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264 American Journal of Hospice & Palliative Care
Volume 18, Number 4, July/August 2001
Note
Supported by Research and Training
Center Grant HB133B980008 from the
National Institute on Disability and
Rehabilitation Research, Washington,
DC.
Abstract
Marijuana has been proposed as
treatment for a widening spectrum of
medical conditions. Marijuana is a sub-
stance with many properties that may be
applicable to the management of amy-
otrophic lateral sclerosis (ALS). These
include analgesia, muscle relaxation,
bronchodilation, saliva reduction, ap-
petite stimulation, and sleep induc-
tion. In addition, marijuana has now
been shown to have strong antioxida-
tive and neuroprotective effects, which
may prolong neuronal cell survival. In
areas where it is legal to do so, mari-
juana should be considered in the
pharmacological management of
ALS. Further investigation into the
usefulness of marijuana in this setting
is warranted.
Key words: ALS, cannabidiol, canna-
binoids, cannabinol, marijuana, symp-
tom management
Introduction
This paper is dedicated
to the memory of Linda Santos.
Over the past few decades, there has
been widening interest in the viable
medicinal uses of marijuana.
1
The
National Institutes of Health (NIH), the
Institute of Medicine (IOM), and the
Food and Drug Administration (FDA)
have all issued statements calling for
further investigation.
2-4
There is a large
body of literature on the effects of can-
nabinoids on chemotherapy-induced
nausea and vomiting, lowering intraoc-
ular pressure in patients with glaucoma,
and treating anorexia in patients with
cancer and AIDS-associated weight
loss.
5-8
Beyond these clinical applica-
tions, there is limited literature describ-
ing other appropriate uses for medicinal
marijuana. The intent of this article is to
provide an overview of the potential
pharmacological role marijuana may
have in the management of amyotroph-
ic lateral sclerosis (ALS).
To date, clinical studies on the medic-
inal value of marijuana have often
reached differing conclusions. Some of
this inconsistency in the scientific litera-
ture likely results from the fact that mari-
juana is a complex plant, containing over
400 chemicals.
9
Approximately 60 are
cannabinoids, chemically classified as
21 carbon terpenes.
9,10
Among the most
psychoactive of these is delta-9-tetrahy-
drocannabinol (THC).
9,10
Because of
Marijuana in the management
of amyotrophic lateral sclerosis
Gregory T. Carter, MD
Bill S. Rosen, MD
Gregory T. Carter, MD, Muscular Dystrophy
Association (MDA), Neuromuscular Disease
Clinic, Department of Rehabilitation Medicine,
University of Washington School of Medicine,
Seattle, Washington.
Bill S. Rosen, MD, Muscular Dystrophy Associa-
tion (MDA), Neuromuscular Disease Clinic, New
Hope Rehabilitation Center, St. Vincent Health-
Care, Billings, Montana.
Pharmaceutical update
this biochemical complexity, charac-
terizing the clinical pharmacology of
marijuana is difficult. Further compli-
cating the evaluation of marijuana is
the variable potency of the plant mate-
rial used in research studies. The clini-
cal pharmacology of marijuana con-
taining high concentrations of THC
may well differ from plant material
containing small amounts of THC and
higher amounts of the other cannabi-
noids. Moreover, the bioavailability
and pharmacokinetics of inhaled mar-
ijuana are substantially different than
those taken by ingestion. THC is not
soluble in water, but is lipid soluble.
11
Varying proportions of other cannabi-
noids, mainly cannabidiol (CBD) and
cannabinol (CBN), are also present in
marijuana, sometimes in quantities
that might modify the pharmacology
of THC or have distinct effects of their
own. CBD is not psychoactive, but
has significant anticonvulsant, seda-
tive, and other pharmacologic activity
likely to interact with THC.
12,13
The
concentration of THC and other can-
nabinoids in marijuana varies greatly,
depending on growing conditions,
plant genetics, and processing after
harvest.
13
In the usual mixture of
leaves and stems distributed as mari-
juana, concentration of THC ranges
from 0.3 percent to 4 percent by
weight.
13,14
However, specially grown
and selected marijuana can contain 15
percent or more THC. Thus, one gram
of marijuana might contain as little as
3 mg or more than 150 mg of THC.
13
THC is a potent psychoactive drug,
and large doses may produce mental
and perceptual effects similar to hallu-
cinogenic drugs.
15,16
Despite this,
THC and other cannabinoids have
remarkably low toxicity and lethal
doses in humans have not been de-
scribed.
17,18
Prior to the last decade, there was
little known about the specific pharma-
cological and molecular effects of mar-
ijuana. However, important advances
have recently taken place that have
greatly increased the understanding of
the receptors and ligands composing
the cannabinoid system. Research has
shown that two major cannabinoid
receptor subtypes exist, and subtype 1
(CB1) is expressed primarily in the
brain, whereas subtype 2 (CB2) is
expressed primarily in the periph-
ery.
19,20
A variety of ligands for these
receptors, based on the cannabinoid
structure, have been synthesized and
studied. These novel ligands are of
interest as both experimental tools and
lead compounds for therapeutic agents.
Experiments performed with several
types of neural cells that endogenously
express the CB1 receptor suggest the
activation of protein kinases may be
responsible for some of the cellular
responses elicited by the CB1 cannabi-
noid receptor.
21
The recent discovery of
the endocannabinoids, i.e. endogenous
metabolites capable of activating the
cannabinoid receptors, and the under-
standing of the molecular mechanisms
leading to their biosynthesis and inacti-
vation, has created a new area in
research on the pharmaceutical appli-
cations of cannabinoids.
22
The characterization of endocanna-
binoids, such as anandamide, and the
detection of widespread cannabinoid
receptors in the brain and peripheral
tissues, suggests that the cannabinoid
system represents a previously unrec-
ognized, ubiquitous network in the ner-
vous system. Cannabinoid receptors are
protein-coupled, transmembrane nu-
cleotides, similar to the receptors of
other neurotransmitters such as dopa-
mine, serotonin, and norepinephrine.
20,22
Dense receptor concentrations are
found in the cerebellum, basal ganglia,
and hippocampus, likely accounting for
the effect of marijuana on motor tone
and coordination as well as mood
state.
20-22
Low concentrations are found
in the brainstem, accounting for the low
potential for lethal overdose.
21,22
A
growing number of strategies for sepa-
rating sought-after therapeutic effects
of cannabinoid receptor agonists from
the unwanted consequences of CB1
receptor activation are now emerging.
Recently, ligands have been developed
that are potent and selective agonists for
CB1 and CB2 receptors as well as
potent CB2-selective antagonists and
inhibitors of endocannabinoid uptake
or metabolism.
21,22
This knowledge
may lead to the design of synthetic can-
nabinoid agonists and antagonists with
high therapeutic potential.
Current pharmacological
management of ALS
Amyotrophic lateral sclerosis, with
an incident rate of five to seven per
100,000 population, is the most com-
mon form of adult motor neuron dis-
ease.
23-26
ALS is a rapidly progressive
neuromuscular disease that destroys
both upper and lower motor neurons,
resulting in weakness, spasticity, and
ultimately death from respiratory fail-
ure. The vast majority of ALS cases
are acquired and occur sporadically.
Emerging evidence suggests that in-
creased oxidative stress from free rad-
ical toxicity or excessive glutamate
activity is what leads to motor neuron
cell death in the brain and spinal
cord.
24,27
There is not yet a known cure for
ALS, although significant research
advances are being made. Riluzole is
approved by the FDA for treatment of
ALS.
24
This drug inhibits the presynap-
tic release of glutamate and reduces
neuronal damage in experimental mod-
els of ALS. In 1995, two clinical trials
showed that riluzole slowed disease
progression.
27
Both of these studies
showed prolonged survival for patients
taking riluzole as opposed to placebo,
although the benefit was modest.
However, there are serious, but rare,
complications of riluzole treatment,
including renal tubular impairment,
hepatitis, and pancreatitis.
27
Because oxidative stress is one of
the proposed pathogenic factors in
ALS, antioxidants are recommended,
265American Journal of Hospice & Palliative Care
Volume 18, Number 4, July/August 2001
including vitamin E, vitamin C, coen-
zyme Q, B-carotene, and N-acetylcys-
teine.
28,29
Creatine, an amino acid natu-
rally found in skeletal muscle and other
tissues, may also have some benefit in
ALS. Creatine given to “ALS mice,” a
transgenic mouse model of ALS, im-
proved motor performance, prolonged
survival, and slowed loss of motor neu-
rons.
30
At present, trials of neurotrophic
factors, anti-oxidants, glutamate antago-
nists, and creatine are ongoing. It is cur-
rently felt that a “cocktail” approach may
be the ideal treatment strategy, including
glutamate antagonists, antioxidants,
and neurotrophic factors.
Application of marijuana for
symptom management of ALS
Amyotrophic lateral sclerosis pre-
sents a multitude of difficult clinical
problems. This section will overview
these problems and discuss the poten-
tial role marijuana may play in their
management. There are both direct and
theoretical applications for using mari-
juana to manage ALS symptoms. Mari-
juana has easily observable clinical
effects with rapid onset (e.g., analgesia,
muscle relaxation, dry mouth, etc.). It
also has neuroprotective properties
that may help prolong neuronal cell
survival over extended use. This next
section will delineate specific clinical
problems encountered in ALS and
describe the potential use of marijuana
to address these.
Pain and immobility
The majority of ALS patients expe-
rience significant pain.
24
The pain is
due largely to immobility, which can
cause adhesive capsulitis, mechanical
back pain, pressure areas on the skin,
and, more rarely, neuropathic pain.
24,31
Synthetic cannabinoids have been
shown to produce an anti-inflammatory
effect by inhibiting the production and
action of tumor necrosis factor (TNF)
and other acute phase cytokines.
32
Additionally, marijuana may reduce
pain sensation, likely through a brain-
stem circuit that also contributes to the
pain-suppressing effects of morphine.
33
Cannabinoids produce analgesia by
modulating rostral ventromedial me-
dulla neuronal activity in a manner sim-
ilar to, but pharmacologically distinct
from, that of morphine. This analgesic
effect is also exerted by some endoge-
nous cannabinoids (anandamide) and
synthetic cannabinoids (methanan-
damide), and may be prevented by the
use of selective antagonists.
34
Thus,
cannabinoids are centrally acting anal-
gesics with a different mechanism of
action than opioids, although the anal-
gesia produced by cannabinoids and
opioids may involve similar pathways
at the brainstem level.
35-37
Despite this
promising basic science research, no
clinical trials currently involving mari-
juana have been performed in patients
with naturally occurring pain. There are
two well-controlled clinical studies
using marijuana in cancer pain that
show significant evidence of analgesic
efficacy, although these studies indicate
there is a narrow therapeutic margin
between the doses that produce useful
analgesia and those producing euphoria
and other CNS effects.
38,39
Concern for drug overuse, within
reason, is pointless in a terminal disease,
and the medication should be given on a
regular dosing schedule and titrated to
the point of comfort.
40
Concomitant use
of narcotics may also be beneficial,
since the opioid receptor system appears
to be separate and distinct from the
cannabinoid system. In that regard, the
anti-emetic effect of marijuana may
help with the nausea sometimes associ-
ated with narcotic medications. Un-
toward effects are the possibly signifi-
cant psychoactive effects of marijuana,
which may include euphoria, but can
also include confusion and paranoia (see
Mood state). Some of these side effects,
such as euphoria, may be quite accept-
able in the final phases of life, when res-
piratory insufficiency or severe pain
require increased doses of analgesia.
40
However, patients and caregivers should
be made aware of these issues and mon-
itor for unwanted effects.
Spasticity
Spasticity in ALS is induced at
266 American Journal of Hospice & Palliative Care
Volume 18, Number 4, July/August 2001
Table 1. Properties of marijuana applicable
to ALS symptom management
ALS symptom Marijuana effect
Pain Nonopioid analgesia and anti-inflammatory
Spasticity Muscle relaxant
Wasting Appetite stimulant
Dyspnea Bronchodilation
Drooling Dry mouth
Depression Euphoria
Dysautonomia Vasodilation
Neuronal oxidation Neuroprotective antioxidant
both the motor cortex and the spinal
cord level through the loss of motor
neuron inhibition.
24
Marijuana has an
inhibitory effect on the gamma-
amino-butyric acid (GABA) pathways
in the central nervous system.
41
This
produces motor neuron inhibition at
spinal levels in mice.
42-45
Baclofen
also works via the GABA pathways
and would theoretically be potentiated
by marijuana. Tizanidine, another
commonly used anti-spasticity drug,
works as an alpha-2 agonist, which is
a different mechanism. Like baclofen
and tizanidine, marijuana does not
cause respiratory depression. This is a
distinct advantage of these drugs over
the benzodiazepines. Despite this,
clinical evidence that marijuana re-
lieves spinal cord spasticity is largely
anecdotal. Large-scale trials or con-
trolled studies to compare marijuana
or THC with currently available thera-
pies have not been performed and
there is no published evidence that
cannabinoids are necessarily superior
to available therapies.
ALS wasting
The term “ALS cachexia” refers to
a phenomenon experienced by some
patients in which weight loss occurs in
excess of that caused by muscle atro-
phy and reduced caloric intake.
24
Both
subcutaneous fat and peritoneal fat are
lost, presumably because of accelera-
tion of the basal metabolic rate.
25
In
patients with ALS cachexia, greater
than 20 percent of body weight is typi-
cally lost over a six-month period.
Clinical studies and survey data in
healthy populations have shown a
strong relationship between marijuana
use and increased eating.
42,46,47
Mari-
juana is reported to increase food enjoy-
ment and the number of times individu-
als eat per day.
14,42
Mechanistic studies
of marijuana on taste and satiety have
shown that it does not affect taste or
produce a collapse of normal satiety
mechanisms.
46
Dronabinol has been
shown to increase appetite and pro-
duce weight gain in AIDS and cancer
patients, although the weight gain is
not in lean body mass.
47
Dronabinol is
approved for the treatment of anorexia
in patients with AIDS-associated
weight loss.
47
Respiratory failure
The terminal event in ALS is usually
directly related to respiratory failure.
Restrictive breathing problems usually
develop in ALS and are due to weak-
ness of the diaphragm, chest wall, and
abdominal musculature.
24,25
Although
cannabinoids will not likely improve
respiratory muscle performance, the
cannabinoids are strong bronchodila-
tors, and pharmacologically active,
aerosolized forms of THC have re-
cently been developed.
48
This was
done via a small particle nebulizer that
generated an aerosol, which could
penetrate deeply into the lungs. In-
halation exposure to aerosolized THC
in mice elicited anti-nociceptive and
bronchodilation effects that were de-
pendent on concentration and expo-
sure time. The anti-nociceptive and
bronchodilation effects occurred with-
in five minutes of exposure. Canna-
binoid receptor antagonists, but not
naloxone, blocked these effects, again
indicating a cannabinoid receptor
mechanism of action separate from
that of the opioids.
48,49
These results
demonstrate that the development of
an aerosolized form of cannabinoids
for human medicinal use is feasible.
Dysphagia
Patients with ALS and bulbar symp-
toms also usually have difficulty control-
ling and swallowing the amounts of sali-
va that are normally present in the oral
cavity. Marijuana is a potent anti-
salivatory compound that swiftly dries
the oral cavity and upper airway.
48,5
Marijuana may be used alone or in con-
junction with other anti-cholinergic
medications to help dry up secretions.
This potentially reduces the risk for
aspiration pneumonia and may make
the patient more comfortable.
Mood state
Reactive clinical depression is ex-
pected in ALS. Marijuana will improve
appetite and sleep, two problems that
may be related to depression. Mari-
juana is often used recreationally for
the “euphoria”-inducing properties,
but, in some patients, it may exacerbate
depression.
51
Further, it is not clear
what effect marijuana will have on the
pseudobulbar palsy or emotional
lability of ALS. Usually, the mental
and behavioral effects of marijuana
consist of a sense of well-being (often
termed a “high”), feelings of relax-
ation, altered perception of time and
distance, intensified sensory experi-
ences, laughter, talkativeness, and
increased sociability when taken in a
social setting.
51-53
Impaired memory
for recent events, difficulty concen-
trating, dreamlike states, impaired
motor coordination, impaired driving
and other psychomotor skills, slowed
reaction time, impaired goal-directed
mental activity, and altered peripheral
vision are commonly associated ef-
fects.
54
With repeated exposure, vary-
ing degrees of tolerance rapidly devel-
op to many subjective and physiologic
effects.
55,56
Thus, intensity of acute
effects is determined not only by THC
dose, but also by past experience, set-
ting, expectations, and poorly under-
stood individual differences in sensi-
tivity. Large inhaled or oral marijuana
doses or even ordinary doses taken by
a sensitive, inexperienced, or predis-
posed person can produce transient
anxiety, panic, feelings of depression
and other dysphoric mood changes,
depersonalization, bizarre behaviors,
delusions, illusions, or hallucina-
tions.
53,56
Depending on the mix of
symptoms and behaviors, the state has
been termed an acute panic reaction,
267American Journal of Hospice & Palliative Care
Volume 18, Number 4, July/August 2001
toxic delirium, acute paranoid state, or
acute mania. These unpleasant effects
are usually of sudden onset, during or
shortly after smoking, or appear more
gradually an hour or two after an oral
dose, often lasting a few hours, and
completely clear without any specific
treatment other than reassurance and a
supportive environment. Subsequent
marijuana doses may be better tolerat-
ed.
56,57
Dysautonomia
Although dysautonomia is not gen-
erally a predominant feature of ALS,
it can cause some unique clinical
problems. Patients may complain of
feeling quite hot, due to alterations in
the autonomic control of peripheral
circulation and perspiration. Mari-
juana produces a transient hypother-
mia and vasodilation, which may ease
these symptoms. Skin temperature
may drop four to six degrees centi-
grade.
50,58,59
However, marijuana is
also a mild diuretic and may produce
dehydration and hypotension. Thus,
blood pressure and fluid intake need
to be monitored in ALS patients that
use marijuana and have dysautono-
mia.
58,59
Neuroprotective
and antioxidant effects
Cannabinoids have significant neuro-
protective and antioxidative effects.
Recent studies have demonstrated the
neuroprotective effects of synthetic,
nonpsychotropic cannabinoids, which
appear to protect neurons from chemi-
cally-induced excitotoxicity.
60-63
Direct
measurement of oxidative stress re-
veals that cannabinoids prevent cell
death by antioxidation. The antioxida-
tive property of cannabinoids is con-
firmed by their ability to antagonize
oxidative stress and consequent cell
death induced by the powerful oxi-
dant, retinoid anhydroretinol. Can-
nabinoids also modulate cell survival
and growth of B-lymphocytes and
fibroblasts.
63
The neuroprotective actions of
cannabidiol and other cannabinoids
were examined in rat cortical neuron cul-
tures exposed to toxic levels of the
excitatory neurotransmitter glutamate,
known to be increased in the spinal cords
of ALS patients. Glutamate toxicity was
reduced by both cannabidiol, a nonpsy-
choactive constituent of marijuana, and
the psychotropic cannabinoid THC.
64
The neuroprotection observed with
cannabidiol and THC was unaffected by
cannabinoid receptor antagonist, indicat-
ing it to be cannabinoid receptor inde-
pendent. Cannabidiol was more protec-
tive against glutamate neurotoxicity than
either ascorbate (vitamin C) or alpha-
tocopherol (vitamin E).
64,65
Cannabinoids have shown efficacy
as immune modulators in animal mod-
els of neurological conditions, such as
experimental allergic encephalomy-
elitis (EAE) and neuritis.
66
These data
suggest that cannabinoids might modi-
fy the presumed autoimmune cause of
other neurological diseases, including
multiple sclerosis (MS). Current data
suggest that the naturally occurring,
nonpsychotropic cannabinoid (canna-
bidiol) may have a potential role as a
therapeutic agent for the neurodegener-
ative disorders produced by excessive
cellular oxidation, such as ALS.
Using marijuana
Smoking anything, including mari-
juana, is not healthful for the lungs
and airway system.
46
Despite risk for
bronchitis, the main advantage of
smoking is rapid onset of effect and
easy dose titration. When marijuana is
smoked, THC in the form of an aero-
sol in the inhaled smoke is rapidly
absorbed and delivered to the brain, as
would be expected of a highly lipid-
soluble drug.
67,68
A healthier option is
vaporization. Because the cannabi-
noids are volatile, they will vaporize
at a temperature much lower than
actual combustion.
16
Heated air can be
drawn through marijuana and the
active compounds will vaporize, which
can then be inhaled. This delivers the
substance in a rapid manner that can
be easily titrated to desired effect.
69
Theoretically, this removes most of
the health hazards of smoking, al-
though this has not been studied.
Additionally, marijuana can be ingest-
ed orally or through a feeding tube,
although oral ingestion is quite differ-
ent than inhalation. The onset of ac-
tion is much slower and titration of
dosing is more difficult.
68,69
Maxi-
mum THC and other cannabinoid
blood levels are only reached one to
three hours after an oral dose.
49
The
same is true of dronabinol capsules,
which also have the disadvantage of
containing only synthetic THC and
none of the other cannabinoids.
47
For ALS patients with severe dys-
phagia, the inhalation route offers addi-
tional advantages beyond rapid onset of
action, particularly compared to the
currently available capsule formulation.
This raises many issues concerning the
best mode of administration. Ideally,
drug administration would be via a
delivery route that is safe, easy to titrate,
and readily dispersed in the body.
Smoking or vaporizing plant material
for inhalation poses difficulties in stan-
dardizing testing paradigms. The devel-
opment of alternative dosage forms,
including an inhaler form into which a
controlled unit dose could be placed
and volatilized would make clinical use
much easier. Aerosolized cannabinoids
have been developed, as described ear-
lier, although they are not yet commer-
cially available.
Legal issues
An in-depth discussion of the legal
ramifications of using medicinal mari-
juana is beyond the scope or intent of
this paper. In some states, it is current-
ly legal to use marijuana for medicinal
purposes.
70-72
In Washington state, a
268 American Journal of Hospice & Palliative Care
Volume 18, Number 4, July/August 2001
not-for-profit cooperative organiza-
tion, the Green Cross, provides high-
quality, medicinal marijuana to pa-
tients for a minimal donation, and
delivers the marijuana to homebound
patients. However, in other states, the
use of marijuana for any purpose
remains illegal. Health care providers
need to know the local laws before
recommending medicinal marijuana
to avoid legally endangering their pa-
tients and themselves.
73-75
All deci-
sions on the ultimate usefulness of a
medical intervention should be based
on a benefit/risk calculation, and mar-
ijuana is no exception to this principle.
Conclusion
Marijuana is a substance with many
properties that are directly applicable
to the management of ALS. These
include analgesia, muscle relaxation,
bronchodilation, saliva reduction, ap-
petite stimulation, sleep induction,
and euphoria. In addition, marijuana
has now been shown to have strong
antioxidative and neuroprotective ef-
fects, which may prolong neuronal
cell survival. From a pharmacological
perspective, marijuana is reasonably
safe with minimal possibility of over-
dose. In states where it is legal to do
so, marijuana should be considered in
the pharmacological management of
ALS.
Moreover, the scientific process
should be allowed to evaluate the
potential therapeutic effects of mari-
juana for ALS and other disorders,
detached from the societal debate over
any potential harmful effects of non-
medical marijuana use.
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