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<div align="center"><font size="4"><b>Chapter Four: THE MEDICAL VALUE OF
MARIJUANA AND RELATED SUBSTANCES</b></font></div>
4.1
Chapter 4.
The Medical Value of Marijuana and Related Substances
Compared to most drugs, the accumulation of medical knowledge about
marijuana has proceeded in reverse. Typically, during the course of drug
development, a compound is first found to have some medical benefit. Following
this, extensive tests are undertaken to determine the safety and proper
dose of the drug for medical use. Marijuana, in contrast, has been widely
used in the United States for decades. 165 In 1996, 68.6 million
people or 32 percent of the United States population over 12 years old
had tried marijuana or hashish at least once in their lifetime although
only five percent were current users. 166
The data on the adverse effects of marijuana are more extensive than
the data on effectiveness. Clinical studies of marijuana are difficult
to conduct. Researchers interested in clinical studies of marijuana face
a series of barriers. Research funds are limited, and there is a daunting
thicket of regulations to be negotiated at the federal (FDA and DEA) and
state levels (see chapter 5). Consequently, the rapid growth in basic
research on cannabinoids contrasts with the scarcity of substantial clinical
studies on medical uses.
This chapter is devoted to an analysis of the therapeutic value of marijuana
and cannabinoids for specific symptoms associated with a variety of conditions.
The risks associated with the medical use of marijuana were discussed
in chapter 3. It should be noted that THC, the primary active ingredient
in marijuana, is an FDA approved drug referred to as dronabinol and marketed
under the brand name Marinol®. Marijuana is primarily advocated as
a relief from the symptoms of disease, rather than a cure.
For the most part, the claims for medical uses of marijuana are for
relief of symptoms, such as nausea, appetite loss, or chronic pain --
each of which can be caused by a variety of diseases or even by the treatments
for disease. Therefore, this chapter is primarily organized by symptoms
rather than diseases There are eight sections. The first six deal with
specific symptoms and conditions and the last two summarize the medical
benefits of marijuana and cannabinoids. The five sections on symptoms
and conditions are as follows: pain, nausea and vomiting, wasting syndrome
and appetite stimulation, spasticity and other neurological symptoms,
and glaucoma.
The IOM study team received reports of over 30 different medical uses
of marijuana, which is more than could be carefully reviewed in a report
of this length; even more uses are reported elsewhere. 66, 67
For most of the infrequently mentioned medical uses of marijuana there
are only a few anecdotal reports. This report reviews only the most prominent
symptoms that are reportedly relieved by marijuana. However, many of those
diseases not reviewed here share common symptoms, such as pain, nausea
and vomiting, and muscle spasms which might be relieved by cannabinoid
drugs.
4.2
Standards for evaluating clinical
Before evaluating individual clinical trials concerning the efficacy
and safety of medical uses of marijuana and cannabinoids, it is useful
to review the general qualities of clinical trials. Clinical trials involve
groups of individuals in which different treatments are compared among
different cohorts, or treatment groups. Such trials measure the efficacy
of a medication, and are required by the FDA for approval of any new drug
or new use of a drug (discussed further in chapter 5).
The degree of assurance that the outcome of a clinical trial is due
to the treatment being tested depends on how well the trial is designed.
Three important factors to consider in evaluating the design of a clinical
trial are: sample selection, subjective effects, and effects that are
independent of the treatment. For sample selection, it is important to
ensure that patients are allocated to different treatment groups in such
a way that the cohorts are not biased towards a particular treatment outcome.
For example, the health status, gender, and ages of different cohorts
should be equivalent. Subjective effects must be controlled because they
influence experimental results in two important ways. First, a patient's
expectation that a treatment will be effective can influence the degree
of its effect (for example, in the control of nausea). Second, the investigator's
expectation can influence his or her interpretation of the treatment effect
(for example, when assessing the level of pain experienced by a patient).
For these reasons, double-blinding, in which neither the subject nor the
person who assesses the drug's effect is aware of the subject's treatment
group, is particularly important in cannabinoid drug studies. Another
important control for subjective effects includes the use of placebo drugs,
which are inert substances, or the use of comparison drugs that have effects
similar to the experimental drug. Finally, the quality of the experimental
design depends on controlling for factors unrelated to the test drug that
might nonetheless influence the treatment outcome. Sequencing effects
are one example of such factor. For example, patients might react differently
to the same medication depending on whether the medication was administered
after an effective or an ineffective treatment. Likewise, compared to
a patient whose symptoms are initially mild, a patient whose symptoms
are initially severe might react differently to the same drug treatment.
Because of the psychological effects associated with cannabinoid drugs,
it is particularly important to consider how such side effects might influence
the therapeutic value of the treatment. Conditions such as pain and nausea
are especially susceptible to subjective influences. For example, depending
on the individual, THC can reduce or increase anxiety; it is important
to determine to what extent this 'side effect' contributes to the therapeutic
effect experienced by the patient.
While double-blind, randomized, controlled clinical trials offer the
highest degree of assurance of drug efficacy; such trials are not always
feasible. For safety reasons, vulnerable population, such as children,
older patients, and women of childbearing age, are often excluded from
experimental drug trials. Nonetheless, such patients are part of everyday
clinical practice. This challenge of integrating the ideal of standardized
and rigorous processes for evaluating the effectiveness of treatments
with everyday clinical practice has encouraged interest in single patient
trials. 71
4.3
Methods for such trials have been established and tested in a variety
of clinical settings, usually under everyday conditions. 70, 109,
162 They are particularly valuable when physicians or patients
are uncertain about the efficacy of treatment for symptomatic diseases.
Controls can be incorporated even in this kind of trial. Such trials
can be double-blinded and can involve cross-over designs in which the
patient is treated with alternating treatments, such as placebo-drug-placebo,
or one drug followed by another drug Most importantly, as with any other
clinical trial, a single patient trial should be designed to permit
objective comparison between treatments.
Analgesia
Pain is the most common symptom for which patients seek medical assistance.5
Pain associated with either structural or psychophysiological disorders
can arise from somatic, visceral, or neural structures. Somatic pain results
from activation of receptors outside the brain and is transmitted back
to the brain via peripheral nerves. Visceral pain results from activation
of specific pain receptors in the gut. It is characterized as a deep aching
or cramping sensation, but the source of the pain is often experienced
at sites remote from the site of receptor activation, a phenomenon known
as referred pain. Neuropathic pain results from injury to peripheral receptors,
nerves, or the central nervous system. It is typically burning and the
skin feels abnormally unpleasant when gently touched (allodynia), and
often occurs in an area of sensory loss -- for example, post-herpetic
neuralgia.
All of the currently available analgesic, or pain-relieving, drugs have
limited efficacy for some types of pain. Some are limited by dose-related
side effects, and some by the development of tolerance or dependence.
Cannabinoids, or any new analgesic, could potentially be useful under
one of the following circumstances:
· There are medical conditions or patients in which they are
more effective than any currently available medication.
· They have a broad clinical spectrum of efficacy and a unique
side effect profile that differs from other analgesics.
· They have synergistic interactions with other analgesics.
· They exhibit "side effects" which are considered
useful in certain clinical situations.
· Their efficacy is enhanced in patients who have developed
tolerance to opioids.
There have not been extensive clinical studies on the analgesic potency
of cannabinoids, but data from animal studies indicate that cannabinoids
could be useful analgesics. In general, cannabinoids seem to be mild to
moderate analgesics. Opiates, such as morphine and codeine, are the most
widely used drugs for the treatment of acute pain. But they are not consistently
effective in chronic pain, they often induce nausea, and sedation and
tolerance might occur in some patients. Recent research has made it clear
that CB1, receptor agonists act upon pathways that
4.4
partially overlap with those activated by opioids but through pharmacologically
distinct mechanisms (see chapter 2). This means that they would likely
have a different side effect profile and perhaps additive or synergistic
analgesic efficacy.
In light of the solid evidence that cannabinoids can reduce pain in
animals (chapter 2), it is important to carefully re-evaluate the evidence
concerning analgesic efficacy in humans, and to ask, what clinical evidence
is needed to help us decide whether cannabinoids have any use in the treatment
of pain?
Clinical studies with cannabinoids
There have been three kinds of studies on the effects of cannabinoids
on pain sensitivity in human volunteers: 1) studies of experimentally-induced
acute pain, 2) studies of post-surgical acute pain, and 3) studies of
chronic pain. Overall, there have been very few studies -- only one since
1981 -- and they have been inconclusive.
Experimentally-induced acute pain
Early studies of cannabinoids in human volunteers using experimental
pain models did not demonstrate consistent analgesia. In fact, three early
studies testing THC on experimental pain caused by a variety of pain modalities
electrical stimulation, tourniquet pain, and thermal pain -- resulted
in an increase in pain sensitivity (hyperalgesia). 23, 88, 112
Other studies also failed to show an analgesic effect of THC, but they
were not well-designed. Raft and coworkers 152 found no evidence
for THC analgesia on pain thresholds and pain tolerance following electrical
stimulation and noxious pressure. But their study suffers from two major
methodological problems. First, they measured only the extremes of pain
sensation -- threshold (the lowest intensity at which a particular stimulus
is perceived as painful) and tolerance (the maximum intensity of pain
that a subject can withstand). Most pain is experienced in an intermediate
range, where effects on pain suppression are most detectable. Modern methods
of pain assessment in humans typically use ratings of the intensity of
the sensation of pain, a measure which has been found to be superior to
assessing the effects of a drug on the extremes of pain. 196
The second problem was that they did not include a positive control; that
is, they did not demonstrate the adequacy of their methodology by showing
that an established analgesic, such as an opiate, was effective under
their study conditions.
Clark and coworkers 23 tested smoked marijuana on thermal
pain in human volunteers, and also failed to observe an analgesic effect.
However, because of the study design the results are inconclusive. First,
there was no positive control to demonstrate the adequacy of their methods;
and second, the study subjects were habitual marijuana users. During the
study they were hospitalized and allowed free access to marijuana cigarettes
for a period of four weeks, consuming an average of 4 to 17 marijuana
cigarettes per day. Pain was tested "approximately every one to two
weeks." Thus it is quite likely that the subjects were tolerant to
THC at the time of testing.
4.5
Cancer Pain
The most encouraging clinical data on the effects of cannabinoids on
chronic pain are from three methodologically sound studies on cancer pain.
Cancer pain can be due to inflammation, mechanical invasion of bone or
other pain sensitive structure, or nerve injury. It is severe, persistent,
and often resistant to treatment with opioids. In one study, Noyes and
coworkers found that oral doses of THC in the range of 5-20 mg produced
analgesia in patients with cancer pain. 141, 142 The first
experiment was a double-blind, placebo-controlled study of 10 subjects
using measures of both pain intensity and pain relief. 142
Each subject received all drug treatments: placebo, 5, 10, 15, and 20
mg THC in pill form each identical in appearance and given on successive
days. Fifteen and 20 mg doses of THC produced significant analgesia. It
is of interest that there were no reports of nausea or vomiting in this
study. In fact, at least half of the patients reported increased appetite.
With a 20 mg dose of THC, patients were heavily sedated and exhibited
"depersonalization," characterized by a state of dreamy immobility,
sense of unreality, and disconnected thoughts. Five of 36 patients exhibited
adverse reactions (extreme anxiety) and were eliminated from the study.
The mean age of the patients was 51 years, so they were probably not experienced
marijuana smokers. Only one patient experienced this effect at the 10
mg dose of THC. A limitation of this study is that there were no positive
controls -- that is, other analgesics that could provide a better measure
of the degree of analgesia produced by THC.
In a subsequent larger single dose study, the same investigators reported
that the analgesic effect of 10 mg of THC was equivalent to 60 mg of codeine,
and 20 mg of THC was equivalent to 120 mg of codeine. 141 (Note
that codeine is a relatively weak analgesic.) The side effect profile
was similar, though THC was more sedating than codeine. In a separate
publication, the same authors published data indicating that patients
had improved mood, a sense of well-being and less anxiety.
These studies on cancer pain are consistent with the results using a
nitrogen analog of THC. Two separate trials were reported: one comparing
this analog to codeine in 30 patients, and a second trial comparing it
to placebo or secobarbital, a short-acting barbiturate. 178
For mild, moderate and severe pain, this THC-derivative was equivalent
to 50 mg of codeine and superior to placebo and to 50 mg of secobarbital.
Surgical Pain
Raft and coworker152 found no analgesic effect of THC on
surgical pain, induced by tooth-extraction. However, that study suffers
from several serious limitations: 1) the tooth extraction included treatment
with the local anesthetic, lidocaine; 2) the pain during the procedure
was assessed 24 hours later, and 3) there was no positive control. Levonantradol
(a synthetic THC analogue) was tested in 56 patients with moderate to
severe post-operative or trauma pain. 93 They were given intramuscular
injections of levonantrodol or placebo 24 to 36 hours after surgery. To
control for previous drug exposure, patients with a history of drug abuse
or addiction, or those receiving an analgesic or anti-inflammatory drug,
tranquilizer, sedative, or
4.6
anesthetic agent within 24 hours of the test drug were excluded from
the study. On average, pain relief was significantly greater for the
levonantradol-treated patients than for the placebo-treated patients.
Because the authors do not report the number or the percent of people
who responded, it is not clear whether this average represents consistent
pain relief for all levonantradol-treated patients or whether some people
experienced great relief and a few experienced none.
Case reports and surveys
The few case reports of clinical analgesia trials for cannabinoids are
not convincing. 89, 122 There are, however, anecdotal surveys
that raise the possibility that, in certain patients with chronic pain
syndromes with prominent spasticity, there might be a role for cannabinoids.
A recent survey of over 100 patients with multiple sclerosis reported
that a large number obtain relief from spasticity and limb pain (discussed
further under section on multiple sclerosis). 29 Several paraplegic
patients reported in an older survey that marijuana use relieved their
phantom pain and headache. 42
Migraine Headaches
There is clearly a need for improved migraine medications. Sumatriptan
(Imitrex) is currently the best available medication for migraine headaches,
but fails to completely abolish migraine symptoms in about 30 percent
of migraine patents. 120, 149 Marijuana has been proposed numerous
times as a treatment for migraine headaches (reviewed by Russo 160),
but there are almost no clinical data on the use of marijuana or cannabinoids
for migraine. Our search of the literature since 1975 yielded only one
scientific publication on the subject. This report presents three cases
in which cessation of daily marijuana smoking was followed by migraine
attacks, which is not convincing evidence that marijuana relieves migraine
headaches. 44 In fact, the same result could have been found
if migraine headaches were a consequence of marijuana withdrawal. While
there is no evidence that marijuana withdrawal is followed by migraines,
when analyzing the strength of reports such as these it is important to
consider all the logical possibilities. Various individuals have claimed
that marijuana relieves their migraines, but at this stage there are no
conclusive clinical data or published surveys about the effect of cannabinoids
on migraines.
There is, however, a possible link between cannabinoids and migraine
which is suggested by the abundance of cannabinoid receptors in the periaqueductal
gray (PAG) region of the brain. The PAG is part of the neural system that
serves to suppress pain and is thought to be involved in the generation
of migraines. 56 The link or lack thereof between cannabinoids
and migraines might be elucidated by examining the effects of cannabinoids
on the PAG. Recent results indicating that both cannabinoid receptor subtypes
are involved in controlling peripheral pain, 16 suggest that
this might be possible. Nonetheless, the PAG offers only a weak
4.7
anatomical correlate between cannabinoid effects on the brain and their
possible role in migraine relief:
Conclusions and Recommendations
Basic Pain Research
A key question to address is whether there is any receptor selectivity
for the analgesic efficacy of cannabinoids. Are the unwanted side effects
(amnesia and sedation) caused by the same receptors in the same brain
regions as those producing the analgesia? If the answer is yes, enhancing
efficacy will not solve the problem of sedation. Similarly, are the pleasant
side effects due to an action at the same receptor? Can the feelings of
well-being and appetite stimulation be separated by molecular design?
The recent results indicating that both cannabinoid receptor subtypes
are independently involved in controlling peripheral pain 16
(discussed in chapter 2) suggest that this might be possible and that
further research in this area is clearly warranted.
Further research into the basic circuitry underlying cannabinoid analgesia
should be valuable. The variety of neural pathways that underlie the control
of pain suggests that a synergistic analgesia "cocktail" might
be effective. For example, Lichtman has shown the involvement of the a2
adrenoreceptor in cannabinoid analgesia. Perhaps a combination of a CB1
agonist and the oc2 agonist (e.g., clonidine) would provide enhanced analgesia
with a lower side effect level.
Clinical Pain Research
Clinical studies should be directed at those populations of pain patients
where there is a demonstrated need for improved management and where the
particular side effect profile of cannabinoids holds promise of a decided
benefit over current approaches. The following patient groups should be
targeted for clinical studies of cannabinoids in the treatment of pain:
· Patients on chemotherapy, especially for the treatment of
mucositis, nausea and anorexia
· Postoperative pain patients as an opioid adjunct to determine
whether nausea and vomiting from opioids are reduced.
· Patients with spinal cord injury, peripheral neuropathic
pain, or central post-stroke pain.
· Patients with chronic pain and insomnia.
· AIDS patients with cachexia, AIDS neuropathy, or any significant
pain problem.
In any patient group, an essential question to be addressed is whether
the analgesic efficacy of opioids can be augmented. The strategy would
be to find the ceiling analgesic effect with an opioid (as determined
by pain intensity and tolerability of side effects) and then add in a
cannabinoid to determine if additional pain relief can be obtained. This
would begin the investigation of potential drug
4.8
combinations. As with any clinical study on analgesic drugs, it will
be important to investigate the development of tolerance and physical
dependence. These are not, of themselves, reasons to preclude the use
of cannabinoids as analgesics, but such information is essential to
the management of many drugs to which patients develop tolerance or
physical dependence.
A secondary question would be to determine whether THC is the only or
the best component of marijuana for analgesia. How does the analgesic
effect of the plant extract compare to that of THC alone? If there is
any difference, then it will be important to identify which combinations
of cannabinoids are the most effective analgesics.
In conclusion, the available evidence from both animal and human studies
indicates that cannabinoids can produce a significant analgesic effect.
One exception is the lack of analgesic effect in studies on experimentally-induced
acute pain, but because of limitations in the design of those studies
they were inconclusive. Further clinical work is warranted to establish
the magnitude of this effect in different clinical conditions and to determine
if the effect is maintained over time. Although the usefulness of cannabinoids
appears to be limited by side effects, notably sedation, there are other
effects, such as anxiolysis, appetite stimulation, and perhaps antinausea
and antispasticity effects that should be studied in randomized, controlled
clinical trials. It is this particular combination of effects that might
warrant development of cannabinoid drugs for certain clinical populations.
Nausea and Vomiting
Nausea and vomiting (emesis) occur under a variety of conditions such
as acute viral illnesses, cancer, radiation exposure, cancer chemotherapy,
postoperative recovery, pregnancy, motion, and poisoning. Both are produced
by excitation of one or a combination of trigger(s) located in the gastrointestinal
tract, brain stem and higher brain centers (figure 4.1, Emesis-stimulating
pathway). 129 There are numerous cannabinoid receptors in the
nucleus of the solitary tract, a brain center that is important in the
control of emesis. 83 84 Although the same mechanisms appear
to be involved in triggering both nausea and vomiting, one can occur without
the other. Much more is known about the neural mechanisms that produce
vomiting than nausea, in large part because the act of vomiting is a complex
behavior involving coordinated changes in the activity of the gastrointestinal
tract, respiratory muscles and posture, whereas nausea is a sensation
primarily involving higher brain centers and lacks a discrete observable
action.108, 130 Most reports on the antiemetic effects of marijuana
or cannabinoids are based on chemotherapy-induced emesis, they are the
subject of the following section.
4.9
FIGURE 4.1 Emesis-stimulating pathways
4.10
Chemotherapy-Induced Nausea and Vomiting
The use of effective chemotherapeutic drugs has produced cures in some
malignancies and retarded the growth of others. Unfortunately, nausea
and vomiting are frequent side effects of these drugs. Nausea ranks behind
only hair loss as a concern of patients on chemotherapy, and many patients
experience it as the worst side effect of chemotherapy. The side effects
can be so devastating that patients abandon therapy or suffer diminished
quality of life. As a result, the development of effective strategies
to control the emesis induced by many chemotherapeutic agents is a major
goal in the supportive care of patients with malignancies.
The mechanism by which chemotherapy induces vomiting is not completely
understood. Studies suggest that emesis is caused by stimulation of receptors
in the central nervous system or in the gastrointestinal tract. This stimulation
appears to be caused by the drug itself, a metabolite of the drug, or
a neurotransmitter. 6 13, 36, 50 In contrast with an emetic
like apomorphine, there is a delay between the administration of chemotherapy
and the onset of emesis. This delay depends on the chemotherapy agent;
emesis can begin anywhere from a few minutes after the administration
of an agent like mustine to an hour for cisplatin.13
The most desirable effect of an antiemetic is to control emesis completely,
which is currently the primary standard in testing new antiemetic agents
(R. Gralla, IOM workshop). Patients recall the number of emetic episodes
accurately, even with antiemetics that are sedating or that affect memory.
105 Thus the desired endpoint of complete control is also a
highly reliable method of evaluation. The degree of nausea can be estimated
through the use of established visual analog scales.a, 22, 59, 105
Another consideration for antiemetic drugs is that the frequency of
emesis varies from one chemotherapeutic agent to another. For example,
cisplatin causes vomiting in more than 99 percent of patients who are
not taking an antiemetic, with approximately 10 vomiting episodes per
dose of cisplatin; whereas methotrexate causes emesis in fewer than 10
percent of patients.59 36, 87 Among chemotherapy agents, cisplatin
is the most consistent emetic known and has become the benchmark for judging
antiemetic efficacy.. To date, antiemetics that are effective with cisplatin
are at least as effective with other chemotherapy agents. Lastly, controlling
for factors such as the influence of prior chemotherapy and balancing
predisposing factors (i.e., gender, age, and prior heavy alcohol usage)
among study groups is vital for reliability. Additionally, reliable randomization
of patients and blinding techniques (easier when there are no psychoactive
effects) are necessary to evaluate e control of vomiting and nausea.
a The visual analog scale is a continuous line representing
all possible levels of a particular sensation. It is an estimation of
a patient's subjective evaluation and not a true measurement. Patients
select a point anywhere on the line to demonstrate the level of sensation
they are experiencing, with one end representing one extreme, such as
no sensations and the other end representing the opposite extreme, such
as a maximum level of that sensation.
4.11
THC/Marijuana Therapy for Chemotherapy-Induced Nausea and Vomiting
Cannabinoids are mildly effective in preventing emesis in some patients
receiving cancer chemotherapy. Several cannabinoids have been tested as
antiemetics, including THC (both  9THC and
8THC) arid two synthetic cannabinoids, nabilone and
levonantradol. In addition, smoked marijuana has been examined.
Antiemetic Properties of THC
The quality and usefulness of antiemetic studies depend on adherence
to the methodological considerations outlined above. Many of the cannabinoid
clinical experiences reported are not based on definitive experimental
methods. In studies where THC was compared to placebo, THC was usually
found to possess antiemetic properties. However, the chemotherapy drug
used varied in most of the trials, and some of the studies consisted of
small numbers of patients. In one study, THC was found to be superior
to placebo for patients receiving chemotherapy with methotrexate, an agent
that is not a strong emetic.19 The same investigators found
only a weak antiemetic effect of THC in a small number of patients receiving
anthracyclines, chemotherapy drugs that more likely to cause emesis than
methotrexate.20
Other trials compared the efficacy of THC with that of prochlorperazine
(Compazine®).145, 163 Compazine® was one of the more
effective antiemetics available in the 1980s, but it was not completely
satisfactory and the search for better agents continued. THC and prochlorperazine
given orally showed similar degrees of efficacy, but those studies often
used various chemotherapeutic agents, even when administered in combination,
THC and prochlorperazine failed to stop vomiting in two-thirds of patients.54
In a carefully controlled double-blind study comparing THC and the antiemetic
drug, metoclopramide, in which no patient had previously received chemotherapy
so anticipatory emesis was not a factor, all patients received the same
dose of cisplatin' and the subjects were randomly assigned to each group
(THC or metoclopramide). Complete control of emesis occurred in 47 percent
of those treated with metoclopramide, as opposed to 13 percent of those
treated with THC.62 Major control (two or fewer episodes) occurred
in 73 percent of the patients given metoclopramide compared to 27 percent
of those given THC. Despite many flaws in experimental methods, those
results suggest that THC reduces chemotherapy-induced emesis.19,
20, 54 164 The studies also indicate that the degree of efficacy
is not high. In 1985. the FDA approved THC in the form of dronabinol for
this treatment (discussed in chapter 5).
The THC metabolite, 11-OH-THC, is more psychoactive than THC but is
a weaker antiemetic.123 Thus it might be possible to design
antiemetic cannabinoids without the psychological effects associated with
marijuana or THC.  8-THC is
less
4.12
psychoactive than THC 153, but was found to completely block
both acute and delayed chemotherapy-induced emesis in a study of eight
children, aged 3-13 years. b Two hours before the start of each cancer
treatment and every six hours thereafter for 24 hours, the children
were given 8THC as oil
drops on the tongue or an a bite of bread (18 mg/m2 body
surface area). The children received a total of 480 treatments. The
only side effects reported were slight irritability in two of the youngest
children (aged 3.5 and 4 years). Based on the prediction that the THC-induced
anxiety effects would be less in children than in adults, the authors
used doses that were higher than those recommended for adults (5-10
mg/m2 body surface area).
Antiemetic Properties of Synthetic THC Analogues
Nabilone (Cesamet®) and levonantradol were tested in a variety of
settings, with results similar to those with THC. While efficacy was observed
in several trials, no advantage emerged for these agents. 179, 189
As with the THC trials, nabilone and levonantradol reduced emesis, but
not as well as other available agents in moderately to highly emetogenic
settings. Neither is commercially available in the United States.
Antiemetic Properties of Marijuana
Among the efforts to study marijuana a preliminary study was conducted
in New York State on a group of 56 cancer patients who were unresponsive
to conventional antiemetic agents.192 These patients were asked
to rate the effectiveness of marijuana compared with results during prior
chemotherapy cycles. Seventy-eight percent of patients in this survey
rated marijuana as "moderately effective" or "highly effective."
The authors concluded that marijuana had antiemetic efficacy, but its
relative value was difficult to determine because no control group was
used and the patient population was varied with respect to previous experiences,
such as prior marijuana use and THC therapy.
A Canadian oncology group conducted a double-blind, cross-over, placebo-controlled
study comparing smoked marijuana with THC given in pill form to 20 patients
receiving a variety of chemotherapeutic drugs. 111 The degree
of emetic control was similar, with only 25 percent of the patients achieving
complete control of emesis. Thirty-five percent of the patients indicated
a slight preference for the THC pills over marijuana; Twenty percent preferred
marijuana and 45 percent expressed no preference.111
b Note that the authors of this study chose to use 8-THC because
it is more stable and easier to produce than 9-THC; it
does not follow from this particular study that marijuana, with its
mixture of cannabinoids, should be a more powerful antiemetic than 9-THC.
4.13
Neither study showed a clear advantage for smoked marijuana over oral
THC, but neither reported data on the time course of antiemetic control,
possible advantages of self-titration with the smoked marijuana, or the
degree to which patients were able to swallow the pills. Patients with
severe vomiting would have been unlikely to be able swallow or keep the
pills down long enough for them to take effect. The onset of drug effect
is much faster with inhaled or injected THC than it is for oral delivery.91,
114, 143 Although many marijuana users have claimed that smoked
marijuana is a more effective antiemetic than oral THC, no controlled
studies have yet been published that analyze this in sufficient detail
to estimate the extent to which that this is the case.
Side Effects Associated with THC/Marijuana in Antiemetic
Therapy
Frequent side effects associated with THC and marijuana include dizziness,
dry mouth, hypotension, moderate sedation, and euphoria or dysphoria.
The side effects seen with smoking marijuana include dizziness, dry mouth,
confusion, and anxiety. 19, 20, 54, 111, 145, 163 179, 189
Dry mouth and sedation are the least troubling side effects to patients.
Perhaps the most troubling side effects are orthostatic hypotension and
dizziness, which could enhance the patient's distress.
There is disagreement as to whether the psychoactive effects of THC
correlate with its antiemetic activity. In the prospective double-blind
trial comparing THC and metoclopramide, the authors report no relationship
between the occurrence of complete antiemetic control and euphoria or
dysphoria. 62 In contrast, other investigators believe that
such psychoactive effects (euphoria or dysphoria) are often associated
with improved antiemetic control. 163 Nevertheless, consensus
exists among most investigators that dysphoric effects are more common
among patients who have not had prior experience with cannabinoids. An
important and unexpected problem encountered in the New York State open
trial with marijuana was the inability of nearly one-quarter of the patients
to tolerate the administration of marijuana by smoking. 192
This intolerance could be due to inexperience with smoking marijuana and
is an important consideration.
Therapy for Chemotherapy-Induced Nausea and Vomiting
Present Therapy
New classes of antiemetics have emerged over the last ten years. They
have dramatically reduced the nausea and vomiting associated with cancer
chemotherapy and literally transformed the acceptance of cisplatin by
cancer patients. These new antiemetics, including selective serotonin
type 3 receptor antagonists, substituted benzamides, corticosteroids,
butyrophenones, and phenothiazines, have few side effects when given on
a short-term basis and are convenient in a variety of clinical settings.
The most effective commonly used antiemetics are serotonin receptor
antagonists (i.e., ondansetron, granisetron) with or without corticosteroids.
38, 60, 92, 147, 157
In a combination trial using dexamethasone (corticosteroid) and a serotonin
4.14
antagonist, complete control of acute cisplatin-induced emesis was
observed in about 75 percent of patients. In tests where the chemotherapy
was only moderately emetogenic, as many as 90 percent of the patients
who received these combinations achieved complete control of emesis.
Side effects of those antiemetic agents include headache, constipation
and alterations in liver function, but are generally well tolerated
by most patients. 14
Other commonly used antiemetics include phenothiazines (i.e., prochlorperazine
[Compazine®], haloperidol) and metoclopramide. Metoclopramide is somewhat
less effective than the serotonin antagonists, and has more side effects
including acute dystonic reactions, drowsiness, diarrhea, and depress
ions.14, 38 Side effects associated with phenothiazines include
severe or acute dystonic reactions, hypotension, blurred vision, drowsiness,
dry mouth, urinary retention, allergic reactions, and occasional jaundice.
14
SIDEBAR: Attitudes of Oncologists Toward Prescribing Marijuana
In the 1990s two groups of investigators conducted three surveys on
the attitudes of clinical oncologists toward prescribing marijuana as
an anti-emetic. These studies are arguably out of date, because the antiemetics
that are available now are so much more effective than they were when
these studies were conducted. Nonetheless, the studies merit attention
because they are still frequently cited as evidence for or against the
use of marijuana as an antiemetic.
The results of the two groups were contradictory. In 1994, by which
time serotonin receptor antagonists (5-HT receptors had become available,
Schwartz and Beveridge174 concluded that oncologists had little
interest in prescribing marijuana to control emesis, whereas Doblin and
Kleiman concluded in 1991 that interest was great.40 Since
1994 the two groups have debated in the literature as to which study represents
the true sentiment among oncologist.39, 175, 180 In fact. there
are numerous methodological differences between the two studies that might
explain the different results.39, 175 Nonetheless, ultimately
these studies are irrelevant. Both studies deal with perceptions rather
than pharmacological realities based on well-designed outcome studies.180
The cost of effective antiemetic regimens can vary markedly depending
on the agent, dose, schedule and route of administration. Overall, oral
regimens cost less than intravenous regimens due to lower pharmacy and
administration costs, as well as lower acquisition costs in many countries.
Regimens costing (to the pharmacy) as low as $30 to $35 per treatment
session have been shown to be effective.61 These costs reflect
the treatment of acute emesis and delayed emesis, with the use of generic
agents where available.
Major progress, generally not well-known to the public, in controlling
chemotherapy-induced acute nausea and vomiting has been made since the
1970s. Patients receiving the most difficult to control emetic agents
now have no more than a 20-30 percent likelihood of experiencing acute
emesis,157 whereas in the 1970s the likelihood was nearly 100
percent despite antiemetics.59, 90 As has been seen, most
4.15
antiemetic studies with cannabinoids present methodological difficulties
and are inconclusive. If one concentrates on the well-conducted trials,
the evidence indicates that cannabinoids reduce emesis in about one
quarter of patients receiving cancer chemotherapy Cannabinoids are not
as effective as several other classes of agents, such as substituted
benzamides, serotonin receptor antagonists and corticosteroids. The
side effects associated with cannabinoid use are generally tolerable.
As with cannabinoids, efficacy was apparent with smoked marijuana, but
the degree of efficacy was no better than that seen with available antiemetic
agents now considered to be marginally satisfactory. At present, the
most effective antiemetic regimens are combinations of oral serotonin
receptor antagonists with dexamethasone in single dose regimens given
prior to chemotherapy. Neither multiple dose regimens nor intravenous
antiemetics provide better control, and both add unnecessary costs.
63, 85
Future Therapy
Advances in therapy for chemotherapy-induced nausea and vomiting will
require discovery of agents that work through different mechanisms than
existing antiemetics, including the serotonin antagonists. Among the proposed
new pathways, agents that involve the neurokinin receptors (NK-1 antagonists)
appear to be the most promising.c In animal models, agents
that block the NK-1 receptor prevent cisplatin-induced emesis. At the
time of this writing, clinical trials with NK-1 receptor antagonists are
underway (phase II or small phase III comparison studies) Preliminary
results indicate that these agents have useful activity in both acute
and delayed chemotherapy-induced emesis and are safe to administer orally.106,
137
It is theoretically possible, considering that the mechanism of cannabinoid
action appears to be different than that of the serotonin receptor antagonists
and of corticosteroids, that added to more effective regimens, THC might
enhance control of emesis. Such combinations should aim to be as convenient
as possible while having few added side effects. The critical issue is
not whether marijuana or cannabinoid drugs might be superior to the new
drugs, but rather whether there is a group of patients who might obtain
added or better relief from marijuana or cannabinoid drugs.
Finally, even with the best antiemetic drugs, the control of nausea
and vomiting that begins or persists 24 hours after chemotherapy remains
imperfect. The pathophysiology appears different than that of acute emesis
and it is more likely to occur with a strong emetic agent, hut it varies
from patient to patient. Treatment to prevent this emesis requires dosing
after chemotherapy as well as before.107
c Neurokinin receptors are found in brain and the gut and
thought to be involved in motor activity, mood, pain, and reinforcement.
They may well be involved in mediating gut sensations, including nausea.
4.16
Conclusions and Recommendations: Chemotherapy-induced
nausea
Most chemotherapy patients are unlikely to want to use marijuana or
THC as an antiemetic. In 1998, there are more effective antiemetic agents
available than were available earlier. By comparison, cannabinoids are
only modest antiemetics. However, since modern antiemetics likely act
through different mechanisms, cannabinoids might be effective in people
who respond poorly to currently used antiemetic drugs, or cannabinoids
might be more effective in combination with the new drugs than either
are alone. For both reasons, studies of the effects of adjunctive cannabinoids
on chemotherapy-induced emesis are worth pursuing for patients whose emesis
is not optimally controlled with other agents.
While some people who spoke to the IOM study team described the mood
enhancing and anxiety reducing effects of marijuana as a positive contribution
to the antiemetic effects of marijuana, one-quarter of the patients in
the New York State study described earlier were unable to tolerate smoked
marijuana. Overall, the effects of oral THC and smoked marijuana are similar,
but there are differences. For example, in the residential studies of
experienced marijuana users by Haney and coworkers, subjects reported
that marijuana made them feel "mellow," 175 whereas
comparable doses of oral THC did not.74 Such differences might
be due to the different routes of delivery of THC, as well as the different
mixture of cannabinoids found in the marijuana plant. As of this writing,
no studies have been published that weigh the relative contributions of
those different factors.
The goal of antiemetic medications is to prevent nausea and vomiting.
Hence, antiemetics are typically given before chemotherapy, in which case,
a pill is an effective from of drug delivery. However, in patients already
experiencing severe nausea or vomiting, pills are generally ineffective,
because of the difficulty in swallowing or keeping a pill down, and slow
onset of the drug effect. Thus an inhalation (but, preferably not smoking)
cannabinoid drug delivery system would be advantageous for treating chemotherapy-induced
nausea.
Until the development of rapid onset antiemetic drug delivery systems,
there will likely remain a subpopulation of patients for whom standard
antiemetic therapy is ineffective and who suffer from debilitating emesis.
It is possible that the harmful effects of smoking marijuana for a limited
period of time might be outweighed by the antiemetic benefits of marijuana,
at least for, patients for whom standard antiemetic therapy is ineffective
and who suffer from debilitating emesis. Such patients should be evaluated
on a case by case basis and treated under close medical supervision.
Wasting Syndrome and Appetite Stimulation
Wasting syndrome in acquired immune deficiency syndrome (AIDS) patients
is defined by the Centers for Disease Control as the involuntary loss
of more than 10 percent of baseline average body weight in the presence
of diarrhea or fever of more than 30 days that is not attributable to
other disease processes. 18 Anorexia, which is a loss of appetite,
can accelerate wasting by limiting intake of the necessary
4.17
nutrients. Both wasting (cachexia) and anorexia are common end-stage
features of certain fatal diseases such as AIDS as well as metastatic
cancers. In AIDS, weight loss of as little as 5 percent is associated
with decreased survival, and a body weight about one-third below ideal
body weight results in death.103, 161
There are two forms of malnutrition: starvation and cachexia Starvation
is the deprivation of essential nutrients and results from underlying
causes such as famine or poverty, malabsorption, and eating disorders
(e.g., anorexia nervosa). Starvation results in metabolic adaptations
that deplete body fat before losses of lean tissue. Cachexia, in contrast,
results from tissue injury such as trauma, infection, or tumor, and is
characterized by a disproportionate loss of lean body mass, such as skeletal
muscle. 98
The key distinguishing factor between starvation and cachexia is that
the effects of starvation can usually be reversed by providing food regardless
of the cause of starvation, while the effects of cachexia can be reversed
only through control of the underlying disease, and at least for some
patients drugs that stimulate metabolism, such as growth hormone or androgenic-anabolic
hormones.
Malnutrition in HIV-Infected Patients
By 1997, there were more than 30 million people worldwide infected with
human immunodeficiency virus (HIV), and this number is predicted to increase
to almost 40 million by the year 2000. 128, 190 Malnutrition
is common among AIDS patients and plays an independent and significant
role in morbidity and mortality.99
Because treatment for malnutrition depends on whether it is caused by
starvation or cachexia, one needs to know what effects HIV infection has
on metabolic processes. The answer depends on the clinical situation and
can be either or both.98
The development of malnutrition in HIV infection has many facets. Malnutrition
in HIV-infected patients results in a disproportionate depletion of body
cell mass,d total body nitrogen, and skeletal muscle mass --
consistent with cachexia.101, 198 Body composition studies
show that the depletion of body cell mass precedes the progression to
AIDS (i.e., falling CD4 lymphocyte counts), suggesting that malnutrition
can be a consequence of the inflammatory response to the underlying viral
infection, rather than a general complication of AIDS.146 In
contrast, weight loss is often episodic and related to acute complications
such as febrile opportunistic infections.115 Mechanisms underlying
wasting in HIV-infected patients vary depending on the stage of HIV infection
and on specific associated complications.
There are many reasons for decreased food intake among AIDS patients.
These include mouth, throat, or esophageal infections or ulcers (oropharyngeal
and esophageal pathology); adverse effects of medications;200
diarrhea; enteric infection,
d Body cell mass is the fat-free cellular mass. It is composed
of the cells of the muscle and organs, plus circulating hematopoietic
cells and the aqueous compartment of adipocytes. It is not fat, extracellular
water, or extracellular solids (such as tendons, etc.).
4.18
malabsorption; serious systemic infection; focal or diffuse neurological
disease; HIV enteropathy, depression; fatigue; and poverty. Nutrient
malabsorption is often the result of microorganism overgrowth or infection
in the gut, especially in the later stages of AIDS. 99, 159
Marijuana, THC, and in HIV-Infected Patients
Despite their frequency of use, there is little published information
about the effectiveness of marijuana or cannabinoids for the treatment
of malnutrition and wasting syndrome in HIV-infected patients. The only
cannabinoid evaluated in controlled clinical studies is THC, or dronabinol.
Short-term (6 weeks? and long term (1 year) therapy with dronabinol was
associated with an increase in appetite and stable weight, and in a previous
short-term (5 weeks) clinical trial in five patients, dronabinol was shown
to increase body fat by one percent.9, 10, 182 In 1992, the
FDA approved THC, under the trade Marinol®, as an appetite stimulant
for the treatment of AID related weight loss. Megestrol acetatee
(Meg ace), an appetite stimulant, is more effective than dronabinol in
stimulating weight gain, and there is no additive effect of dronabinol
when used in combination with megestrol acetate.187 HIV/AIDS
patients are the largest group of patients who use dronabinol. However,
some reject dronabinol because of the intensity of neuropsychologic effects,
an inability to easily titrate the oral dose, and the delayed onset together
with the prolonged duration of its action.3 There is evidence
to suggest that cannabinoids modulate the immune system (see chapter 2,
section on Cannabinoids and the Immune System), which might be a problem
in immunologically-compromised patients. No published studies have formally
evaluated the use of any of the other cannabinoids in AIDS wasting or
as an appetite stimulant.
Anecdotes abound that smoked marijuana is useful for the treatment of
HIV associated anorexia and weight loss.24, 66 Some individuals
report a preference for smoked marijuana over oral THC because it gives
them the ability to titrate the effects, depending on how much they inhale.
In controlled laboratory studies on normal, healthy adults, smoked marijuana
was shown to increase body weight, appetite, and food intake.49,
121 Unfortunately, there have been no controlled studies of the
effect of smoked marijuana on appetite, weight gain and body composition
in AIDS patients. At the time of this writing, Donald Abrams at the University
of California at San Francisco (UCSF) is conducting the first clinical
trial to test the safety of smoked marijuana in AIDS patients, and the
results are not yet available.
A major concern with marijuana smoking in HIV-infected patients is that
they might be more vulnerable than other marijuana users to immunosuppressive
effects of marijuana, or to the exposure of infectious organisms associated
marijuana plant material (see chapter 3, Marijuana Smoke).
e Megestrol acetate is a synthetic derivative of progesterone
that can stimulate appetite and cause significant weight gain when given
in high doses (320 to 640 mg/d) to AIDS patients.58
4.19
Therapy for Wasting Syndrome in HIV-Infected Patients
Present Therapy
Generally, therapy for wasting in HIV-infected individuals has focused
on appetite stimulants. Few therapies have proven successful in the treatment
of the AIDS wasting syndrome. The stimulant studied most is megestrol
acetate, which has been shown to increase food intake about 30 percent
over baseline for reasons that remain unknown. Its effect in producing
significant weight gain is dose-dependent, but the majority of the weight
gain is fat tissue, not lean body mass. Although the findings are still
preliminary, anabolic compounds, such as testosterone or growth hormone,
might be useful in preventing the loss of, or help in restoring, lean
body mass in AIDS patients. 11, 46, 68, 173 Additionally, enteral
and parenteral nutrition have been evaluated and shown to increase weight,
but again, the increase is more due to body fat than to lean body mass.
100, 102
Encouraging advances in the antiviral treatment of HIV infection coupled
with developments in the prophylaxis and therapy of opportunistic infections
have recently changed the outlook for the long-term health of HlV-infected
individuals. Death rates have halved, and the frequency of serious complications,
including malnutrition, has fallen markedly. 98, 135
Future Therapy
The primary focus of future therapies for wasting in HIV-infected patients
is to increase lean body mass as well as appetite. Active systemic infections
are associated with profound anorexia which is believed to be mediated
by cytokines that stimulate inflammation through their actions within
and outside the brain. 134 Cytokine inhibitors such as thalidomide
have been under investigation as potential treatments to increase lean
body mass and reduce malnutrition. Even though cannabinoids do not appear
to restore lean body mass, they might be useful as adjunctive therapy.
For example, cannabinoids could be used as an appetite stimulant in patients
with diminished appetite who are undergoing resistance exercises or anabolic
therapy to increase lean body mass. Additionally, cannabinoids could be
beneficial for a variety of effects, such as increased appetite while
reducing the nausea and vomiting caused by protease inhibitors, as well
as the pain and anxiety associated with AIDS.
Considering current knowledge about malnutrition in HIV infection, cannabinoids,
by themselves, will not likely be a primary therapy for this condition,
but might be useful in combination with other therapies. Specifically,
the proposed mechanism of action of increasing food intake, would most
likely be ineffective in promoting an increase in skeletal muscle mass
and functional capacity, the goal in the treatment of cachexia in AIDS
patients (D. Kotler, Columbia University, personal communication, 1998).
4.20
Malnutrition in Cancer Patients
Malnutrition in cancer patients compromises their quality of life and
contributes to the progression of their disease. Approximately 30 percent
of Americans will develop cancer in their lifetimes, of whom two-thirds
will die as a result of their disease. 5 Depending on the type
of cancer, 50-80 percent of patients will develop cachexia, and up to
50 percent of these patients will die, in part, as a result of cachexia.
12, 41 The cachexia appears to result from the tumor itself,
and cytokines (proteins secreted by the host during an immune response
to tumor? are likely important factors in this development. Cachexia does
not occur in all cancers, but generally occurs at the late stages of advanced
cancers, such as pancreas, lung, and prostate.
The only cannabinoid evaluated for treating cachexia in cancer patients
is dronabinol, which has been shown to improve appetite and promote weight
gain. 58 Present treatments for cancer cachexia are similar
to that for cachexia in AIDS patients. These treatments are usually indicated
at late stages of advanced disease, and include megestrol acetate and
enteral and parenteral nutrition. Megestrol acetate stimulates appetite
and promotes weight gain in cancer patients, although the gain is mostly
fat mass (reviewed by Bruera 1998 15 ). Both megestrol acetate
and dronabinol result in dose-related side effects that can be troublesome
for patients: megestrol acetate can cause hyperglycemia and hypertension,
and dronabinol can cause dizziness and lethargy. Cannabinoids have also
been shown to modulate the immune system (see chapter 2, Cannabinoids
and the Immune System)' which could be contraindicated for certain cancer
patients (both the chemotherapy and the cancer can be immunosuppressive).
Future treatments will probably depend on the development of methods
that block cytokine actions, and the use of selective 32-adrenergic receptor
agonists to increase muscle masses. 15, 77 Additionally, treatments
for cancer cachexia will most likely need to identify the patients' individual
needs, in that some patients might need only a cytokine inhibitor, while
others could benefit from combined approaches, such as an appetite stimulant
and ,B2-adrenergic receptor agonists. In this respect, cannabinoids such
as THC might prove useful as part of a combination therapy as an appetite
stimulant, antiemetic, analgesic and anxiolytic, especially for patients
in late stages of the disease.
Anorexia Nervosa
Anorexia nervosa, a psychiatric disorder characterized by distorted
body image and self-starvation, affects an estimated 0.6 percent of the
United States population, with a greater predominance in girls than boys.
5 The mortality rate is high, and response to standard treatments
is poor.
THC appears to be ineffective in treating this disease. In one study
it caused severe dysphoric reactions in 3 of 11 patients. 69
One possible explanation for the
4.21
dysphoria is that THC increases appetite and thus intensifies the mental
conflict between hunger and food refusal.14 malnutrition.199
Furthermore, such patients may have underlying psychiatric disorders
(schizophrenia, depression) in which cannabinoids might be hazardous
(see chapter 3 Psychological Harms).
Current treatments include psychological techniques to overcome emotional
or behavioral problems and dietary intervention to reverse the malnutrition.199
Pharmacological treatments such as antidepressants have been used in addition
to psychotherapy, but tend to lack the desired level of efficacy.34
Recently, alterations in a gene for one of the serotonin receptors have
been identified in some patients with anorexia nervosa. 47
The possibility of a genetic component presents a pathway for the development
of new drugs to treat this disease.
Recommendations
The profile of cannabinoid drug effects suggests that they are promising
for treating wasting syndrome in AIDS patients. Nausea, appetite loss,
pain, and anxiety are all afflictions of wasting and all can be mitigated
by marijuana Although there are medications that are more effective than
marijuana for these problems, they are not equally effective for all patients.
Thus we recommend the development and clinical testing of a rapid onset
(that is, within minutes) form of THC for such patients. We do not recommend
smoking. The long-term harms from smoking make it a poor drug delivery
system, particularly for patients with chronic illnesses.
Terminal patients raise different issues. For those patients, the medical
harms of smoking are of little consequence. For terminal patients suffering
debilitating pain or nausea and for whom all indicated medications have
failed to provide relief, the medical benefits of smoked marijuana might
outweigh the harms.
Neurological Disorders
Neurological disorders are those that affect the brain, spinal cord,
or peripheral nerves and muscles in the body. Marijuana has been proposed
most often as a source of relief for three general types of neurological
disorders: muscle spasticity, particularly for multiple sclerosis patients
and spinal cord injury victims; movement disorders, such as Parkinson's
disease, Huntington's disease, and Tourette's syndrome; and epilepsy.
Note that marijuana is not proposed as a cure for such disorders, merely
that it might relieve certain associated symptoms.
Muscle Spasticity
Spasticity is the increased resistance to passive stretch of muscles
and increased deep tendon reflexes. Muscles may also contract involuntarily
(flexor and
4.22
extensor spasms). In some cases these contractions are debilitating
and very painful, and require therapy to relieve the spasms and associated
pain.
There are numerous anecdotal reports that marijuana can relieve the
spasticity associated with multiple sclerosis or spinal cord injury, and
animal studies have shown that cannabinoids affect motor areas in the
brain -- areas that might influence spasticity 55, 82, 132, 171
Multiple Sclerosis
As the name implies, "multiple sclerosis" (MS) is a condition
in which multiple areas of the CNS are affected. Many nerve fibers become
demyelinated,f some are destroyed, and scars form (sclerosis)
resulting in plaques scattered throughout the white matter of the CNS.
MS exacerbations appear to be caused by abnormal immune activity which
causes inflammation and myelin destruction in the brain (primarily the
periventricular area), brain stem or spinal cord. The demyelination slows
or blocks transmission of nerve impulses and results in an array of symptoms
such as fatigue, depression, spasticity, ataxia (inability to control
voluntary muscular movements), vertigo, blindness, and incontinence. Approximately
90 percent of MS patients eventually develop spasticity. With an estimated
2.5 million MS patients worldwide, spasticity is a major concern for many
patients and physicians.136 Spasticity is variably experienced
as muscle stiffness, muscle spasms, flexor spasms, or cramps, muscle pain
or ache. The tendency for the legs to spasm at night (flexor spasms) can
interfere with sleep.
Marijuana is frequently reported to reduce the muscle spasticity associated
with this disease.66, 125 In a mail survey of 112 MS patients
that regularly use marijuana, patients reported that spasticity was improved
and the associated pain and clonus decreased.29 However, a
double-blind placebo-controlled study on postural responses in 10 MS patients
and 10 normal volunteers indicated that marijuana smoking impairs posture
and balance in MS patients as well as normal volunteers.65
Nevertheless, the 10 MS patients felt that they were clinically improved.
The subjective improvement, while intriguing, does not constitute unequivocal
evidence that marijuana relieves spasticity. Survey data do not measure
the degree of placebo effect, estimated to be as great as 30 percent in
pain treatments.124, 133 Furthermore, surveys do not separate
the effects of marijuana or cannabinoids on mood and anxiety from spasticity.
The effects of THC on spasticity were evaluated in a series of three
clinical trials testing a total of 30 patients.25, 150, 191
They were 'open trials,' which means the patients were informed before
treatment that they would be receiving THC. Based on patient report or
clinical exam by the investigator, spasticity was less severe after the
THC treatment. However, THC was not effective in all patients and frequently
caused unpleasant side-effects. Spasticity was also reported to be less
severe in a single case study after nabilone treatment (figure 4.2). 119
f Myelin is the lipid covering that surrounds nerve cell
fibers and facilitates the conduction of signals along nerve cells and
ultimately between the brain, spinal cord and the rest of the body.
4.23
FIGURE 4.2 Effect of nabilone on multiple sclerosis symptoms
4.24
FIGURE LEGEND 4.2
Figure 4.2 shows the results of an e-of-1 trial in which a 45-year-old
man with multiple sclerosis was given 4-week treatments alternately with
placebo and nabilone, which he received every second day.119
In this study design, the patient served as both experimental subject
and control; that is, his treatment sequence was: nabilone-placebo-nabilone-placebo.
This pattern of alternating treatment reduces the possibility that the
observed changes are unrelated to the drug and are not simply due to other
factors that changed with the passage of time. The results of this study
are consistent with the possibility that THC might relieve spasticity,
but this study, although more rigorous than many self-report studies for
psychoactive substances, still has problems.
First, although the patient could not distinguish the treatments at
the time of taking the pill, he felt sedated after the nabilone. Thus
it is not possible to know how much the expectation of relief contributed
to his perception of relief: Second, the study measured his perception
of pain in which spasticity is an important, but not the only, factor.
It is not possible to know to what extent nabilone affected the perception
of pain versus the stimulus that generated the pain -- in this case, involuntary
muscle contractions. Because it is unaffected by conscious control, the
frequency of nocturia is clearer evidence of the effect of THC, although
it might also represent how well the patient slept. This single case is
intriguing, but not definitive proof that THC can reliably relieve spasticity.
4.25
In general, the abundant anecdotal reports are not well-supported by
clinical data (summarized in table 4.1) But this is more due to the limitation
of the studies than to negative results. There are no supporting animal
data to encourage clinical research in this area, but there are also no
good animal models for spasticity in MS. Without an appropriate model,
studies to determine how marijuana or THC might relieve spasticity cannot
be conducted. Nonetheless, the survey results suggest that it would be
useful to investigate the potential therapeutic value of cannabinoids
in relieving symptoms associated with MS. Such research would require
the use of objective measures of spasticity such as the pendulum test.g
Since THC is mildly sedating, it is also be important to distinguish this
effect from anti-spasticity effects in any such investigations. Mild sedatives
such as Benadryl® or benzodiazepines would be useful controls for
studies on the ability of cannabinoids to relieve muscle spasticity. The
regular use of smoked marijuana, however, would be contraindicated in
a chronic condition such as MS.
g The pendulum test is an objective and accurate measure
of MS-induced spasticity. It is done by videotaping a patient who lies
supine on a table with his or her leg extending off the edge. The leg
is dropped and the resulting motion is mathematically analyzed by computer
to provide a quantitative measure of spasticity.
4.26
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