ALSUntangled No. 16: Cannabis

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Amyotrophic Lateral Sclerosis, 2012; 13: 400 –404
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about cannabinol, although it appears to have distinct
pharmacological properties from cannabidiol. Can-
nabinol has anticonvulsant, sedative, and other phar-
macological activities likely to interact with the effects
of THC (19–22). Cannabinol may induce sleep and
may provide some protection against seizures for
epileptics (22).
Cannabis Receptors and Endogenous Ligands
Recent advances have increased understanding of
the receptors and endogenous ligands composing
the cannabinoid system (23–36). Two major can-
nabinoid receptor subtypes exist: CB1 is predomi-
nantly expressed in the brain, and CB2 is primarily
found on the cells of the immune system (23,37–39).
Both receptors are G protein-coupled, 7-segment
transmembrane proteins, similar to the receptors of
dopamine, serotonin, and norepinephrine (39,40).
Dense cannabinoid receptor concentrations are
found in the cerebellum, basal ganglia, and hip-
pocampus, likely accounting for the effect of exog-
enously administered cannabinoids on motor tone
and coordination as well as mood state (41–43). Low
concentrations are found in the brainstem, perhaps
accounting for the low potential for lethal overdose
with cannabinoid-based medicines (44–47).
The discovery of endocannabinoids, (i.e. endog-
enous metabolites capable of activating the cannab-
inoid receptors), and an improved understanding of
the molecular mechanisms leading to their biosynthe-
sis, release, and inactivation, have inspired research
on the pharmaceutical applications of cannabinoid-
based medicines (40). A growing number of strate-
gies for separating sought after therapeutic effects of
cannabinoid receptor agonists from the unwanted
consequences of CB1 receptor activation are emerging.
Ligands have been developed that are potent and
selective agonists for CB1 and CB2 receptors, potent
CB1 selective antagonists, and inhibitors of endo-
cannabinoid uptake or metabolism (48). Distinct
varieties of cannabis contain different combinations
of partial cannabinoid agonists and antagonists, which
could be utilized in designing synthetic cannabinoid
Introduction
In a widely viewed series of Internet videos called
“ Surviving ALS, ” Cathy Jordan reports that regu-
larly smoking cannabis has dramatically slowed her
ALS progression, and improved her mood and appe-
tite (see for example http://www.youtube.com/
watch?v ⫽ -kf8wTBiUDU). Indeed, cannabinoids
and manipulation of the endocannabinoid system
may well have disease-modifying potential in ALS
(1–9). Moreover, cannabis could potentially be use-
ful in managing the symptomatology in ALS (10–13).
Here, on behalf of PALS who are asking about it, we
critically review the evidence for cannabis in ALS.
What Is Cannabis?
Cannabis is a remarkably complex plant. There are
several existing phenotypes, with each containing over
400 distinct chemical moieties (14–22). Approximately
70 are chemically unique and classifi ed as plant
cannabinoids (14–17). Cannabinoids are lipophilic
21 carbon terpenes, biosynthesized predominantly via
a recently discovered deoxyxylulose phosphate path-
way (14). Delta-9 tetrahydrocannabinol (THC) and
delta-8 THC appear to produce the majority of the
psychoactive effects of cannabis (18,19). Delta-9
THC, the active ingredient in dronabinol (Marinol)
is the most abundant cannabinoid in the plant and
this has led researchers to hypothesize that it is the
main source of the drug ’ s impact. However, other
major plant cannabinoids, including cannabidiol and
cannabinol, may modify the pharmacology of THC
and have distinct effects of their own. Cannabidiol is
the second most prevalent of cannabis ’ s active ingre-
dients and may produce most of its effects at moder-
ate, mid range doses. Cannabidiol becomes THC as
the plant matures and THC over time breaks down
into cannabinol. Up to 40% of the cannabis resin in
some strains is cannabidiol (16). The amount varies
according to plant. Some varieties of Cannabis sativa
have been found to have no cannabidiol (16). Can-
nabidiol appears to modulate and reduce untoward
effects of THC (18). Cannabidiol breaks down to
cannabinol as the plant matures. Much less is known
ALSUntangled No. 16: Cannabis
The ALSUntangled Group
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ALSUntangled Update 16 401
agonists and antagonists as well as cannabis strains
with high therapeutic potential.
Why Might Cannabis Work in ALS?
The fact that CB2 receptors have been found on
immune cells suggests that cannabinoids play a role in
the regulation of the immune system. Indeed, recent
studies show that cannabinoids can down regulate
cytokine and chemokine production, which in turn
suppresses infl ammatory responses (49–52). Since the
pathophysiology of ALS may involve neuroinfl amma-
tion (53,54), agents such as cannabinoids that modu-
late this process could potentially be useful.
Alternatively, or in addition, cannabinoids might
act similarly to tamoxifen, a Food and Drug Admin-
istration (FDA)-approved drug used to treat breast
cancer (55–57). Both cannabinoids and tamoxifen
are terpenes, organic, lipid soluble compounds that
readily penetrate the CNS (55). In a 60 patient pilot
study, PALS taking tamoxifen reportedly had
improved survival and no signifi cant side effects
(56); unfortunately this study has yet to be pub-
lished so it cannot be peer reviewed. A follow up
study is underway (http://www.clinicaltrials.gov/ct2/
show/NCT01257581? term ⫽ tamoxifen ⫹ als&rank
⫽ 1). Tamoxifen may affect ALS by modulating
infl ammation, or by altering glutamate uptake (55).
Endocannabinoids can also modulate glutamatergic
neurotransmission indirectly via NMDA receptors
(33,34,36).
What Relevant Animal Data Exists in ALS?
Beyond the theoretical, observations in mice support
the idea that the endocannabinoid system might be
involved in the pathophysiology of ALS. Endogenous
cannabinoids are elevated in spinal cords of symptom-
atic G93A-SOD1 mice (9). mRNA levels, receptor
binding, and function of CB2, but not CB1, receptors
are dramatically and selectively up-regulated in spinal
cords of G93A-SOD1 mice in a temporal pattern par-
alleling disease progression (2). The sensitivity of CB1
receptors in controlling both glutamate and GABA
transmission is potentiated in the striatum of symp-
tomatic G93A-SOD1 ALS mice (5).
Other animal studies suggest that treatment
with cannabinoids could be useful. Treatment with
Delta(9)-THC at onset of tremors delayed motor
impairment and prolonged survival in G93A-SOD1
mice (58). Daily injections of the selective CB2 ago-
nist AM-1241, initiated at symptom onset in G93A-
SOD1 ALS mice, increased survival after disease
onset by 56% (2). Treatment of post symptomatic,
90-day-old G93A-SOD1 mice with a synthetic
cannabinoid, WIN55,212–2, improved motoneuron
survival and muscle force at 120d although this did
not improve overall survival (6). Genetic ablation of
the (Fatty Acid Amide Hydrolase) FAAH enzyme,
which results in raised levels of the endocannabinoid
anandamide by preventing its breakdown, delayed
disease onset in G93A-SOD1 ALS mice but did not
affect survival (6). Ablation of the CB1 receptor had
no effect on disease onset in G93A-SOD1 ALS mice
but signifi cantly extended life span. These animal
studies all have signifi cant methodological fl aws,
including small sample size, lack of randomization
and lack of blinding.
What Are the Effi cacy, Safety and Costs of
Cannabis in Human ALS?
A small randomized, double-blind placebo-controlled
crossover trial of oral THC at 5mg twice daily was
conducted in PALS, with the goal of improving
cramps. (59). While this was well-tolerated, there was
no effect on cramp frequency or intensity, or on sec-
ondary outcome measures including fasciculation
frequency, quality of life, sleep or depression. This
27 patient trial may well have been underpowered for
some of these outcomes. A small trial of dronabinol
in PALS was previously published as an abstract and
indicated good tolerability (11). However Dronabi-
nol is 100% Delta-9 THC, the most psychoactive
ingredient in cannabis. Natural cannabis contains, at
best, 20% THC. There are varying physiological
effects when the other cannabinoid forms are present,
as is the case with natural cannabis plant material.
Moreover, while glutamate toxicity is reduced by
both CBD (cannabadiol - nonpsychoactive), and
THC, the neuroprotection observed with CBD
appears greater than THC (60–62). Most patients
fi nd dronabinol too sedating and associated with too
many psychoactive effects (63–66). Dronabinol is not
an appropriate substitute for cannabis in this setting.
Within the PatientsLikeMe online community,
48 members with ALS reported taking cannabis in
a variety of forms, durations and dosages. Benefi ts
described included improved speech, swallowing,
secretions, fasciculations, appetite, sleep and mood.
Side effects included dry mouth, clumsiness, dizzi-
ness, pneumothorax and sore throat.
What Would be Needed to Test Cannabis in
Human ALS Clinical Trials?
Doing multi-center clinical research trials for PALS
using cannabis would pose many unique barriers.
First of all there is no commercial manufacturer of
cannabis, thus these studies would have to be funded
either by the federal government or privately, as it
is not likely there would be industry funding. Obtain-
ing the trial drug would require the investigators to
gain access to a large, reliable supply of cannabis
that is legal for medical research. At present, the
only source of cannabis that can be legally used in
research in the United States is through the National
Institute on Drug Abuse (NIDA). Unfortunately
NIDA provides low-potency material, and makes
the cannabis available only to projects it approves.
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402 The ALSUntangled Group
NIDA supplies cannabis with a THC content, by
weight, of 2–4% typically, although it has supplied
cannabis with an 8% by weight THC content on
occasion (67). Although THC is not the ideal target
compound per se, it is a relative indicator of potency
and quality. For comparison, the average THC con-
tent of cannabis at randomly surveyed medical
cooperatives in California is approximately 15 to
20% (68). Thus, an independent source of cannabis
would be needed to ensure a consistently high can-
nabinoid content that may be strong enough to pos-
sibly alter the disease progression. An independent
cannabis source would also allow investigators to
avoid NIDA ’ s arbitrary and lengthy review process
that it mandates before providing any cannabis for
research. Historically NIDA has derailed clinical
trial plans by refusing to supply cannabis, even after
the research protocols were approved by the FDA
(69,70). Nonetheless, it is possible, with coordi-
nated effort, to effectively do double-blind, random-
ized, placebo controlled clinical trials with cannabis.
To properly evaluate both subjective and objective
effects, cannabinoid blood levels should be followed
as well, to further ensure adequate data for a
dose-response curve. Mode of drug delivery could
be via vaporization, which would allow for dosing
standardization (71,72).
Another interim option would be clinical trials
with Sativex ® , a product from GW Pharmaceutical
company in the UK. Sativex is a natural cannabinoid
pharmaceutical product, administered as an oral
spray absorbed by the patient ’ s mouth. The drug is
obtained from natural cannabis and standardized by
weight to be 50% THC and 50% cannababidiol
(CBD)(73). This makes it a much better choice than
Marinol (dronabinol). Yet this is not as desirable as
natural cannabis, which contains a multitude of other
therapeutic cannabinoids, many of which are not psy-
choactive, such as cannabinol (CBN). One of the
ALSUntangled team (GTC) has tried to get GW to
pursue this but has not had success to date, with the
company decision being based on fi nancial informa-
tion. GW Pharma openly acknowledges that it needs
a large patient base to be fi nancially viable and is thus
targeting multiple sclerosis (MS). Finally Sativex is
not available as of yet in the United States.
Conclusions
Cannabis has biological properties including immu-
nomodulation and effects on excitototoxicity that
suggest it could be useful in ALS. Evidence from
small, non-randomized, unblinded animal studies
suggest that it could potentially slow ALS progres-
sion, and anecdotal reports suggest that it could
ameliorate troubling ALS symptoms. Given all this,
ALSUntangled supports further careful study of
cannabis and cannabinoids, the active ingredients
contained therein. Natural cannabis, as a single
agent, provides advantages similar to a multiple drug
trial given its numerous mechanisms of action. A
possible next step would be a small case series of
well-characterized PALS using cannabis at con-
trolled dosages that could potentially be monitored
by blood levels of cannabinoids, compared to
matched controls, performed in a geographic area
where it would be legal.
The ALSUntangled Group currently consists of
the following members: Gregory Carter, Richard Bed-
lack, Orla Hardiman, Lyle Ostrow, Edor Kabashi,
Tulio Bertorini, Tahseen Mozaffar, Peter Andersen,
Jeff Dietz, Josep Gamez, Mazen Dimachkie, Yunxia
Wang, Paul Wicks, James Heywood, Steven Novella,
LP Rowland, Erik Pioro, Lisa Kinsley, Kathy Mitch-
ell, Jonathan Glass, Sith Sathornsumetee, Hubert
Kwiecinski, Jon Baker, Nazem Atassi, Dallas Forshew,
John Ravits, Robin Conwit, Carlayne Jackson, Alex
Sherman, Kate Dalton, Katherine Tindall, Ginna
Gonzalez, Janice Robertson, Larry Phillips, Michael
Benatar, Eric Sorenson, Christen Shoesmith, Steven
Nash, Nicholas Marigakis, Dan Moore, James
Caress, Kevin Boylan, Carmel Armon, Megan
Grosso, Bonnie Gerecke, Jim Wymer, Bjorn Oskars-
son, Robert Bowser, Vivian Drory, Jeremy Shefner,
Terry Heiman-Patterson, Noah Lechtzin, Melanie
Leitner, Robert Miller, Hiroshi Mitsumoto, Todd
Levine, James Russell, Khema Sharma, David Saper-
stein, Leo McClusky, Daniel MacGowan, Jonathan
Licht, Ashok Verma, Michael Strong, Catherine
Lomen-Hoerth, Rup Tandan, Michael Rivner, Steve
Kolb, Meraida Polak, Stacy Rudnicki, Pamela
Kittrell, Muddasir Quereshi, George Sachs, Gary
Pattee, Michael Weiss, John Kissel, Jonathan Gold-
stein, Jeffrey Rothstein, Dan Pastula. Note: this paper
represents a consensus of those weighing in. The
opinions expressed in this paper are not necessarily
shared by every investigator in this group.
Disclosures: ALSUntangled is sponsored by the
Packard Center and the Motor Neurone Disease
Association.
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The ALSUntangled Group currently consists of the
following members: Richard Bedlack, Orla Hardiman,
Tulio Bertorini, Tahseen Mozaffar, Peter Andersen,
Jeff Dietz, Josep Gamez, Mazen Dimachkie, Yunxia
Wang, Paul Wicks, James Heywood, Steven Novella,
LP Rowland, Erik Pioro, Lisa Kinsley, Kathy
Mitchell, Jonathan Glass, Sith Sathornsumetee,
Hubert Kwiecinski, Jon Baker, Nazem Atassi, Dallas
Forshew, John Ravits, Robin Conwit, Carlayne
Jackson, Alex Sherman, Kate Dalton, Katherine
Tindall, Ginna Gonzalez, Janice Robertson, Larry
Phillips, Michael Benatar, Eric Sorenson, Christen
Shoesmith, Steven Nash, Nicholas Marigakis, Dan
Moore, James Caress, Kevin Boylan, Carmel Armon,
Megan Grosso, Bonnie Gerecke, Jim Wymer, Bjorn
Oskarsson, Robert Bowser, Vivian Drory, Jeremy
Shefner, Terry Heiman-Patterson, Noah Lechtzin,
Melanie Leitner, Robert Miller, Hiroshi Mitsumoto,
Todd Levine, James Russell, Khema Sharma, David
Saperstein, Leo McClusky, Daniel MacGowan,
Jonathan Licht, Ashok Verma, Michael Strong,
Catherine Lomen-Hoerth, Rup Tandan, Michael
Rivner, Steve Kolb, Meraida Polak, Stacy Rudnicki,
Pamela Kittrell, Muddasir Quereshi, George Sachs,
Gary Pattee, Michael Weiss, John Kissel, Jonathan
Goldstein, Jeffrey Rothstein, Dan Pastula. Note: this
paper represents a consensus of those weighing in.
The opinions expressed in this paper are not
necessarily shared by every investigator in this
group.
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