal
combustible byproducts and can be inhaled without generating
smoke. Oral absorption of the cannabinoids, on the other
hand, results in a lower bioavailability (5–20%) due to gastric
degradation and extensive first-pass effect. The peak effect may
Concentration-response
curve
50
25
–25
Log (ligand concentration)
CB1 receptor response
(% of maximum)
0
Full agonist (HU-210)
Partial agonist (THC)
Antagonist (rimonabant)
Inverse agonist (CBD)
Agonist + antagonist
Agonist + inverse agonist
?
Figure 1. Concentration–response curves of cannabinoid
compounds on the CB1 receptor. The full agonist is the com-
pound HU-210, which is a synthetic cannabinoid; the partial ago-
nists are THC, which is a cannabinoid found in cannabis, and
anandamide, which is an endocannabinoid found in humans; the
antagonist is rimonabant, a synthetic cannabinoid studied for
weight control; and the inverse antagonist is CBD, which has no
direct CB1 activity but is postulated to be an example of an
inverse agonists. It is unknown what exact combination of ago-
nists, antagonists and inverse agonists is in cannabis and the
result of this combination.
CB1: Cannabinoid-1; CBD: Cannabidiol; HU-210: 3-(1,1´- dimethyl-
heptyl)-6aR, 7, 10, 10aR-tetrahydro-1-hydroxy-6, 6-dimethyl-6H-
dibenzo[b, d]pyran-9-methanol; THC: D
9
-tetrahydrocannabinol.
Permission obtained from John Wiley and Sons.
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1454 Expert Rev. Neurother. 14(12), (2014)
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also be significantly delayed (~1–3 h), resulting in difficulty
with appropriate dosing, and self-dosing by patients [3,4]. THC
and CBD are extremely lipophilic compounds; they ultimately
accumulate in the adipose tissue and are mainly metabolized in
the liver [4,11].
Epilepsy
The potential role of marijuana as a treatment for epilepsy was
brought to the forefront in August 2013 by a TV special report
on a child with Dravet syndrome, a severe epilepsy of child-
hood. Charlotte, the subject in this report, had failed conven-
tional treatments, was deteriorating, and had a dramatic
response to oral administration of an oil prepared from a strain
of cannabis that was high in CBD and low in THC (the canna-
bis strain became known as Charlotte’s Web). Other similar
reports have followed, and patients and families now routinely
inquire about the possible use of marijuana for treatment.
Evidence in humans
Only two small double-blinded, placebo-controlled studies of
cannabinoids in epilepsy have been published. In both studies,
daily oral CBD was used as an adjunct to antiepileptic drugs.
One study demonstrated a beneficial effect in seven out of
eight patients [12], while the other showed no improvement in
12 patients [13]. A Cochrane database review concluded that no
reliable conclusions could be drawn regarding the efficacy of
cannabinoids as a treatment for epilepsy, and could only con-
clude that a short-term dose of 200–300 mg daily of CBD was
safe [14].
Animal studies
The anticonvulsant profiles of cannabis-derived botanical drug
substances rich in cannabidivarin and containing CBD were
found to have significant anticonvulsant effects in models of
acute seizures such as the pentylenetetrazole, audiogenic seizure
and pilocarpine-induced convulsions [15]. CBD was also found
effective in the penicillin model, where it decreased the propor-
tion of the most severe tonic–clonic seizures and seizure-related
mortality [16]. In mice, CBD prevented tonic convulsions
caused by a convulsant current and by convulsant doses of
GABA inhibitors, 3-mercaptoproprionic acid, picrotoxin, isoni-
cotinic acid hydrazine, pentylenetetrazole and bicuculline. CBD
also prevented 3-mercaptoproprionic acid-induced lethality [17].
Another in vitro model of generalized epilepsy showed that
CBD reduces excitability, epileptiform EEG activity and
reduces seizure severity and lethality [18].
The above evidence is clearly insufficient to conclude on the
efficacy and safety of marijuana or CBD in epilepsy, but cer-
tainly seems sufficient to pursue rigorous research. According
to the American Epilepsy Society [19],‘at present, the epilepsy
community does not know if marijuana is a safe and effective
treatment, nor do they know the long-term effects that mari-
juana will have on learning, memory and behavior, especially
in infants and young children’. Thus, the authors support the
position of the American Epilepsy Society, which is to urge the
DEA ‘to change marijuana from its current Schedule I status
to allow researchers to conduct studies more efficiently’.At
least one such trial is ongoing in children.
What to do now?
In states where medical marijuana is legal, at this point (until
more is known about the efficacy and safety), it would proba-
bly have a legitimate place in ‘desperate’patients such as those
frequently encountered at level IV epilepsy centers.
A reasonable approach would be to license only those centers
that are truly comprehensive and offer all ‘conventional’treat-
ments, including modern anti-epileptic drugs, neurostimulation
and surgery. In this regard, CBD should be treated at this
point like any ‘investigational’treatment that is always preceded
by EEG-video monitoring to confirm the diagnosis and identify
candidates for standard therapies such as surgery and neurosti-
mulation. For example, we certainly would not want CBD
offered to patients with psychogenic seizures or patients with
straightforward surgically remediable epilepsy. Once intractable
epilepsy has been ascertained, exactly where CBD will belong
in the treatment algorithm (vs medications, epilepsy surgery,
diet and neurostimulation) is likely to vary among centers and
evolve over time.
Headaches
The pathophysiology of migraine is not fully understood, but
is thought to involve the activation of the trigeminovascular
system followed by neurogenic inflammation in the dura mater.
Nitric oxide is thought to play a role in the activation of the
trigeminovascular system by activating perivascular afferent
nerve fibers (via serotonin) in the meninges, thereby contribut-
ing to the release of vasoactive neuropeptides, including sub-
stance P and calcitonin gene related peptide [20]. This
activation is inhibited by acute antimigraine drugs, and inhibi-
tion of neuronal activation is highly predictive of the antimi-
graine potential. The role of the endocannabinoid system in
migraine remains unclear. CB1 receptors are located in the tri-
geminal ganglion, in the spinal trigeminal tract and nucleus,
and in other pain processing areas, such as the periacqueductal
gray matter, thalamus, cingulate and frontal cortices and the
amygdala [21]. Anandamide, N-arachidonolethanolamide (AEA),
is an endocannabinoid thought to play a role in migraine. It
potentiates 5-hydroxytryptamine (HT)
1A
and inhibits 5-HT
2A
receptors, supporting a potential therapeutic role in acute
migraine similar to triptans (which are agonists at 5-HT
1B/1D
and 5-HT
1A
receptors). AEA is active in the periaqueductal
gray matter, which is thought to be a migraine generator [22].
AEA may also have a modulatory role on the trigeminovascular
system [23].
In a rat model, AEA was able to inhibit neurogenic dural
vasodilation, calcitonin gene-related peptide, capsaicin and
nitric oxide-induced dural vasodilation by binding to
CB1 receptors in the spinal trigeminal tract and nucleus cauda-
lis [24]. In the same model, a CB1 receptor antagonist, AM251,
was able to reverse the inhibition of the dural vasodilation
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mediated by anandamide. Another rat model demonstrated
that CB1 receptors can inhibit trigeminal neurons with A fiber
and C fiber input in the trigeminocervical complex in response
to electrode activation of the ophthalmic division of the trigem-
inal nerve [24].
Human data
There is anecdotal support and experimental evidence for the
use of cannabis for migraine, but randomized controlled trials
are lacking. Experimental evidence suggests there are reduced
levels of AEA in the cerebrospinal fluid of patients with chronic
migraine and analgesic overuse headache. These results suggest
that impairment of the endogenous cannabinoid system may
result in increased calcitonin gene-related peptide and no pro-
duction, allowing for activation of the trigeminovascular sys-
tem, subsequent sensitization and potential for ‘chronification’
of pain [25]. Evidence suggests that there is increased degrada-
tion of AEA in platelets of female (but not male) migraineurs,
suggesting that the decreased level of circulating AEA may con-
tribute to a reduced pain threshold [26]. PET has also demon-
strated increased CB1 receptor binding in women with
migraine, most pronounced in the anterior cingulate, mesial
temporal and prefrontal and superior frontal cortices, areas well
known to be involved in the affective component of pain [27].
There are anecdotal individual case reports of cannabis use
for cluster headaches, one of the most disabling types of head-
ache. For example, acute cluster attacks can be aborted with
dronabinol, a synthetic THC, and within 5 min of inhalation
of marijuana [28,29]. By contrast, in a survey of cluster headache
patients who used cannabis, a significant portion of patients
reported worsening, requiring reduced use during the active
cluster headache periods [30].
Randomized controlled studies of cannabis for treatment of
chronic headache are needed. Until there is adequate evidence,
the exact role of cannabis for the management of chronic head-
ache disorders remains unclear. At this point, therefore, canna-
bis may be considered in patients who are refractory to all
conventional therapies, including adequate trials of oral preven-
tive and rescue agents, optimization of non-pharmacological
interventions (biofeedback, physical therapy and cognitive
behavioral therapy) and injections (nerve blocks and botulinum
toxin).
Multiple sclerosis
Unlike other neurologic diseases, MS has not had specific treat-
ments for a long time. FDA-approved disease-modifying treat-
ments were not available until 1993. This created an
environment where complementary and alternative medicine
therapies became an important option for MS, and their use is
still common. Complementary and alternative medicine thera-
pies for MS include low-dose naltrexone, hyperbaric oxygen,
Ginkgo biloba, bee venom and cannabinoids (marijuana deriva-
tives) [31,32]. Of the complementary and alternative medicine
therapies, cannabinoids have been the most studied in MS.
They have been studied in different formulations, such as oral
cannabinoids, mucosally delivered cannabinoids and smoked
cannabis. Despite a decent amount of research conducted on
cannabinoids and their potential symptomatic benefit in MS,
many questions remain. Chief among them is what particular
symptoms of MS – pain, spasticity, tremor and urinary
dysfunction – could benefit from its use relative to potential
side effects [2].
Human evidence
A large UK clinical trial was conducted in the early 2000s to
assess the benefit of oral cannabinoids (synthetic THC) for
MS-related spasticity [33]. The trial was placebo controlled
involving 630 subjects. Cannabinoids did not improve spastic-
ity (primary outcome measure), but did demonstrate benefit in
the secondary outcome measures assessing patient-reported
effects on spasticity and mobility. A limitation of the study was
that subjects became ‘unblinded’due to the side effects of can-
nabinoids, such as lightheadedness and dry mouth. This study,
along with a separate one specifically addressing another oral
cannabinoid’s effect on tremor in MS patients failed to show
any significant improvement in MS-related tremor [33,34].
In another UK placebo-controlled clinical trial, oral cannabi-
noids were administered to assess for symptomatic relief of mus-
cle stiffness and pain [35]. The study met its primary outcome
measure, as the proportion of subjects experiencing relief of
muscle stiffness was nearly twice as large in the cannabinoid arm
versus placebo. Similar results were reported in relief from body
pain and sleep quality. The ‘unblinding’effect of adverse events
(dizziness and dry mouth) was again a possible confounder.
Nabiximols (Sativex
, GW Pharmaceuticals, London, UK),
an oromucosal delivery system for cannabinoids, has been stud-
ied extensively for MS-related symptoms. It is currently avail-
able for MS-related spasticity in 11 countries, and has received
regulatory approval in an additional 13 countries. One large
multicenter European clinical trial had a unique study
design [36]. Phase A was a preliminary, single-blind, 4-week
treatment period to identify responders to nabiximols. The
investigator was aware that all subjects were receiving nabixi-
mols, but the subjects were told they would receive either pla-
cebo or nabiximols. Those subjects with at least a 20%
reduction in spasticity as determined by a validated self-
reporting tool were eligible for entry into Phase B, which was a
12-week, double-blind, randomized, placebo-controlled,
parallel-group study. The study design was an attempt at creat-
ing a ‘real-world’clinical setting that reflects how symptomatic
therapies are used, that is, patients who have side effects or no
efficacy are unlikely to remain on treatment. Results showed
that nabiximols improved spasticity, specifically in subjects who
had undergone a successful 4-week ‘treatment trial’and dem-
onstrated failure to adequately respond to other antispasticity
therapies. Studies of nabiximols for other MS-related symptoms
such as tremor and urinary dysfunction were not as conclu-
sive [36,37]. Specifically, a small study to assess its ability to treat
detrusor overactivity in MS patients failed to show a reduction
in urinary incontinence episodes [38].
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Smoked cannabis has also been studied for its effect on
various symptoms of MS. One such small study found that
smoked cannabis was superior to placebo in reducing treatment-
resistant spasticity [39]. Another small study examined the short-
term effects of smoked marijuana on balance, and found that it
led to worsening objective balance and posture [40].
Symptomatic management of MS is challenging, and there is
a clear need for additional options. Nabiximols (Sativex) is
available in many countries for the treatment of MS-related
spasticity, and may have a role. Other marijuana derivatives
and smoked marijuana have shown benefit in spasticity and
pain, but whether they could also effectively treat other symp-
toms of MS remains unclear. Nonetheless, MS symptoms of
pain and spasticity were the ones in which marijuana was
‘probably effective’according to the recent AAN review [2].
Neuromuscular disease
Cannabis is often self-administered to relieve symptoms of neu-
romuscular diseases. There are numerous anecdotal reports and
testimonies on the benefit of cannabis on pain, spasticity, mood
and even survival. As in other neurologic diseases, the poor effi-
cacy and tolerability of currently available treatments have
driven the search for alternative treatments for neuropathic pain.
Neuropathic pain
Neuropathic pain is defined as ‘pain arising as a direct conse-
quence of a lesion or disease affecting the somatosensory sys-
tem’[41]. Pain can be experienced with lesions affecting
peripheral or CNS pain integration centers. Current treatment
options have limited efficacy and many patients have pain that
is refractory to existing treatments. Oral medications, including
tricyclic antidepressants, serotonin reuptake inhibitors and cal-
cium channel ligands (gabapentin and pregabalin), are often
used as first-line treatments. Compounding their limited effi-
cacy, these medications cause significant side effects that limit
tolerability. Tramadol and opioid analgesics have shown effi-
cacy, but there is concern regarding their long-term safety and
risk of addiction and overdose.
The interest in cannabis dates back to the 1800s when
smoked cannabis administered to dogs was found to attenuate
their response to pain [42]. The mechanism by which cannabis
mediates pain appears to be through the cannabinoid receptors
CB1 and CB2, since they are found in central and peripheral
nervous system sites associated with pain processing [43,44]. Vari-
ous animal models of induced neuropathic pain have shown
that cannabinoids can attenuate hyperalgesia and allodynia [45].
There are few human trials evaluating the efficacy and safety
of smoked and vaporized cannabis in treating neuropathic pain.
In patients with HIV-associated distal sensory predominant pol-
yneuropathy, smoked cannabis resulted in a 30% pain relief
versus placebo and was well tolerated [46]. Another placebo-
controlled trial of smoked cannabis for HIV painful sensory
neuropathy also demonstrated efficacy with a drop in daily pain
by 34% [47]. In patients with both central and peripheral
neuropathic pain, vaporized cannabis had an analgesic effect
with minimal psychoactive effects, but the effect lasted only
1–2 h [48].
Thus, while a modest efficacy of cannabis on neuropathic
pain has been demonstrated, the benefit of cannabis over cur-
rently available treatments is less clear. Side effects of oral neu-
roleptics and tricyclic antidepressants often limit their
usefulness. On the other hand, few patients withdrew from
cannabis studies due to tolerability. Typical side effects
included feeling high, psychoactive effects and memory dys-
function at higher concentrations, all of which rapidly
reversed [49]. In addition, cannabis not only improves pain but
also other common comorbid symptoms such as nausea,
depressed mood, anxiety and disturbed sleep [50]. Thus, canna-
bis may allow simplification of treatment regimen and avoid-
ance of polypharmacy. Of course, opioids are also used in the
treatment of neuropathic pain. A benefit of cannabis over opi-
oid medications is the low risk of respiratory depression, possi-
bly due to the low levels of cannabinoid receptors in areas that
control heart rate and respiration [45].
The role that cannabis will play in the treatment of neuro-
pathic pain is yet to be determined. For patients whose pain is
well controlled on currently available therapies, there is no clear
benefit of either adding or switching to cannabis. However,
patients with chronic neuropathic pain refractory to other anal-
gesic medication have benefited from various formulations of
cannabinoids [45].
Amyotrophic lateral sclerosis
Cannabis has some theoretical benefits in patients with amyo-
trophic lateral sclerosis (ALS). Neuroinflammation may play a
role in the pathogenesis of ALS, and cannabis may participate
in the regulation of the immune system via its action at the
CB2 receptors, which are present on the immune cells. Canna-
binoids can downregulate cytokine and chemokine production,
which are pro-inflammatory. In addition, endogenous cannabi-
noids may also provide neuroprotection by its modulation of
the excitotoxic glutaminergic neurotransmission [51]. In a trans-
genic mice model, cannabinol delivered subcutaneously signifi-
cantly delayed disease onset by 2 weeks, although survival was
not affected [52]. In another study using the same mice model,
THC administered at the onset of symptoms delayed motor
impairment and prolonged survival versus control [53].
There are several symptoms in ALS that potentially can be
ameliorated by cannabis. These symptoms include pain, spastic-
ity, weight loss, dyspnea, sialorrhea and depression. While there
are multiple studies showing that cannabis decreased these symp-
toms in other disorders, there is a dearth of clinical trials assessing
the effect of cannabis, specifically in ALS. However, in surveys of
patients with ALS, cannabis use was credited with improving
speech, swallowing, appetite loss, sialorrhea and mood [51,54].
Clearly, additional research into the benefit of cannabis in
ALS is needed, especially, again, in regards to specific com-
pounds, routes of administration and dosing. In addition, the
challenge of delivering effective dose to patients with compro-
mised lung and swallowing function has to be overcome.
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Movement disorders
The cannabinoid receptor (CB1) and its endogenous cannabi-
noid ligand, arachidonylethanolamide (anandamide), have been
shown to be heavily distributed in the basal ganglia [55]. Animal
research with synthetic cannabinoid agonists and antagonists can
either increase or decrease the locomotor activity depending on
the dose, site of injection (brain or systemic) and species [56,57].
The consideration of cannabinoids in humans to treat move-
ment disorders, including Parkinson’s disease (PD), is theoreti-
cally reasonable, as high densities of G protein-coupled
CB1 receptors are present in the globus pallidus and pars retic-
ulata of substantia nigra regions of brain that are part of the
neural network critical for the automatic execution of learned
movements [58]. As in other areas, there is little clinical research
on the use of cannabis for treatment of movement disorders.
Parkinson’s disease
Although the successful use of tincture of C. indica to treat PD
was first described in Europe by Sir William Gowers in his
landmark textbook of neurology [59], the number of clinical
reports on pharmacotherapeutics of cannabis for PD and other
movement disorders is limited.
In a survey of 630 PD patients, cannabis use was reported
by 25% of 339 patients who responded to the question-
naires [60]. Many patients reported daily oral intake of half a
teaspoon of fresh or dried leaves. None of the patients had a
history of cannabis ingestion prior to using it to treat PD
symptoms, nor were they advised by a medical professional to
ingest it. Approximately 46% of patients noted mild or sub-
stantial improvement of their PD symptoms. Thirty percent
experienced improvement in resting tremor, 45% reported
diminished bradykinesia and 38% reported reduced rigidity.
A recent open-label observational study on the effects of
smoked cannabis in 22 patients reported improvement in both
motor and non-motor features of PD [61]. The mean total score
on the motor component of the Unified Parkinson Disease
Rating Scale improved significantly. Analysis of specific motor
symptoms revealed statistically significant improvement in
tremor, rigidity and bradykinesia. The authors also reported
significant improvement in sleep and pain scores and no clini-
cally significant adverse effects (AEs).
There are currently few options available to treat levodopa-
induced dyskinesias, experienced by advanced PD patients. These
involuntary choreiform movements are associated with overactiv-
ity of the globus pallidus and glutamatergic striatal excitation [61].
Striatal cannabinoid receptors exist on GABA terminals and
could theoretically improve dyskinesia by enhancement of
GABA transmission in the globus pallidus [62]. These findings
have been echoed by several preclinical experiments [63], although
clinical trials have not demonstrated consistent results. One ran-
domized, double-blind, crossover study evaluated the use of oral
cannabis for treatment of levodopa-induced dyskinesia in 19 PD
patients, and found no significant improvement in patients using
cannabis compared to placebo [64]. Conversely, another random-
ized, double-blind, placebo-controlled study in seven PD patients
found that nabilone, a cannabinoid agonist, resulted in a 22%
mean reduction in levodopa-induced dyskinesia compared to
placebo [65]. The AAN review deemed marijuana ‘probably
ineffective’for treating levodopa-induced dyskinesias [2].
Huntington’s disease
Huntington’s disease (HD) is a hereditary neurodegenerative
disease that affects mood, mentation and movement. Research
with gene-silencing agents is advancing in preclinical animal
models, but at present there are no human studies with siRNA
to stop or reverse the progression of the disease. This leaves
neurologists with a set of medications that can provide relief
from the symptoms of chorea, psychosis and depression.
Preclinical studies with cannabinoids have been performed in
HD animal models, several of which demonstrated preservation
of striatal neurons [66]. Despite anecdotal reports circulating in
the social media on the benefits of cannabis for relief of chorea,
painful dystonia and as a mood enhancer, there are no well-pow-
ered, double-blind, placebo-controlled studies of cannabinoids
for the treatment of HD. One double-blind, randomized, cross-
over study evaluated the use of CBD versus placebo in 15 neuro-
leptic-free HD patients [67]. No improvements were reported in
primary variables, although the study was underpowered.
Another double-blind, placebo-controlled crossover study evalu-
ated nabilone as treatment for HD in 44 patients and found no
significant improvements in the total or motor subscores [68,69].
Dystonia
Dystonia is a hereditary or acquired condition of generalized or
focal abnormal muscle posturing and movement. The effect of
cannabinoids on dystonia is unclear. In one report, cannabi-
noids improved generalized dystonia in a patient with Wilson’s
disease [70]. An open-label evaluation of CBD in doses up to
600 mg/day over a 6-week period demonstrated a 20–50%
dose-related reduction in dystonia [71]. Conversely, another
double-blind, randomized, placebo-controlled study of nabilone
in patients with generalized and segmental primary dystonia
did not find any significant improvement [72].
Tourette’s syndrome
Gilles de la TS is characterized by motor and vocal tics. Several
anecdotal reports indicate that cannabis and THC may improve
TS symptoms. A small double-blind, placebo-controlled, ran-
domized, crossover, single-dose trial of THC, using an examiner
and self-rating scales as outcome measures, found a significant
improvement of tics following treatment compared to placebo,
and no serious adverse events [73]. Another randomized, double-
blind, placebo-controlled study of 24 TS patients over 6 weeks
on THC found no significant difference [74].
Sleep disorders
Limited data exist on the utility of cannabis/cannabinoids in
the treatment of sleep disorders. Furthermore, the studies that
have been performed have serious limitations, including a small
sample size and lack of randomization or control group. Only
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a handful of studies with small sample sizes looked at objective
polysomnogram (PSG) findings [75]. There are no studies avail-
able on the effects of cannabinoids in patients with narcolepsy,
restless legs syndrome and obstructive sleep apnea syndrome.
The majority of published studies looked at the effect of
cannabinoid on the quality of sleep, sleep architecture and sleep
latency. The most robust data available are in patients with
spasticity, pain or a medical condition leading to sleep prob-
lems [76]. The studies showed reduced nocturnal sleep distur-
bance and improved sleep. There is also some evidence that
showed cannabinoids may possibly decrease the amount of
slow-wave sleep. Multiple studies have also demonstrated
decreased sleep latency without significant effect on the number
of nocturnal arousals [75]. This finding is in keeping with sub-
jective sensation of relaxation that cannabis users describe [76].
Conversely, sleep problems are a commonly reported with-
drawal problem in patients abstaining from cannabis use [77].
There is also some evidence that patients with post-traumatic
stress disorder and sleeping problems use cannabis for coping.
About half of these patients with post-traumatic stress disorder
reported using cannabis for treatment of sleep problems. Fur-
thermore, the patients with the most severe post-traumatic
stress disorder tended to use cannabis more frequently [78].
Patients also self-reported using cannabis for the treatment of
anxiety and depression [78–80], which are extremely common in
patients with psychophysiological insomnia.
A PSG study of patients after cessation of heavy marijuana
use found lower total sleep times, less slow-wave sleep, worse
sleep efficiency, longer sleep latency and shorter REM
latency [81]. Indeed, sleep disturbances are an important reason
for failure to discontinue marijuana use.
Cannabis may be used for its actual or perceived sleep-
promoting properties. Although evidence suggests that cannabis
is likely beneficial for sleep initiation, tolerance may develop
over time, potentially leading to cannabis use disorder. Again
sleep disturbances are a primary symptom of cannabis with-
drawal, and may be a significant risk factor for relapse and
abuse [82].
More studies are needed to further elucidate the role of canna-
bis in the treatment of commonly encountered sleep disorders
such as insomnia and restless legs syndrome, and its effects in
patients with narcolepsy and obstructive sleep apnea syndrome.
Alzheimer’s disease
Alzheimer’s disease (AD) accounts for more than half of the
cases of dementia and affects 30–50% of people over the age
of 85. The main pathological features include plaques compris-
ing amyloid-b(Ab) and neurofibrillary tangles resulting from
hyperphosphorylation of tau protein fibrils. Accumulation of
these is felt to lead to inflammation, oxidative stress, deficits in
neurotransmission and ultimately cell death. Presently, the only
medications approved by the FDA to treat AD simply target
symptoms and have a modest effect on the slope of cognitive
and functional loss over time, without any real disease-
modifying properties.
It has been established that abnormalities in the endogenous
cannabinoid system are present in AD. Conflicting data exist
with regard to CB1 receptor expression, which in some cases
shows a decrease and in others shows no change [83,84]. How-
ever, CB2 receptor expression increases, and correlates with the
levels of Ab42 and plaque density [85]. In addition, cannabi-
noids have been demonstrated to inhibit tau hyperphosphoryla-
tion [86], inhibit acetylcholinesterase (the same mechanism by
which three of the four currently FDA-approved medications
for AD work) and prevent Abaggregation [87]. CB receptor
agonism has been shown to double the clearance of Abacross
the blood–brain barrier [88], and CBD and THC have been
shown to have neuroprotective antioxidant effects [89]. Several
studies have shown that stimulation of CB2 receptors decreases
migroglial activation and lowers the Ablevels in transgenic
mice [90].
Because of these in vitro and animal model effects on known
mechanisms of AD, many have postulated that cannabis may
have a role as a potential therapeutic agent for AD. However,
limited data exist in that regard. C. sativa extract administered to
normal mice was associated with impaired performance in the
Morris water maze test, a standard animal model of learning and
memory [91]. In humans, recreational use of marijuana has been
shown to impair critical thinking and memory, both during and
for days after use [92], and to cause neuropsychological decline
from childhood to midlife in persistent users [93]. Though this
effect is most often attributed to the psychoactive properties of
THC, to some it seems counterintuitive to treat a progressive
cognitive disorder with the derivatives of a drug known to
worsen cognitive impairment. On the other hand, CBD was
recently shown to improve socialization and object recognition
in transgenic AD mice [94]. This reinforces the concept that the
therapeutic effects of cannabinoids, particularly those without
significant psychoactive effects, should continue to be examined.
Limited human data does exist with regard to treatment of
behavioral disturbances in dementia with cannabinoids. Several
pilot studies with dronabinol have shown significant decreases
in agitation, as well as improvement in Clinical Global Impres-
sion scores, sleep and eating in patients with severe demen-
tia [95]. As there are no FDA-approved medications for
agitation, and many of the traditionally used medications carry
black box warnings for elderly dementia patients, this is an area
that warrants further exploration.
Adverse effects of cannabis preparations
The recent AAN review [2] on medical cannabis preparations
for selected neurologic disorders compiled and analyzed the
AEs gathered from analysis of 29 studies. Of 1619 patients
treated with cannabinoids for less than 6 months, 6.9%
stopped the medication because of AEs. Of the 1118 who
received placebo, 2.2% stopped because of AEs. Symptoms
that caused medication withdrawal were not recorded in some
studies. However, symptoms that appeared in at least two stud-
ies in patients treated with cannabinoids included nausea,
increased weakness, behavioral or mood changes, suicidal
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ideation or hallucinations, dizziness or vasovagal symptoms,
fatigue and feelings of intoxication. With preparations contain-
ing higher doses of THC, psychosis, dysphoria and anxiety
were more likely to be reported. Higher THC concentrations,
however, were not typical for the clinical studies reviewed.
A recent review of AEs of short-term use included impaired
short-term memory, motor incoordination, altered judgment
and in high doses, paranoia and psychosis [92].
One study of chronic medical cannabis for a duration of
1 year revealed 31 of 207 patients treated with cannabis extract
(15%) stopped medication, as did 28 of 197 treated with THC
(14%) and 10 of 207 given placebo (5%) [96]. However, AEs
were not necessarily the reason medication was stopped. For
example, cannabinoids inhibit many enzymes of the cytochrome
P450 system, which will cause interactions with other medica-
tions being taken concurrently, especially opiates for pain.
No direct fatalities (overdoses) have been attributed to mari-
juana, even in recreational users of increasingly potent mari-
juana, possibly because of the lack of endocannabinoid
receptors in the brainstem [2]. Of course, the sedative effects of
some cannabis preparations can indirectly endanger patients
who perform dangerous tasks such as driving and operating
heavy machinery. In addition, smoking and, possibly, even the
use of vaporized preparations expose users to carbon monoxide
and other respiratory toxins.
A review of 25 studies on the safety and efficacy of CBD
reported that administration did not induce side effects across a
wide range of dosages, including acute and chronic dose regi-
mens, using various modes of administration [97]. Oral adminis-
tration of 10 mg CBD daily for 21 days did not induce any
changes in neurological (including EEG), clinical (including
ECG), psychiatric, blood or urine examinations. Oral CBD in
epileptic patients (200–300 mg daily for 135 days) was well
tolerated and no signs of toxicity or serious side effects were
detected on neurological and physical examinations, blood and
urine analysis, and repeated ECGs and EEGs [12]. The only
mild AE was initial somnolence that resolved in most subjects.
Exacerbation of psychosis in pre-existing schizophrenia is
commonly reported as a potential AE of cannabis. However,
several studies demonstrate that cannabis use does not cause or
increase the likelihood of schizophrenia [98,99]. In one study, the
frequency of cannabis use increased substantially in the UK
over a period from 1996 to 2005 in a cohort of 600,000 sub-
jects per year (aged 16–44), while the incidence and prevalence
of schizophrenia declined or remained stable. More recently,
another study [99] found that an increased familial morbid risk
for schizophrenia is the most likely underlying basis for schizo-
phrenia in cannabis users and not cannabis use by itself. How-
ever, cannabis use may precipitate disorders in persons who are
vulnerable to developing psychosis or exacerbate the disorder in
those who have already developed schizophrenia [92].
Cardiopulmonary AEs
Cannabis use has been reported to result in AEs on the cardio-
vascular system, including tachycardia, palpitations and
fluctuations in blood pressure. These effects are uncommon in
controlled clinical trials, but several case reports have described
atrial fibrillation, myocardial infarction and TIA associated
with cannabis use [5,100].
When it is smoked, marijuana carries a risk of pulmonary
complications. Cannabis contains a similar number of carcino-
genic compounds to cigarette smoke. Some formulations may
even contain higher concentrations of these detrimental compo-
nents. This puts patients at risk for cancers such as lung or
head and neck cancers [5,101]. In addition, cannabis use has
been associated with overall decreased pulmonary function,
chronic obstructive pulmonary diseases and pulmonary infec-
tions. There are also reports that failed to find significant pul-
monary pathology in long-term cannabis smokers, especially if
they were light smokers, 2–3 times per month [102]. In a feder-
ally sponsored ‘Compassionate Investigational New Drug pro-
gram of the FDA’, mild changes in pulmonary function were
found in patients who smoked marijuana daily for at least a
decade (averaging 10 marijuana cigarettes daily) [103].
Cannabis dependence & abuse
The potential for drug dependence and abuse is a concern of
those who promote tight restrictions and insist on maintaining
cannabis in Schedule I, in the company of heroin, LSD and
3,4-methylenedioxy-methamphetamine, drugs with ‘no accept-
able medical use and with a high abuse liability’. It is estimated
by the National Institute on Drug Abuse that about 10% of
adult users are at risk for development of drug dependence;
this risk increases drastically for those who start young or who
use marijuana daily [92]. Chronic use of cannabis results in tol-
erance to many of its effects, gradual escalation of amount of
drug used over time and development of psychological depen-
dence, a transient state of drug-seeking behavior and craving.
Unlike dependence on CNS depressants (opioids, barbiturates,
alcohol and benzodiazepines), there is sparse evidence for the
development of physical dependence to cannabis preparations.
Some individuals may experience transient anxiety and insom-
nia and other psychological symptoms upon cessation of
chronic high dose of marijuana [1]. There is no frank with-
drawal syndrome with attendant physiological signs of absti-
nence (i.e., seizures, tremors, perspiration or abdominal
cramps) that would be required to infer a state of physical
dependence. Some authors view cannabis as the most com-
monly abused drug in the USA and worldwide [80], often seen
as a gateway drug, that is, leading to addiction to more danger-
ous drugs. However, a recent study of a representative sampling
of US 12 graders showed that alcohol was the ‘gateway’drug,
leading to the use of tobacco, marijuana and other illicit sub-
stances. Moreover, students who used alcohol exhibited a sig-
nificantly greater likelihood of using both licit and illicit
drugs [104].
AEs on neuro-imaging
Imaging studies have suggested that subjects who regularly
smoke cannabis, when compared to occasional smokers, exhibit
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gray matter volume reduction in the medial temporal cortex,
temporal pole, parahippocampal gyrus, insula and orbitofrontal
cortex, regions rich in cannabinoid CB1 receptors [105]. Onset
of smoking cannabis before the age of 18 correlated with the
magnitude of gray matter volume reduction in the cerebral
hemispheres. However, significant gray matter atrophy was also
noted in ‘heavy’users of cannabis, regardless of the age of
onset. Another study reported that young marijuana smokers
have brain ‘abnormalities’even if they only smoked one joint
per week [106]. A closer examination of this report reveals flaws
in subject selection, analysis of data and interpretation. This
team of researchers performed a single MRI scan of 20 young
persons between 18 and 25 years of age. Brain MRI scans
from 10 subjects who smoked marijuana at least once per week
(but were not ‘dependent’) were compared to MRI scans from
10 ‘control’subjects who had not smoked in the last year and
had smoked less than five-times in their lifetime. The amount
smoked by these two cohorts was based on self-report, and
hence the sorting of subjects into smokers and non-smokers
was not absolute. The marijuana user group did not exclude a
subject if they had used other illicit substances in the past.
However, subjects’self-report on other drugs may be unreli-
able. A person is not likely to reveal the truth to the authority
figures about the extent and nature of their personal illicit sub-
stance use. To deal with illicit substance use objectively, the
researchers performed urine toxicology screens to make sure all
subjects had not recently used any of a spectrum of psychoac-
tive drugs (ranging from amphetamines to benzodiazepines and
ethanol). All subjects were assessed for evidence of problem
alcohol use, and if positive, they were not included. However,
the marijuana smokers reported drinking a greater number of
alcoholic drinks per week than the control participants. The
primary analysis was a comparison of brain structures of smok-
ers to that of ‘non-smokers’. The overall findings indicated that
the volumes of the left nucleus accumbens and amygdala, but
not the right side, were different in marijuana users compared
to that of controls. Of course, the better comparison would
have been a study of brain structures before ever using cannabis
and after a year of using it regularly. Despite the weak design
of this study, the difference indicated these two left brain struc-
tures were very slightly larger (‘abnormal’?) than in control sub-
jects. The clinical relevance of this observation is not clear,
especially since the cannabis and non-cannabis users had no
cognitive or behavioral problems. These differences might
reflect normal variations in brain structure, just as men and
women’s brains differ slightly in structure. Moreover, these
brain differences might have already been present in those who
chose to smoke more frequently and just as likely could have
been interpreted as a predictor of those who were predisposed
to enjoy smoking at least one cannabis joint per week. Thus,
the data provide an association, but no cause and effect.
Expert commentary
Cannabis in various preparations has a long history as a medi-
cal substance. Only in the last century was its use relegated by
legislation to the underground as a recreational substance.
Despite the outlaw designation, practitioners of alternative and
complementary medicine have continued to explore medical
applications of cannabis. A wave of legal restrictions on the
medical use of cannabis is gradually being lifted, opening the
doors for legitimate research and well-controlled clinical trials.
Eventually, there may be widespread availability of
cannabinoid-based medications, which physicians are ill-
prepared to prescribe. On the one hand, cannabis derivatives
cannot be suddenly made available without rigorous scientific
data on efficacy and safety. On the other hand, excessive regu-
lations such as prohibition and rigid ‘war-on-drugs’rhetoric
make research impossible. As if often true, those extreme pas-
sionate positions are unlikely to be helpful and moderation is
in order. Cannabinoid drugs should neither be completely out-
lawed to the point of preventing research nor available
without regulations.
Five-year view
A review of the Pubmed publications reveals that the number
of papers on the effects of cannabis preparations in humans has
nearly doubled in the last 5 years. Therefore, one might predict
that in the next 5 years, the number of publications will con-
tinue to increase. However, the total number of human studies
is low and will remain low till the current regulatory restric-
tions on human studies are changed. For example, the absolute
number of human studies published in 2009 was 23, and by
2013, there were 43 papers. The 5-year total number of human
studies (from 2009 to 2013) was only 178, a fraction (16%) of
the total 1074 papers pulled up with the key words cannabis
or cannabinoids.
There are at least five reasons to expect research on the ther-
apeutic applications of cannabis to increase in the near future.
The prohibition on the use of medical cannabis is being lifted
by individual states. Presently, there are 23 states in the US
that permit cannabis for a number of medical indications. This
number is projected to increase despite opposition by organiza-
tions that either benefit from the current prohibition or who
are concerned about the spread of use for non-medical reasons,
that is, recreational use. Re-scheduling of cannabis from Sched-
ule I by the FDA and DEA will likely take place sooner than
later. For the first time in 20 years, a federal appellate court is
hearing evidence challenging the DEA’s classification of canna-
bis as a Schedule I drug. Re-scheduling cannabis so that it can
be prescribed similar to approved controlled substances such as
benzodiazepines will provide a strong impetus for both basic
research and therapeutic trials. Greater understanding of the
endogenous cannabinoid system in the context of neurological
disease and aging will provide a strong rationale to apply spe-
cific cannabinoids (alone or in combination) for treatment of
specific diseases. Neuropharmacologists, who have been trained
on the one drug–one receptor model, are starting to recognize
that agents like the phyto-cannabinoids (THC and CBD) have
greater therapeutic effects when given together than when given
in isolation (the ‘entourage’effect). Hence, the newer
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commercial pharmaceutical agents, like Sativex, will contain
various proportions of THC and CBD. Major pharmaceutical
companies will develop novel drugs that can alter the activity
of endogenous cannabinoids to either increase anandamide (the
primary endogenous cannabinoid) or to block the cannabinoid
receptor in brain (CB1).
Considering the reasons mentioned earlier, there will likely
be a surge of clinical research to elucidate the optimal cannabis
products for specific neurologic conditions.
Financial & competing interests disclosure
K Kalidas is on the speakers’ bureau for Allergan and Depomed. L Katzin is
on the speakers’ bureau for Grifols and Baxter pharmaceuticals. D Robertson
has served as a consultant for Biogen Idec, Genzyme/Sanofi Aventis, Teva
Neuroscience and Pfizer; is on the speakers’ bureau for Biogen Idec, Pfizer,
EMD Serono, Genzyme/Sanofi Aventis, Novartis, Teva Neuroscience, Mal-
linckrodt and Acorda; and has received grant support from Biogen
Idec, Genzyme/Sanofi Aventis, Novartis, Sun Pharma, MedImmune,
GlaxoSmithKline and Roche/Genetech. T Vu is on the speakers’ bureau for
Allergan. AG Smith has received grant/research support from Merck,
Eli Lilly, AVID Radiopharmaceuticals, Eisai, TauRx and Cognate nutri-
tionals. T Zesiewicz receives research support from GSK Pharmaceuticals,
UCB Pharmaceuticals, Astellas Pharmaceuticals, Friedreich’s Ataxia
Research Alliance, Allon Pharmaceuticals, Edison Pharmaceuticals and
ViroPharma Inc. J Sanchez-Ramos is on the speakers bureau for UCB Phar-
maceuticals. Dr. Benbadis has served as a consultant for Cyberonics, Eisai,
Lundbeck, Sunovion, Supernus, UCB pharma, Upsher-Smith. He is on the
speakers bureau for Cyberonics, Eisai, Glaxo Smith Kline, Lundbeck,
Sunovion, Supernus, UCB pharma and has received grant support from
Cyberonics, Lundbeck, Sepracor, Sunovion, Supernus, UCB pharma,
Upsher-Smith. Dr. Benbadis received royalties as an author or Editor for
Emedicine-Medscape-WebMD, UpToDate. The authors have no other rele-
vant affiliations or financial involvement with any organization or entity
with a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
• The Cannabis plant consists of a large number of cannabinoids, many of which interact with CNS receptors to produce biological effects
that may improve neurologic functions and disorders for which there are few effective treatments.
• Most of the evidence for beneficial effects of cannabis is from observation and open-label studies, but there are some high-quality
clinical trials of cannabinoids using gold standard designs (double-blind, placebo-controlled studies) that report its therapeutic effects.
• In our view, the adverse effects reported in the literature are most often benign, though there are deleterious effects that depend
highly on the route and frequency of administration (e.g., inhalation and pulmonary symptoms).
• Some reports overemphasize the potential for drug dependence, even suggesting that cannabis is a ‘gateway’drug to ‘hard’drugs of
abuse. In addition, the ‘amotivational syndrome’that is often mentioned as an adverse effect of chronic use is poorly documented.
• Medical (regulated) use is clearly not the same as recreational use.
• There is a need for more research, both basic and clinical. Pharmaceutical companies would do well to research specific cannabinoid
molecules or agents that selectively benefit specific symptoms or conditions. The critical variables are the respective proportions of
specific compounds, routes of administration and dosing.
• It is possible that combinations of cannabinoids are necessary to produce clinical benefits, so that quality control measurements of the
principal bioactive components of the preparation will be helpful when conducting future clinical studies.
• Sensationalized media anecdotes tend to not provide a denominator and do not report failures because those do not increase ratings.
They should not be the basis for our decisions.
• A common theme of all neurology specialties is that referral centers treat the most refractory, difficult and often ‘desperate’patients.
For these, medical marijuana should be considered. However, until we have more and better data, they should only be considered after
more standard and proven treatments have been exhausted, and should not be offered ‘out of order’to patients who are not compliant
with, or want to bypass, standard treatments.
References
1. Institute of Medicine (US); Joy JE,
Watson SJ, Benson JA. editors. Marijuana
and medicine: assessing the science base.
Washington (DC): National Academies
Press (US); 1999. PMID 25101425
2. Koppel BS, Brust JCM, Fife T, et al.
Systematic review: efficacy and safety of
medical marijuana in selected neurologic
disorders. Report of the Guideline
Development Subcommittee of the
American Academy of Neurology.
Neurology 2014;82(17):1556-63
3. Borgelt LM, Franson KL, Nussbaum AM,
Wang GS. The Pharmacologic and Clinical
Effects of Medical Cannabis.
Pharmacotherapy 2013;33(2):195-209
4. Gold Standard, Inc. Marijuana, Medical.
Clinical Pharmacology. database online
Available from: www.clinicalpharmacology.
com [Last Accessed: 15 March 2014]
5. Seamon MJ, Fass JA, Maniscalco-Feichtl M,
Abu-Shraie NA. Medical Marijuana and the
developing role of the pharmacist. Am J
Health-Syst Pharm 2007;64:1037-44
6. Ben Amar M. Cannabinoids in medicine:
a review of their therapeutic potential.
J Ethnopharmacol 2006;105:1-25
7. Kumar RN, Chambers WA, Pertwee RG.
Pharmacological actions and therapeutic
uses of cannabis and cannabinoids.
Anaesthesia 2001;56:1059-68
Review Benbadis, Sanchez-Ramos, Bozorg et al.
1462 Expert Rev. Neurother. 14(12), (2014)
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Selim R Benbadis on 11/30/14
For personal use only.
8. Pertwee RG. Cannabinoid pharmacology:
the first 66 years. Br J Pharmacol 2006;
147(suppl 1):S163-71
9. Pertwee RG, Howlett AC, Abood ME,
et al. International union of basic and
clinical pharmacology. LXXIX. Cannabinoid
receptors and their ligands: beyond CB and
CB. Pharmacol Rev 2010;62:588-631
10. Ibrahim MM, Porreca F, Lai J, et al.
CB2 cannabinoid receptor activation
produces antinociception by stimulating
peripheral release of endogenous opioids.
Proc Natl Acad Sci 2005;102:3093-8
11. Agurell S, Halldin M, Lindgren JE, et al.
Pharmacokinetics and metabolism of delta
1-tetrahydrocannabinol and other
cannabinoids with emphasis on man.
Pharmacol Rev 1986;38:21-43
12. Cunha JM, Carlini EA, Pereira AE, et al.
Chronic administration of cannabidiol to
healthy volunteers and epileptic patients.
Pharmacology 1980;21:175-85
13. Ames FR, Cridland S. Anticonvulsant effect
of cannabidiol. S Afr Med J 1986;69:14
14. Gloss D, Vickrey B. Cannabinoids for
epilepsy. Cochrane Database Syst Rev
2012;6:CD009270
15. Hill TD, Cascio MG, Romano B, et al.
Cannabidivarin-rich cannabis extracts are
anticonvulsant in mouse and rat via a
CB1 receptor-independent mechanism. Br J
Pharmacol 2013;170(3):679-92
16. Jones NA, Glyn SE, Akiyama S, et al.
Cannabidiol exerts anti-convulsant effects in
animal models of temporal lobe and partial
seizures. Seizure 2012;21:344-5
17. Consroe PF, Benedito MA, Leite JR, et al.
Effect of cannabidiol on behavioral seizures
caused by convulsant drugs or current in
mice. Eur J Pharmacol 1982;83:293
18. Jones NA, Hill AJ, Smith I, et al.
Cannabidiol displays antiepileptiform and
antiseizure properties in vitro and in vivo.
J Pharmacol Exp Ther 2010;332:569-77
19. American Epilepsy Society. www.aesnet.org/
sites/default/files/file_attach/AboutAES/
PositionStatements/AES%20Position%20on
%20Medical%20Marijuana.pdf [Last
accessed 25 August 2014]
20. Ward T. Migraine diagnosis and
pathophysiology. Continuum Lifelong
Learning Neurol 2012;18:753-63
21. Greco R, Gasperi V, Maccarrone M,
Tassolleri C. The endocannabinoid system
and migraine. Exp Neurol 2010;224:85-91
22. Juhsz G, Lazary J, Chase D, et al.
Variations in the cannabinoid receptor
1 gene predispose to migraine. NeurosciLett
2009;461:116-20
23. Akerman S, Kaube H, Goadsby PJ.
Anandamide is able to inhibit trigeminal
neurons using an in vivo model of
trigeminovascular-mediated nociception.
J Pharmacol Exp Ther 2003;309:56-63
24. Akerman S, Holland PR, Goadsby PJ.
Cannabinoid (CB1) receptor activation
inhibits trigeminovascular neurons.
J Pharmacol Exp Ther 2007;320:64-71
25. Sarchielli P, Pini LA, Coppola F, et al.
Endocannabinoids in chronic migraine: CSF
findings suggest a system failure.
Neuropsychopharmacology 2007;32:
1384-90
26. Cupini LM, Bari M, Battista N, et al.
Biochemical changes in the
endocannabinoid system are expressed in
platelets of female but not male
migraineurs. Cephalalgia 2006;26:277-81
27. Van der Schueren BJ, Van Laere K,
Gerard N, et al. Interictal
type 1 cannabinoid receptor binding is
increased in female migraine patients.
Headache 2011;52:433-40
28. Brian M. Cannabinoids and hallucinogens
for headache. Headache 2013;53:447-58
29. Robbins MS, Tarshich S, Solomon S,
Grosberg BM. Cluster attacks responsive to
recreational cannabis and dronabinol.
Headache 1999;49:914-16
30. Leroux E, Taifas I, Valade D, et al. Use of
Cannabis among 139 cluster headache
sufferers. Cephalalgia 2013;33:208-13
31. Schwarz S, Knorr C, Geiger H.
Complementary and alternative medicine
for multiple sclerosis. Mult Scler 2008;14:
1113-19
32. Yadav V, Bever C, Bowen J, et al. Summary
of evidence-based guideline: complementary
and alternative medicine in multiple
sclerosis: Report of the Guideline
Development Subcommittee of the
American Academy of. Neurology
Neurology 2014;82:1083-92
33. Zajicek J, Fox P, Sanders H, et al.
Cannabinoids for treatment of spasticity and
other symptoms related to multiple sclerosis
(CAMS study): multicentre, randomised
placebo controlled trial. Lancet 2003;362:
1517-26
34. Fox P, Bain PG, Glickman S, et al. The
effect of cannabis on tremor in patients with
multiple sclerosis. Neurology 2004;62:
1105-9
35. Zajicek JP, Hobart JC, Slade A, for
MUSEC Research Group. Multiple sclerosis
and extract of cannabis: results of the
MUSEC trial. J Neurol Neurosurg
Psychiatry 2012;83:1125-32
36. Novotna A, Mares J, Ratcliffe S, et al.
A randomized double blind placebo
controlled, parallel group, enriched design
study of nabiximols (Sativex) as add-on
therapy in subjects with refractory spasticity
caused by multiple sclerosis. Eur J Neurol
2011;18:1122-31
37. Collin C, Davies P, Mutiboko IK,
Ratcliffe S; Sativex Spasticity in MS Study
Group. Randomized controlled trial of
cannabis-based medicine in spasticity caused
by multiple sclerosis. Eur J Neurol 2007;14:
290-6
38. Kavia RB, De Ridder D,
Constantinescu CS, et al. Randomized
controlled trial of Sativex to treat detrusor
overactivity in multiple sclerosis. Mult Scler
2010;11:1349-59
39. Corey-Bloom J, Wolfson T, Gamst A, et al.
Smoked cannabis for spasticity in multiple
sclerosis: a randomized, placebo-controlled
trial. CMAJ 2012;184:1143-50
40. Greenberg HS, Werness SA, Pugh JE, et al.
Short-term effects of smoking marijuana on
balance in patients with multiple sclerosis
and normal volunteers. Clin Pharmacol
Ther 1994;55:324-8
41. Dworkin RH, O’Connor AB, Audette J,
et al. Recommendations for the
pharmacological management of
neuropathic pain: an overview and literature
update. Mayo Clin Proc 2010;85:s3-14
42. Dixon WE. The pharmacology of Cannabis
indica. Br Med J 1899;2:1354-7
43. Herkenham M, Lynn AB, Johnson MR,
et al. Characterization and localization of
cannabinoid receptors in rat brain:
a quantitative in vitro autoradiographic
study. J Neurosci 1991;111:563-83
44. Fox WA, McIntyre P, et al. Peripheral
Nerve injury induces cannabinoid receptor
2 protein expression in rat sensory neurons.
Neuroscience 2005;135:235-45
45. Rahn EJ, Hohmann AG. Cannabinoids as
pharmacotherapies for neuropathic pain:
from the bench to the bedside.
Neurotherapeutics 2009;6(4):713-37
46. Toperoff EW, Vaida F, et al. Smoked
medicinal cannabis for neuropathic pain in
HIV: a randomized, crossover clinical trial.
Neuropsychopharmocology 2009;34:672-80
47. Jay CA, Shade SB, et al. Cannabis in
painful HIV-associated sensory neuropathy.
Neurology 2007;68(7):515-21
Medical marijuana in neurology Review
informahealthcare.com 1463
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Selim R Benbadis on 11/30/14
For personal use only.
48. Marcotte WT, Deutsch R, et al. Low dose
vaporized cannabis significantly improves
neuropathic pain. L Pain 2013;14(2):136-48
49. Marcotte WT, Tsodikov A, et al.
A randomized, placebo-controlled, crossover
trial of cannabis cigarettes in neuropathic
pain. J Pain 2008;9(6):506-21
50. Abood ME, Aggarwal SK, et al. Cannabis
and amyotrophic lateral sclerosis:
hypothetical and practical applications, and
a call for clinical trials. Am J Hosp Palliat
Care 2010;27(5):347-56
51. The ALS Untangled Group. ALS Untangled
No. 16: cannabis. Amyotrophic Lateral
Sclerosis 2012;13:400-4
52. Hong WS, Witting A, et al. Cannabinol
delays symptom onset in SOD1 (G93A)
transgenic mice without affecting survival.
Amyotroph Lateral Scler Other Motor
Neuron Disord 2005;6(3):182-4
53. McAllister SD, Rizvi G, et al. Amyotrophic
lateral sclerosis: delayed disease progression
in mice by treatment with a cannabinoid.
Amyotroph Lateral Scler Other Motor
Neuron Disord 2004;5(1):33-9
54. Amtmann D, Weydt P, Johnson KL, et al.
Survey of cannabis use in patients with
amyotrophic lateral sclerosis. Am J Hosp
Palliat Care 2004;21:95-104
55. Egertova
´M, Elphick MR. Localisation of
cannabinoid receptors in the rat brain using
antibodies to the intracellular C-terminal
tail of CB. J Comp Neurol 2000;422(2):
159-71
56. Long LE, Chesworth R, Huang XF, et al.
Behavioural comparison of acute and
chronic Delta9-tetrahydrocannabinol and
cannabidiol in C57BL/6JArc mice. Int J
Neuropsychopharmacol 2010;13:861-76
57. Meschler JP, Conley TJ, Howlett AC.
Cannabinoid and dopamine interaction in
rodent brain: effects on locomotor activity.
Pharmacol Biochem Behav 2000;67:567-73
58. Sagredo O, Garcı
´a-Arencibia M, de Lago E,
et al. Cannabinoids and neuroprotection in
basal ganglia disorders. Mol Neurobiol
2007;36(1):82-91
59. Gowers W. A manual of diseases of the
nervous system. P. Blakiston Son and Co;
Philadelphia PA: 1888
60. Venderova
´K, Ru
˚zicka E, Vorı
´sek V. Survey
on cannabis use in Parkinson’s disease:
subjective improvement of motor
symptoms. Survey on Cannabis Use in
Parkinson’s Disease. Mov Disord 2004;
19(9):1102-6
61. Lotan I, Treves TA, Roditi Y, Djaldetti R.
Cannabis (medical marijuana) treatment for
motor and non-motor symptoms of
Parkinson disease: an open-label
observational study. Clin Neuropharmacol
2014;37:41-4
62. Fox SH, Henry B, Hill M, et al.
Stimulation of cannabinoid receptors
reduced levodopa-induced dyskinesia in the
MPTP-lesioned nonhuman primate model
of Parkinson’s disease. Mov Disord
2002;17:1180-7
63. Conti LH, Johannesen J, Musty R, et al. In:
Chesher G, Consroe P, Musty R, editors.
Marijuana: An international research report.
National campaign against drug abuse
monograph series no. 7. Canberra: Autralian
Government Publishing Service; 1988.
153-6
64. Carroll CB, Bain PG, Teare L, et al.
Cannabis for dyskinesia in Parkinson
disease: a randomized double-blind
crossover study. Neurology 2004;63:
1245-50
65. Sierzdan K, Fox SH, Hill M, et al.
Cannabinoids reduce levodopa-induced
dyskinesia in Parkinson’s disease: a pilot
study. Neurology 2001;57:2108-11
66. Sagredo O, Pazos MR, Valdoelivas S,
Fernandez-Ruiz J. Cannabinoids: novel
medicines for the treatment of Huntington’s
disease. Recent Pat CNS Drug Discov.
2012;7(1):41-8
67. Cosroe P, Laguna J, Allender J, et al.
Controlled clinical trial of cannabinoid in
Huntington’s Disease. Pharmacol Biochem
Behav 1991;40:701-8
68. Huntington Study Group. Unified
Huntington’s disease rating scale: reliability
and consistency. Mov Disord 1996;2:
136-42
69. Curtis A, Mitchell I, Patel S, et al. A pilot
study using nabilone for symptomatic
treatment of Huntington’s disease. Mov
Disord 2009;24:2254-9
70. Uribe Roca MC, Micheli F, Viotti R.
Cannabis sativa and dystonia secondary to
Wilson’s disease.Mov Disord 2005;20(1):
113-15
71. Consroe P, Sandyk R, Snider SR. Open
label evaluation of cannabidiol in dystonic
movement disorders. Int J Neurosci 1986;
30(4):277-82
72. Fox SH, Kellett M, Moore AP, et al.
Randomised, double-blind,
placebo-controlled trial to assess the
potential of cannabinoid receptor
stimulation in the treatment of dystonia.
Mov Disord 2002;17(1):145-9
73. Mu
¨ller-Vahl KR, Schneider U, Koblenz A,
et al. Treatment of Tourette’s syndrome
with D-9-tetrahydrocannabinol (THC):
a randomized crossover trial.
Pharmacopsychiatry 2002;35:57-61
74. Mu
¨ller-Vahl KR, Schneider U, Prevedel H,
et al. D9-tetrahydrocannabinol (THC) is
effective in the treatment of tics in Tourette
syndrome: a 6-week randomized trial. J Clin
Psychiatry 2003;64:459-65
75. Gates PJ, Albertella L, Copeland J. The
effects of cannabinoid administration on
sleep: a systemic review of human studies.
Sleep Med Rev 2014. Available from:
http://dx.doi.org/10.1016/i.
smrv.2014.02.005
76. Green B, Kavanagh D, Young R. Being
stoned: a review of self-reported cannabis
effects. Drug Alcohol Rev 2003;22:453-60
77. Allsop DJ, Norberg MM, Copeland J, et al.
The cannabis withdrawal scale development:
patterns and predictors of cannabis
withdrawal and distress. Drug Alcohol
Depend 2011;119:123-9
78. Bonn-Miller MO, Babson KA, Vandrey R.
Using cannabis to help you sleep:
heightened frequency of medical cannabis
use among those with PTSD. Drug Alcohol
Depend 2014;136:162-5
79. Walsh Z, Callaway R, Belle-Isle L, et al.
Cannabis for therapeutic purposes: patient
characteristics, access, and reasons for use.
Int J Drug Policy 2013;24:511-16
80. Zvolensky MJ, Bernstein A, Marshall EC.
Anxiety vulnerability factors and disorders
and tobacco and marijuana use and
disorders: emerging theory and research
explicating their relations. Addict Behav
2008;33(11):1383-4
81. Bolla KI, Lesage SR, Gamaldo CE, et al.
Sleep disturbance in heavy marijuana users.
Sleep 2008;31:901-8
82. Babson KA, Bonn-Miller MO. Sleep
Disturbances: implications for Cannabis
Use, Cannabis Use Cessation, and Cannabis
Use Treatment. Curr Addict Rep 2014;1:
109-14
83. Fagan SG, Campbell VA. The influence of
cannabinoids on generic traits of
neurodegeneration. Brit J Pharmacol
2014;171:1347-60
84. Aso E, Ferrer I. Cannabinoids for treatment
of Alzheimer’s disease: moving toward the
clinic. Front Pharmacol 2014;5:37-47
85. Solas M, Francis PT, Franco R, et al.
CB2 receptor and amyloid pathology in
frontal cortex of Alzheimer’s disease
patients. Neurobiol Aging 2013;34:805-8
86. Esposito G, De Filippis D, Carnuccio R,
et al. The marijuana component cannabidiol
Review Benbadis, Sanchez-Ramos, Bozorg et al.
1464 Expert Rev. Neurother. 14(12), (2014)
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Selim R Benbadis on 11/30/14
For personal use only.
inhibits beta-amyloid-induced tau protein
hyperphosphorylation through Wnt/beta-
catenin pathway rescue in PC12 cells. J Mol
Med 2006;84:253-8
87. Eubanks LM, Rogers CJ, Beuscher AE.
4th, et al. A molecular link between the
active component of marijuana and
Alzheimer’s disease pathology. Mol Pharm
2006;3:773-7
88. Bachmeier C, Beaulieu-Abdelahad D,
Mullan M, et al. Role of the cannabinoid
system in the transit of amyloid beta across
the blood brain barrier. Mol Cell Neurosci
2013;56:255-62
89. Hampson AJ, Grimaldi M, Lolic M, et al.
Neuroprotective antioxidants from
marijuana. Ann N Y Acad Sci 2000;899:
274-82
90. Martin-Moreno AM, Brera B, Spuch C,
et al. Prolonged oral cannabinoid
administration prevents neuroinflammation,
lowers beta-amyloid levels and improves
cognitive performance in TgAPP2576 mice.
J Neuroinflamm 2012;9:8
91. Abdel-Salam OME, Salem NA, et al.
Cannabis-induced impairment of learning
and memory: effect of different nootropic
drugs. EXCLI J 2013;12:193-214
92. Volkow ND, Baler RD, Compton WM,
et al. Adverse Health Effects of Marijuana
Use. N Engl J Med 2014;70:2219-27
93. Meier MH, Caspi A, Ambler A, et al.
Persistent cannabis users show
neuropsychological decline from childhood
to midlife. Proc Natl Acad Sci USA 2012;
109(40):E2657-64
94. Cheng D, Low JK, Logge W, et al. Chronic
cannabidiol treatment improves social and
object recognition in double transgenic
APPswe/PS1DE9 mice. Psychopharm (Berl)
2014. [Epub ahead of print]
95. Woodward MR, Harper DG, Stolyar A,
et al. Dronabinol for the Treatment of
Agitation and Aggressive Behavior in
Acutely Hospitalized Severely Demented
Patients with Non-cognitive Behavioral
Symptoms. Am J Geri Psych 2014;22:
415-19
96. Zajicek JP, Sanders HP, Wright DE, et al.
Cannabinoids in multiple sclerosis (CAMS)
study: safety and efficacy data for
12 months follow up. J Neurol Neurosurg
Psych 2005;76:1664-9
97. Bergamaschi MM, Queiroz RH,
Zuardi AW, Crippa JA. Safety and side
effects of cannabidiol, a Cannabis sativa
constituent. Curr Drug Saf 2011;6:237-49
98. Frisher M, Crome I, Martino O, Croft P.
Assessing the impact of cannabis use on
trends in diagnosed schizophrenia in the
United Kingdom from 1996 to 2005.
Schizophr Res 2009;113:123-8
99. Proal AC, Fleming J, Galvez-Buccollini JA,
Delisi LE. A controlled family study of
cannabis users with and without psychosis.
Schizophr Res 2014;152:283-8
100. Lindsay AC, Foale RA, Warren O, et al.
Cannabis as a precipitant of cardiovascular
emergencies. Int J Cardiol 2005;104:230-2
101. Moore BA, Augustson EM, Moser RP,
et al. Respiratory effects of marijuana and
tobacco use in a U.S. sample. J Gen Intern
Med 2005;20:3307
102. Pletcher MJ, Vittinghoff E, Kalhan R, et al.
Association between marijuana exposure and
pulmonary function over 20 years. JAMA
2012;307:173-81
103. Russo E, Mathre ML, Byrne A, et al.
Chronic cannabis use in the Compassionate
Investigational New Drug program:
an examination of benefits and adverse
effects of legal clinical Cannabis. J Clin
Psychiatry 2002;2:3-57
104. Kirby T, Barry AE. Alcohol as a gateway
drug: a study of US 12th graders. J Sch
Health 2012;82:371-9
105. Battistella G, Fornari E, Annoni JM, et al.
Long-term effects of cannabis on brain
structure. Neuropsychopharmacology 2014;
39(9):2041-8
106. Kuster JK, Lee S, et al. “Cannabis Use Is
Quantitatively Associated with Nucleus
Accumbens and Amygdala Abnormalities in
Young Adult Recreational Users”.
J Neurosci 2014;34(16):5529-38
Medical marijuana in neurology Review
informahealthcare.com 1465
Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Selim R Benbadis on 11/30/14
For personal use only.
