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8.1 Historical background
Cannabis has had a long history of medical and
therapeutic use in India and the Middle East (Grinspoon and
Bakalar, 1993; Mechoulam, 1986; Nahas, 1984) where it has
been variously used as an analgesic, anti-convulsant,
anti-spasmodic, anti-emetic, and hypnotic. Cannabis was
introduced to British medicine in the mid-nineteenth
century by O'Shaugnessy (1842) who had gained clinical
experience with the drug while an Army surgeon in India
(Mechoulam, 1986; Nahas, 1984). He recommended its use for
the relief of pain, muscle spasms, and convulsions
occurring in tetanus, rabies, rheumatism and epilepsy
(Nahas, 1984). Partly as the result of his advocacy,
cannabis came to be widely used as an analgesic,
anti-convulsant and anti-spasmodic throughout the middle
part of the 19th century in Britain and the USA.
The medical use of cannabis declined around the turn of
the present century. Because the active constituents of
cannabis were not isolated until the second half of the
twentieth century, cannabis continued to be used in the
form of natural preparations which varied in purity and,
hence in effectiveness. The use of cannabis was largely
supplanted by other pharmaceutically purer drugs, which
could be given in standardised doses to produce more
dependable effects. These included the opiates, aspirin,
chloral hydrate, and the barbiturates (Mechoulam, 1986;
Nahas, 1984). In the early part of the century, the medical
use of such crude cannabis preparations was further
discouraged by laws which treated cannabis as a "narcotic"
drug and severely restricted its availability. It finally
disappeared from the American pharmacopoeia in the early
1940s after the passage of the Marijuana Tax Act (Grinspoon
and Bakalar, 1993), although it continued to be used in
Australia into the 1960s (Casswell, 1992).
THC, the major psychoactive ingredient of cannabis, was
not isolated until 1964 (Goani and Mechoulam, 1964),
shortly before cannabis achieved widespread popularity as a
recreational drug among American youth. Its widespread
recreational use, and its symbolic association with a
rejection of traditional social values, undoubtedly
hindered pharmaceutical research into its therapeutic uses.
Consequently, the rediscovery of some of its traditional
therapeutic uses was largely serendipitous, as was the
discovery of some newer uses. For example, its value as an
anti-emetic agent in the treatment of nausea caused by
cancer chemotherapy seems to have been rediscovered by
young adults who had used cannabis recreationally prior to
undergoing chemotherapy for leukemia (Grinspoon, 1990).
From the mid-1970s some clinical research on the
therapeutic value of cannabis and cannabinoids was
undertaken. On the whole, however, this research has been
very thin and uneven, and, consequently, many of the claims
for the therapeutic efficacy of cannabinoids rely heavily,
and, in the case of rare medical conditions, solely upon
anecdotal evidence, that is, the testimonies of individuals
who claim to have derived medical benefit from its use
(e.g. Grinspoon and Bakalar, 1993; Randall, 1990), and
small numbers of cases reported by physicians (e.g. Consroe
et al, 1975; Meinck et al, 1989).
Evidence will be reviewed for the best-supported
therapeutic uses of cannabinoids. The review begins with
the evidence on the effectiveness of cannabinoids as
anti-emetic drugs for nausea caused by cancer chemotherapy,
and as agents to control intra-ocular pressure in glaucoma.
Briefer reviews are provided of the evidence in favour of
other putative therapeutic uses of cannabinoids which are
less well supported by clinical evidence, chief among which
are its uses as an anti-convulsant, an anti-spasmodic, and
an analgesic agent. The value and limitations of the
largely anecdotal evidence of efficacy in these latter
conditions will also be briefly considered. The review will
include a discussion of the controversy in the United
States about "marijuana rescheduling" which has coloured
much recent discussion of the issue. This controversy
concerns the vexatious issue of whether smoked cannabis
should be available for medical use in addition to
synthetic cannabinoids such as THC.
8.2 Cannabinoids as anti-emetic agents
Profound nausea and vomiting can be such serious
complications of chemotherapy and radiotherapy for cancer
that patients may discontinue potentially life-saving
treatment (Institute of Medicine, 1982). Although various
types of drugs (e.g. the phenothiazines) have been shown to
be effective in controlling nausea and vomiting in cancer
patients, substantial minorities of patients do not benefit
from these drugs. The seriousness of the problem of
chemotherapy-induced nausea, and the incomplete success of
existing treatments, prompted oncologists in the late 1970s
and early 1980s to take a particular interest in the
anti-emetic properties of cannabinoids (Institute of
Medicine, 1982).
8.2.1 Clinical trials
One of the earliest trials of the effectiveness of THC
as an anti-emetic was prompted by patient reports that
smoking marijuana relieved nausea and vomiting (Sallan et
al, 1975). In this study, 22 patients (10 males and 12
females, average age 30 years) with a variety of neoplasms
were studied. In 20 patients, the nausea and vomiting had
proven resistant to existing anti-emetic drugs. A
randomised placebo-controlled trial with crossover was
used, in which patients were randomly assigned to receive
oral THC (10mg per m2) and placebo in one of four different
orders (THC-placebo-THC; THC- placebo-placebo;
placebo-THC-placebo; placebo-THC-THC). Outcome was assessed
by grading patients' self-reports of nausea and vomiting
after THC and placebo into three categories: complete
response if there was vomiting after placebo but not after
THC; partial response if there was a greater than 50 per
cent reduction in nausea and vomiting after THC compared to
placebo; and no response if there was a less than 50 per
cent reduction in nausea and vomiting.
Ten patients completed all three courses of THC and
placebo and vomited on at least one trial. After excluding
one trial because of a variation in the chemotherapy dose,
there were 29 trails available for analysis, 14 of placebo
and 15 of THC. All 14 placebo trials resulted in no
response, while in the 15 THC trials there were five
complete responses, seven partial responses, and three no
responses. This difference was statistically significant
when full and partial responses were combined. Most
patients (13/16) reported a "high" after receiving THC, an
experience which was correlated with the anti-emetic
effect. The most common side-effect was somnolence which
curtailed activities for two to six hours in a third of
patients. Only two patients experienced any symptoms of
toxicity, (both after receiving 20mg doses of THC), namely,
visual distortions and hallucinations and depression
lasting several hours. Sallan et al reported "preliminary"
observations from several patients that smoking marijuana
produced an equivalent anti-emetic effect to oral THC.
A trial by Chang et al (1979) largely supported the
findings of Sallan et al. In this study 15 patients with
osteogenic sarcoma (10 males and five females, average age
24 years) served as their own controls in the course of
monthly high dose methotrexate therapy. They were assigned
to receive three THC and three placebo trials in randomised
order during six treatment sessions. THC (10mg per m2 of
body area) and placebo were administered orally five times
at three hourly intervals, beginning two hours before
chemotherapy. If the patients vomited, the remaining doses
of either THC or placebo were administered by smoking a
cigarette using a standardised smoking technique. The
effect of THC and placebo were assessed by nursing staff
who rated various endpoints (e.g. number of vomiting and
retching episodes, volume of emesis, degree and duration of
nausea) without being aware of which treatment patients had
received. Patient response was graded into three
categories: excellent (greater then 80 per cent reduction
after THC by comparison with placebo in each of these
endpoints); fair (greater than 30 per cent and less than 80
per cent reduction), and no response (less than 30 per cent
reduction).
The results showed that eight patients had an excellent
response, six a fair response, and one had no response. On
all endpoints THC produced a statistically significant
reduction in nausea and vomiting by comparison with
placebo. There was also a dose-response relationship
between blood levels of THC and the incidence of nausea and
patient reports of feeling "high". Generally, higher THC
blood levels were achieved when marijuana was smoked than
when THC was taken orally. There were few side effects
reported, with sedation being the most common (12/15
patients). Four patients experienced five dysphoric
reactions in the course of 281 THC drug doses (2 per cent),
none of which lasted more than 30 minutes, and all of which
were successfully managed with simple reassurance.
In a second phase of the study, four patients who had an
excellent response to THC in the first phase were retested
under double-blind conditions using two placebo trials in
the next 10 treatments. A small number of patients who had
a fair response were also studied using an increased dose
of THC. All patients showed a reduction in the average
anti-emetic benefit of THC, decreasing from excellent to
fair in the case of previous excellent responders, and from
fair to no response in the case of the fair responders.
Chang et al hypothesised that the decline in effect
reflected either the development of tolerance to the
effects of THC, or the development of conditioned nausea
and vomiting that was resistant to the anti-emetic effects
of THC.
Since these early studies, a large number of controlled
clinical studies have been conducted which compared the
effectiveness of THC with either a placebo or with other
anti-emetic drugs (see Carey et al, 1983; Poster et al,
1981; Levitt, 1986 for reviews). The results of this
literature have sometimes been unfairly described as
"confused" (e.g. Carey et al, 1983; Nahas, 1984). This
description betrays an unreasonably high expectation of the
consistency of results from studies which have generally
used small samples of heterogenous patients who have
received various forms of chemotherapy. It also ignores the
fact that the cross-over studies comparing the anti-emetic
effects of THC with placebo have generally reported greater
anti-emetic effects for THC than placebo (Poster et al,
1981); the single exception to this finding was a study
which had a sample size of only eight patients.
Comparisons of the effectiveness of oral THC with that
of existing anti-emetic agents have been less consistent
than the results of comparisons with placebo. Nonetheless,
the results have generally indicated that THC is at least
equivalent in effectiveness to the widely used anti-emetic
drug prochlorperazine (Carey et al, 1983; Levitt, 1986).
The inconsistencies in this case arise because some studies
have shown THC to be superior, probably because of the
practice in some trials of enlisting patients whose nausea
had previously proven resistant to prochlorperazine (Carey
et al, 1983).
The equivalence of THC and prochlorperazine has been
supported by the results of one of the largest and best
conducted studies (Ungerleider et al, 1982). In this study
214 patients with a variety of forms of cancer (carcinomas,
sarcomas, lymphomas and leukemias) were recruited if they
had already undergone chemotherapy and experienced nausea
and vomiting, or they were to receive a form of
chemotherapy which had a high emetic potential. Patients
were randomly assigned to receive a paired trial of either
oral THC followed by prochlorperazine or vice versa. The
dose of THC was dependent on body surface area (7.5mg if
less than 1.4m2, 10mg for 1.4 to 1.8m2, and 12.5mg for
greater than 1.8m2). Separate analyses were conducted on
three groups of patients: patients who received their
cancer chemotherapy on a single day some weeks apart
(N=98); patients who received their chemotherapy on a daily
basis over several successive days (N=41); and patients who
discontinued the trial after a single episode of either THC
or prochlorperazine. Outcomes were patient self-ratings of
nausea and vomiting, and a variety of mood states and
behaviours.
The results showed that there "were no statistically
significant differences in the anti-nausea/anti-emetic
effect of THC and prochlorperazine" (p640) in any of the
three patient groups, even though there were differences
between patients in the single- and multiple-day
chemotherapy regimens in the time course of the nausea.
There were differences in mood and behaviour between the
THC and prochlorperazine trials, with patients reporting
greater impairment of concentration and less social
interaction after receiving THC. There were also more side
effects from THC than prochlorperazine, with sedation,
sleepiness and mental clouding being the most common. There
was no difference in the frequency of panic attacks between
the two drugs. Despite these differences in side effects
there was a small patient preference in favour of THC as an
anti-emetic, with 41 per cent experiencing less nausea on
THC, 31 per cent experiencing less nausea on
prochlorperazine, and 29 per cent reporting no difference
in effectiveness. The effectiveness of THC was not related
to age or prior experience with marijuana, but it was
related to the experience of side effects, with patients
experiencing them reporting less nausea.
Given the wide variety of patients who have been studied
in terms of age and type of cancer, the wide variety of
chemotherapeutic agents that have been used to treat their
cancers, and the variety of different anti-emetics with
which THC has been compared, the fact that findings of
these studies are generally positive for THC is more
impressive than the apparent differences in outcome. The
positive results from the controlled trials also seem to be
borne out by clinical experience with cannabinoids in
managing cancer patients. A recent survey of a large sample
of American oncologists, for example, found that 44 per
cent of oncologists had recommended marijuana to at least
one cancer patient, and 64 per cent of these physicians
reported that it was successful controlling nausea in at
least half of their patients. Overall, just under half of
the oncologists in the sample (44 per cent) believed that
cannabinoids could be safely used in the treatment of
nausea caused by chemotherapy and radiotherapy (Dobin and
Kleiman, 1991). A similar proportion (48 per cent) reported
that they would prescribe marijuana for their patients if
it was legal.
The general conclusion on the available literature is
that THC is superior to placebo, and equivalent in
effectiveness to other widely-used anti-emetic drugs, in
its capacity to reduce the nausea and vomiting caused by
some chemotherapy regimens in some cancer patients. There
are a number of issues that remain to be resolved in
deciding upon the clinical role of cannabinoids as
anti-emetic agents in cancer chemotherapy. These issues
include: the types of nausea against which it may be most
effective, and hence the types of patients for which they
are most appropriately prescribed; the degree of patient
tolerance of the psychotropic side effects of THC and other
cannabinoids; the potential seriousness of possible THC
induced immunosuppression in patients who are already
immunologically compromised; the most effective dosing
schedules for THC as an anti-emetic; the potential use of
THC in combination with other anti-emetic drugs; and the
extent to which the motivation for the use of THC may have
been reduced by the availability of newer anti-emetic drugs
that are more effective than prochlorperazine (the main
anti-emetic drug in the 1980s).
8.2.2 Which patients?
Which patients with what types of nausea are the most
suitable for treatment with cannabinoids as anti-emetics?
Patients with various forms of cancer have been the most
extensively investigated patient group, but the numbers of
different types of cancer have been too small to allow
convincing analyses of differences in patient response. The
same point can be made about types of chemotherapy
regimens; they have varied widely in these studies, and
have often not been reported, but there has been no
systematic analysis of the effectiveness of cannabinoids in
controlling emesis produced by different agents. It is
uncertain to what extent the cannabinoids may be effective
against nausea from other causes. The mechanisms that
produce nausea are not well understood but there are
believed to be one or more protective mechanisms located in
the brain stem that can be triggered by a variety of emetic
agents. This raises the possibility that cannabinoids may
be therapeutically useful against nausea from a variety of
causes.
8.2.3 Side effects
The psychoactive effects of cannabis which are prized by
recreational users - euphoria, relaxation, drowsiness - are
not always welcomed by older patients, most of whom are
cannabis-naive. In some studies a substantial minority of
such patients have discontinued the use of THC because of
the unwelcome dysphoria and somnolence (Levitt et al,
1986). This has not been a universal experience, so further
research is required to discover to what extent this has
been the result of unnecessarily large doses, or poor
patient preparation for these effects, and failure to
adequately manage them by reassurance. What does seem to be
the case is that the experience of some psychological
effects of THC, including the "high", is necessary for the
occurrence of a clinically significant anti-emetic effect.
This fact has led to the search, so far unsuccessful, for
cannabinoid derivatives of THC which possess its
anti-emetic properties but not its psychoactive ones. The
recent discovery of the cannabinoid ligand and receptor,
and receptor subtypes (see pp7-8) has encouraged
researchers to believe that this may be an achievable goal
(Iversen, 1993).
A potentially more serious side effect of therapeutic
THC is its possible immunosuppressive effect. Any such
effect would limit its use as an anti-emetic in the
treatment of cancer, since cancer patients experience
immune suppression as a side effect of their treatment.
There are several reasons why this may be less serious an
issue that it seems at first glance. First, there are
doubts about the existence of any immunosuppressive effect
of cannabinoids (see Section 6.2 on the immune system,
pp62-68), and the effect is small in those studies which
report one. Second, the clinical significance of any such
effects is doubtful in the use of THC in cancer
chemotherapy. Such use would be intermittent, and
relatively short-term, and the possible gain in increased
life expectancy from being able to complete a course of
cancer chemotherapy is such that most patients would be
prepared to take the risk, in the same way that they chose
to undergo the highly toxic chemotherapy in the first
place.
8.2.4 Unresolved clinical issues
If THC has a place in the management of nausea from
cancer treatment (Poster et al, 1981), and perhaps other
causes, a number of clinical issues remain to be resolved
(Levitt, 1986). Foremost among these is the best way in
which to administer the drug. Should it be given well in
advance of treatment at low doses to ensure a stable blood
level, or should it be given in larger doses shortly before
chemotherapy or radiotherapy? This issue has not been
systematically studied (Levitt, 1986).
An additional question is whether there is any clinical
benefit to be derived from combining THC with existing
anti-emetic agents. There is suggestive evidence that there
might be, since the mechanisms of action, while not well
understood, appear to be different, raising the possibility
that there may be positive synergistic effects from the
combination of THC and other anti-emetics. One single-blind
study of the combination of dronabinol and
prochlorperazine, for example, suggested that the
combination of these drugs may have a superior anti-nausea
effect to either drug used alone (Plasse et al, 1991).
Clearly, more research is warranted on this issue,
especially as it may enable cannabinoids to be used as
anti-emetics at lower doses with fewer unwanted
psychotropic effects.
It seems surprising that the desirability of undertaking
research on dosing and combined use of cannabinoids was
highlighted by Poster et al in 1981 and by the Institute of
Medicine in 1982. Yet very little research has been done,
and THC has not been routinely incorporated into the
management of nausea caused by cancer chemotherapy. One of
the likely reasons has been the American controversy about
the rescheduling of marijuana under the Controlled
Substances Act, which some argue has discouraged clinical
research on cannabinoids (see below). Another reason has
been that the motivation for further research on the
anti-emetic properties of THC has been removed by the
recent development of newer anti-emetic drugs which are
superior to prochlorperazine (Iversen, 1993), the "gold
standard" drug when the major controlled trials were
conducted on cannabis in the 1970s and 1980s. In the
absence of trials comparing THC with these newer drugs, its
comparative efficacy is unknown, although given its
approximate equivalence to prochlorperazine it is likely to
be inferior to the newer drugs.
8.3 Cannabinoids as anti-glaucoma agents
Glaucoma is the leading cause of blindness in the United
States, affecting two million people and producing 300,000
new cases each year (Adler and Geller, 1986). It is a
condition "which is generally characterised by an increase
in intraocular pressure ... that progressively impairs
vision and may lead to absolute blindness" (Adler and
Geller, 1986, p54). Although its causes are not understood,
it is believed to involve an obstruction to the outflow of
the aqueous humour in the eye leading to a gradual increase
in intraocular pressure (IOP) which, if untreated, may
damage the optic nerve, resulting in blindness. Its
incidence increases over the age of 35, especially among
individuals who are myopic (i.e. short-sighted). Although
various drugs are available which reduce IOP, all possess
unwanted side-effects and patients may become tolerant to
their therapeutic effects.
The effects of cannabis in reducing IOP were discovered
serendipitously by researchers and patients in the early
and middle 1970s. Hepler and his colleagues (1971, 1976)
observed a substantial decrease in IOP while researching
the effects of cannabis intoxication on pupil dilation.
They demonstrated that both cannabis and oral THC produced
substantial reductions in IOP in both normal volunteers and
patients with glaucoma (Hepler and Petrus, 1976; Hepler et
al, 1976). Subsequent research identified THC as the agent
responsible for producing this effect (Adler and Geller,
1986).
Around the same time, patients with glaucoma who had
used cannabis recreationally also discovered its
therapeutic effects. One such patient, Robert Randall, used
cannabis daily to control his glaucoma. When arrested for
possession and cultivation of cannabis, he successfully
used the defence of "medical necessity" arguing, with the
support of his physicians, that he would go blind if he
stopped his cannabis use. He subsequently was given legal
access to cannabis for medical purposes (Randall Affidavit,
in Randall, 1988).
Although there have been a number of case reports of the
successful use of cannabis in the management of glaucoma
(e.g. Grinspoon and Bakalar, 1993; Randall, 1990), there
have not been any controlled clinical studies of its
effectiveness and safety in the long-term management of
glaucoma. Informed clinical opinion has been that THC is an
effective anti-glaucoma agent when used acutely, but there
are doubts about its effectiveness with chronic use because
of the development of tolerance to its effects on IOP
(Jones et al, 1981). Ophthalmologists who are opposed to
the clinical use of THC point to a number of major
disadvantages. First, because THC is not water-soluble, it
cannot, unlike other anti-glaucoma agents, be applied
topically to the eye to ensure that enough is absorbed to
produce a clinically significant reduction in IOP. Second,
as a consequence, THC must be absorbed systemically in
order to produce a therapeutic effect on IOP, which means
that patients must experience the psychoactive effects of
THC in order to derive its therapeutic benefits against
glaucoma. Third, because glaucoma is a chronic condition,
THC or cannabis would need to be taken in substantial doses
on a daily basis over long periods of time, if not for the
remainder of adult life. There has been an understandable
concern about the health risks of chronic daily cannabis
use (e.g. Hepler, 1990; American Academy of Ophthalmology,
1990).
The position adopted by the American Academy of
Ophthalmology has been to insist that cannabis has no
accepted medical use in the management of glaucoma, and
cannot have such medical use until a large controlled trial
has been conducted into its safety and effectiveness in
daily chronic use. There has been no evidence that the
Academy has any interest in, or has given any encouragement
to, the conduct of such a trial. Consequently, its position
is that THC and other cannabinoids should not be used be in
the management of glaucoma.
A contrary position has been taken by Randall, who has
argued that patients should be allowed to make the choice
between the uncertain health risks of chronic cannabis use
and the more certain risks to sight of poorly controlled
glaucoma:
"People with life- and sense-threatening diseases are
routinely confronted by stark choices ... [between] the
devastating consequences of a debilitating, progressive
disease ... [and] often highly damaging biological and
mental consequences of the toxic chemicals required to
check the progression of disease. .. Viewed in this medical
context, marihuana is more benign and far less damaging
that the synthetic toxins routinely prescribed by
physicians" (cited in Grinspoon and Bakalar, 1993,
p153)
8.4 Cannabinoids and neurological
disorders
8.4.1 Anti-convulsant
Historically one of the commonest medical uses of
cannabis preparations has been as an anti-convulsant.
O'Shaughnessy (1842), for example, recommended the use of
cannabis to control seizures in epilepsy, tetanus and
rabies (Nahas, 1984). Animal studies have provided some
support for this use in showing that THC has dual effects
on convulsions, i.e. they can produce convulsions in
susceptible animals, and suppress the maximum severity of
convulsions from a variety of causes, while cannabidiol
(CBD) appears to be a potent anti-convulsant (Chesher and
Jackson, 1974; Consroe and Snider, 1986; Institute of
Medicine, 1982).
Despite this animal evidence, there is very limited
evidence on the therapeutic effects of cannabinoids in
humans with epilepsy. There are a small number of case
studies of individuals with epilepsy in which the
recreational use of cannabis appeared to enhance the
anti-convulsant effects of more traditional anti-convulsant
medication (e.g. Consroe et al, 1975; Grinspoon and
Bakalar, 1993). There is a single randomised placebo
controlled study of the administration of CBD in 15
patients with epilepsy that was not well controlled by
conventional anti-convulsants. Four of the eight patients
who received CBD in addition to their usual anti-convulsant
drugs were free of seizures throughout the study period,
and three were improved. By contrast, only one out of seven
patients in the placebo condition showed any clinical
improvement (Cunha et al, 1980). Despite this suggestive
evidence of efficacy in epilepsy, CBD has not been widely
used in clinical management. Perhaps this is not surprising
given the absence of evidence of its efficacy, the
existence of other effective anti-convulsant drugs, and
concerns about the safety of chronic use in the management
of a chronic disease. It is perhaps more surprising that
there has been no further research on the anti-convulsant
properties of CBD, especially as it has no psychoactive
side effects (Nahas, 1984).
8.4.2 Anti-spasmodic
Cannabinoids have been used in an empirical way in the
management of some patients with movement disorders, a
variety of syndromes that have in common a deficit in
non-pyramidal motor control function, which is expressed in
usually one or more of the non-epileptic, abnormal
involuntary movements, such as those found in Parkinson's
disease, Huntington's disease, multiple sclerosis, and
spasticity. Although a number of drugs may be of benefit in
the management of these conditions, they are not always
effective, and may produce troublesome side-effects
(Consroe and Snider, 1986).
There has been some animal evidence which indicates that
THC and its analogues produce a broad spectrum of
neurological effects, which include alterations in motor
function, and changes in muscle tone and reflexes. The
acute motor effects in normal humans - ataxia,
tremulousness and subjective weakness - also suggest a
potential for therapeutic effects in some movement
disorders (Consroe and Snider, 1986).
The evidence that cannabinoids have therapeutic effects
in patients with movement disorders is largely anecdotal.
Grinspoon and Bakalar (1993), for example, present four
case histories of individuals with multiple sclerosis whose
condition improved while they smoked marijuana, and
deteriorated after they stopped smoking. Meinck et al
(1989) report a case history of a young man with multiple
sclerosis with severe limb and gait ataxia who complained
of erectile impotence. After smoking marijuana his gait
improved sufficiently to be able to walk unaided, and he
was able to achieve and sustain an erection. When cannabis
was withdrawn under medical supervision, the patient's
motor function deteriorated to the point where he was
unable to walk without assistance.
There has been one controlled study by Clifford (1983)
who examined the effects of THC on tremor in eight patients
(four male and four female) with advanced multiple
sclerosis who had ataxia and tremor. Five patients reported
subjective benefit from THC and there was objective
evidence of benefit in two of these cases. Single-blind
placebo challenge in these cases produced evidence that
their clinical condition deteriorated when given placebo
and improved with the reinstatement of THC.
Grinspoon and Bakalar (1993) described several case
histories of individuals with paraplegia and quadriplegia
who reported that cannabis use helped to reduce muscle
spasm. The experiences of these individuals were supported
by similar reports obtained from a survey of 43 individuals
with spinal cord injuries, 22 of whom reported that they
used cannabis to control their muscle spasm.
The only controlled trial of a cannabinoid in a movement
disorder has been an evaluation of the effects of CBD on
severity of chorea in patients with advanced Huntington's
disease (Consroe et al, 1991). This study was prompted by
the authors' observation that CBD had improved the
condition of an individual with Huntington's disease
(Sandyck et al, 1988). In this study 19 Huntington's
patients were enrolled in a double-blind controlled trial
in which they received six weeks administration of CBD or
placebo in a cross-over design. The outcome was the
severity of chorea, as assessed by blind clinical ratings,
patient self-report, and a variety of measures of motor
function. Although the study had sufficient statistical
power to detect a relatively small clinical benefit, there
was no evidence of improvement in chorea on any of the
clinical, self-report or motor measures. In the light of
Consroe et al's failure to replicate the earlier favourable
single case, further controlled trials are warranted before
any of the cannabinoids can be routinely used in treating
movement disorders.
8.5 Cannabinoids as anti-asthmatic
agents
Smoked cannabis, and to a lesser extent oral THC, have
an acute bronchodilatory effect in both normal persons and
persons with asthma (Tashkin et al, 1975; Tashkin et al,
1976). Tashkin et al (1975), for example, compared the
bronchodilator effect of smoked cannabis with that of a
standard clinical dose of the bronchodilator isoproterenol
in relieving experimentally induced asthma in asthmatic
patients. They found that smoking a 2 per cent-THC cannabis
cigarette produced a bronchodilator nearly equivalent to
that of a clinical dose of isoproterenol.
Despite this early suggestion of a therapeutic effect in
asthma, cannabinoids have not been used therapeutically,
nor have they been extensively investigated as
anti-asthmatic agents other than by Tashkin and his
colleagues (Tashkin, 1993). A major obstacle to therapeutic
use has been the route of administration. Oral THC produces
a smaller bronchodilator effect after a substantial delay,
and when used as an inhalant produces irritation and reflex
bronchoconstriction. Hence, smoking marijuana has been the
most dependable way of delivering a clinically effective
dose of THC. There is an understandable concern among
clinical researchers that smoking is an unsuitable mode of
administering any drug, and an especially inappropriate way
to administer a drug to patients with asthma, because it
would inevitably involve the delivery of other noxious
chemicals that would nullify its therapeutic value in the
short term, and carry an increased risk of other
respiratory disease and possibly cancer in the long term
(Tashkin, 1993). The unwanted psychotropic effects from
marijuana smoking have also been a barrier to its use as an
anti-asthmatic drug. Some investigators (e.g. Graham, 1986)
have nonetheless argued that the suitability of THC as a
spray should be further investigated because of the
possible hazards of the chronic use of the more widely-used
beta-blocker antagonists. The recent discovery of the
cannabinoid receptor and ligand may prompt a re-examination
of this question.
8.6 Cannabinoids as analgesics
There is some animal evidence that THC has an analgesic
effect which operates via a different mechanism from that
of the opioid drugs (Segal, 1986). There is a small amount
of human experimental studies which have reported mixed
evidence of an analgesic effect (Nahas, 1984). There has
been little clinical evidence beyond historical use for
various forms of chronic pain, including migraine,
dysmenorrhoea, and neuralgia, and the small number of case
histories of its use in chronic pain, dysmenorrhoea, labour
pain, and migraine reported by Grinspoon and Bakalar
(1993).
Only one double-blind controlled cross-over study has
been reported. This study compared the analgesic effect of
THC and codeine in patients with cancer pain (Noyes et al,
1975). The findings suggested that 20mg of THC was of
equivalent analgesic effect to 120mg of codeine. However,
neither drug produced substantial analgesia in these
patients, and the majority of patients found the
psychotropic effects of 20mg of THC sufficiently aversive
that they discontinued its use. Clearly, much more basic
pharmacological and animal investigation is required before
cannabinoids or their derivatives have any clinical use as
analgesics. Nevertheless, such investigations may be worth
pursuing because of the dependence potential of the more
potent opioid analgesics, and the likelihood that any
cannabinoid mediated analgesic effect operates by a
different mechanism to that of the opioids.
8.7 Other possible therapeutic uses
A variety of other therapeutic uses have been suggested,
although few have been investigated in any depth. In the
late 1940s, for example, there were some investigations of
the therapeutic uses of the euphoriant properties of
cannabis, as a possible anti-depressant agent in the form
of synhexil, a synthetic cannabis analogue. The results in
one uncontrolled study were positive, but these were not
replicated in later studies using lower doses (Nahas, 1984;
Grinspoon and Bakalar, 1993). None of these suggestions
have been further investigated, probably because of the
potential for THC to produce dysphoric and other unwanted
psychotropic side effects.
8.8 Cannabis and AIDS
One of the areas of greatest contemporary interest in
the therapeutic uses of cannabinoids and cannabis has been
their possible roles as an anti-nausea agent, an appetite
stimulant and an analgesic in patients with AIDS (Randall,
1989). The development of this interest seems to have
replicated the earlier discovery of the anti-emetic effects
of cannabis in young cancer patients in the 1970s. AIDS
patients often experience nausea and weight loss, either
while receiving cytotoxic drugs to suppress HIV, or as a
direct effect of the AIDS spectrum diseases. Many patients
have been recreational cannabis users, and so have reported
that the smoking of marijuana produces a diminution in
their nausea, an increased appetite, reduced pain, and
general improvements in well being. AIDS advocacy groups
have accordingly argued that marijuana should be made
legally available to AIDS patients (e.g. Randall,
1991).
So far the bulk of evidence for these therapeutic claims
has been provided by case reports (see Randall, 1989).
There has been one small uncontrolled study of 10
symptomatic AIDS patients which suggested that dronabinol
(synthetic THC) may be effective in reducing nausea and
stimulating appetite (Plasse et al, 1991). The evidence of
its anti-emetic properties in cancer patients seems to
support its potential application in AIDS treatment, and is
deserving of further investigation.
A potential concern with the use of cannabinoids in HIV
positive individuals and AIDS patients is the possible
immunosuppressive effects of cannabinoids. Although, as
argued above, this effect is likely to be small and of
limited concern when used intermittently in cancer
patients, it is of potentially greater significance in AIDS
patients, since cannabis would be used regularly by
patients with a major immune system disorder. Even a small
impairment in immunity may have major consequences for HIV
and AIDS affected individuals. Recent epidemiological
evidence does something to allay this concern. A large
prospective cohort study of HIV/AIDS in homosexual and
bisexual men recently failed to find any relationship
between cannabis use, or any other psychoactive drug use,
and the rate at which HIV positive men developed clinical
AIDS (Kaslow et al, 1989). Nonetheless, the issue of
immunosuppression needs to be explicitly investigated in
any research which is undertaken into the therapeutic uses
of cannabinoids in the treatment of AIDS.
8.9 The limitations of anecdotal
evidence
Much of the case for the therapeutic uses of
cannabinoids as other than anti-emetic agents depends upon
anecdotal evidence from case histories. Such evidence has
justifiably come to be distrusted as evidence of
therapeutic effectiveness in clinical medicine, especially
in the case of chronic conditions which have a fluctuating
course of remission and exacerbation. In such diseases, it
is difficult to exclude alternative explanations of any
apparent relationship between the use of a drug (e.g. THC)
and an improvement in a patient's condition. Among the
alternative explanations that are most difficult to exclude
in a single case or even a succession of single cases is
simple coincidence: that is, there may be no relationship
between the use of the drug and improvement; the apparent
relationship between the two may have arisen because the
use of the drug preceded an improvement in the patient's
condition that would have occurred in its absence. This is
especially likely to occur in a chronic condition with a
fluctuating course. In addition, the well-known placebo
effect which is observed in many conditions may explain the
apparent benefits of a drug or other treatment. It is for
these reasons that this review has relied upon evidence
from controlled clinical trials in appraising the
therapeutic uses of cannabinoids.
Grinspoon and Bakalar (1993) have attempted to defend
anecdotal evidence of therapeutic efficacy of cannabinoids.
They argue that a double standard has been used in the
appraisal of the safety and efficacy of cannabinoids:
anecdotal evidence of harm has been readily accepted while
anecdotal evidence of benefit has been discounted. Although
at first glance "double standards" may seem to describe the
behaviour of the regulatory authorities, it is defensible
to use different standards of proof when evaluating the
benefits and the costs of therapeutic drugs. It is
reasonable to err on the side of caution by requiring
stronger evidence of benefit from putatively therapeutic
drugs in order to ensure that the possible risks incurred
by their therapeutic use do not outweigh their benefits.
Moreover, this behaviour is not peculiar to the therapeutic
appraisal of cannabinoids; it is standard practice in the
therapeutic appraisal of all drugs. Medical practitioners
are encouraged to report cases histories of possible
adverse effects of prescribed drugs. Such reports are
treated as a noisy but necessary way of detecting rare but
serious side effects of drugs that have not been detected
in clinical trials or animal studies.
8.10 The politics of therapeutic cannabinoid
use
A puzzle in the field of cannabinoid therapeutics is
that despite the positive appraisal of the therapeutic
potential of cannabinoids as anti-emetics and anti-glaucoma
agents, they have not been widely used. Nor has the
detailed type of clinical pharmacological research been
undertaken on optimal methods of clinical use in those
areas where the cannabinoids do have therapeutic potential
(e.g. as anti-emetics). Part of the reason for this is that
research on the therapeutic use of these compounds has
become a casualty of the debate in the United States about
the legal status of cannabis. This emerges from an
inspection of the arguments recently advanced for and
against an application to the United States Drug
Enforcement Agency to change the status of marijuana under
the Controlled Substances Act, 1970 from a schedule I drug
which has no accepted medical use to a schedule II drug
which has an accepted medical use (see Randall, 1988, 1989,
1990).
The proponents of rescheduling (National Organisation
for the Reform of Marijuana Laws, Alliance for Cannabis
Therapeutics, and Cannabis Corporation of America) have
argued that marijuana should be available for medical use,
as smoking is the most effective mode of delivering THC for
some therapeutic purposes. The opponents of rescheduling
(Drug Enforcement Agency, International Chiefs of Police,
The National Federation of Parents for a Drug Free Youth)
have countered that marijuana has no therapeutic use, since
its few uses are better met, either by other more effective
drugs which do not have the psychoactive effects of THC, or
by the oral delivery of synthetic cannabinoids. They have
been supported by medical researchers and practitioners who
argue for the therapeutic superiority of pharmaceutically
pure drugs which can be given in defined doses (e.g.
Levitt, 1986; Mechoulam, 1988; Nahas, 1984).
Medical researchers who have supported the rescheduling
of marijuana (e.g. Grinspoon and Bakalar, 1993; Merritt,
1988; Mikuriya, 1990; Morgan, 1990; Weil, 1988) have argued
that smoked cannabis is superior to oral synthetic
cannabinoids in effectiveness and has a lower risk of
producing unwanted psychoactive side-effects. Apart from
the unsuitability of oral medication for patients who are
vomiting, their main arguments in favour of smoking as a
route of THC administration are similar to the reasons
recreational users often give for preferring smoking to the
oral use of cannabis. The greater bioavailability of THC
via smoking produces a more dependable therapeutic effect,
which is more easily controlled because users have a
greater ability to titrate their dose, and hence, to
maximise the desired effects while minimising the
unpleasant effects. An additional argument sometimes used
is that there may be other cannabinoids present in the
crude plant product which modulate the undesired side
effects, including the unpleasant dysphoric effects of THC
(Grinspoon and Bakalar, 1993). There is also suggestive
evidence that smoked cannabis is as effective as oral THC,
and may be preferred by patients because of the greater
control they have over dose (Chang et al, 1979).
Opponents of marijuana rescheduling argue that the
undesirable psychoactive side effects of THC disqualify it
from widespread medical use, whatever the route of
administration. Most also believe that smoking is a
medically unacceptable route of administration of THC
because it is unsuitable for very young and very old
patients, there is a risk of infection with micro-organisms
which may contaminate the plant material, and there is the
danger that chronic smoke inhalation may produce or
exacerbate bronchitis, and expose the user to carcinogens
(e.g. Levitt, 1986; Mechoulam, 1988; Nahas, 1984).
The proponents of rescheduling respond that none of
these are compelling reasons for rejecting smoked marijuana
for therapeutic purposes until more potent and specific
therapeutic cannabinoids have been identified and
synthesised. Smoking, they point out, would not be a
compulsory method of administration; only an option for
those patients who preferred it, as would the use of
cannabinoids if patients did not like their psychoactive
effects. The contamination of micro-organisms reported with
blackmarket cannabis can be overcome, they argue, by
standardising dose and using an anti-microbial treatment,
as has been done by National Institute on Drug Abuse (NIDA)
in preparing cannabis cigarettes for research (Randall,
1988). The risks of bronchitis and respiratory tract
cancers, it is argued, are small with the intermittent and
time-limited smoking of cannabis that would occur in the
course of cancer chemotherapy. In any case, proponents of
rescheduling argue, it is probably a risk that many
patients with a life-threatening illness may be prepared to
run, as shown by their preparedness to take highly toxic
and carcinogenic anti-cancer agents.
Weil (1988) has argued that some opponents have used
double standards in appraising the risks of marijuana
smoking. According to Weil, the most common psychoactive
effects of marijuana (euphoria, somnolence and dysphoria)
are minor, non-life-threatening and self-limiting effects
that can be easily managed, and are of much less severity
than the side effects of many other widely-used therapeutic
drugs. Medical witnesses for the government, he claims, "do
not contrast marijuana's supposed adverse effects with the
known adverse effects of drugs routinely prescribed for the
treatment of conditions like cancer, glaucoma and multiple
sclerosis. Instead, ... [they] compare marijuana to some
abstract, unobtainable standard of perfection" (p437).
Merritt (1988) has made a similar point in criticising
the arguments raised against the therapeutic use of
marijuana to manage glaucoma: " ... each drug family used
in glaucoma therapy is capable of producing a lethal
response, even when properly prescribed and used .. [p470]
[but] these drugs are all deemed "safe" for use in glaucoma
therapy .. because their adverse consequences are
considered less threatening to the patient than blindness"
(p472). Yet marijuana is excluded from therapeutic use
because of a possible risk of cancer from long-term daily
smoking. "I cannot see", observes Merritt, "how an alleged
case of marijuana-induced lung cancer which results in
death is significantly different in result from an acute
adverse reaction to a myotic drug which results in
respiratory failure, except, of course, that the patient
with cancer is likely to outlive the patient who is unable
to draw in a breath of air" (p474).
Although the debate about the rescheduling of marijuana
has been ostensibly about the safety and efficacy of
marijuana use, it has been driven by the debate about the
legal status of recreational marijuana use. For example,
some of the groups advocating the therapeutic use of
cannabis have also been proponents of cannabis legalisation
(e.g. NORML), thereby fuelling the fears of opponents of
cannabis use that success in the campaign for marihuana
rescheduling will be the thin edge of a wedge to legalise
cannabis. Other proponents of legalisation (e.g. Grinspoon
and Bakalar, 1993) have turned this reasoning around, by
arguing for the legalisation of cannabis as a way of making
cannabis available for therapeutic purposes.
On the other side of the argument are those opponents of
marijuana use who fear that the admission that marijuana,
or any of its constituents, may have a therapeutic use will
send the "wrong message" to youth. This has led to the
denial that cannabinoids have any therapeutic effects, and
to attempts to stifle all scientific inquiry into any such
effects. For example, Mr Bernstein representing the
National Federation of Parents for a Drug Free Youth had
the following to say in his summing up against Rescheduling
marijuana before Judge Young (1989):
"If marijuana were to be rescheduled to Schedule II,
what kind of message are we sending to a nation that is
engaged in a battle for it's very survival because of
epidemic drug abuse? ... will not the message be that
marijuana is good for cancer, good for glaucoma, good for
spasticity and a host of other illnesses? Now to all of
this who are the most vulnerable? The answer is, of course,
our young people. Their reaction will be that if it is good
for all of these things, it can't be bad for me. We then
have another youngster trying marijuana, the gateway drug
and probably starting down the road that leads to nowhere
but destruction" (in Randall, 1989, p395).
It is unfortunate that a connection has been forged
between the debates about the legal status of cannabis as a
recreational drug and the use of cannabinoids for
therapeutic use. Any such connection is spurious, since
there is a world of difference between the use of
controlled doses of a purified drug under medical
supervision and the recreational use of crude preparations
of a drug. In a rational world, clinical decisions about
whether to use pure cannabinoid drugs should not be
abrogated because crude forms of the drug may be abused by
those who use it recreationally. As a community we do not
allow this type of thinking to deny us the use of opiates
for analgesia. Nor should it be used to deny access to any
therapeutic uses of cannabinoids derivatives that may be
revealed by pharmacological research.
8.11 Conclusions
The following provisional conclusions can be drawn on
the available evidence. First, there is good evidence for
the therapeutic potential of THC as an anti-emetic agent.
Although uncertainty exists about the most optimal method
of dosing and the advantages and disadvantages of different
routes of administration, there is sufficient evidence to
justify it being made available in pure synthetic form to
cancer patients. In the light of the recent development of
more effective anti-emetic agents, it remains to be seen
how widely used the cannabinoids will be. Second, there is
reasonable evidence for the potential efficacy of THC in
the treatment of glaucoma, especially in cases which have
proved resistant to existing anti-glaucoma agents. Further
research is clearly required, but this should not prevent
its use under medical supervision in poorly controlled
cases, provided patients make informed decisions about its
use in the light of information about the possible health
risks of long-term use. Third, there is sufficient
suggestive evidence of the potential usefulness of various
cannabinoids as analgesic, anti-asthmatic, anti-spasmodic,
and anti-convulsant agents to warrant further basic
pharmacological and experimental investigation, and perhaps
clinical research into their effectiveness.
Despite the basic and clinical research work which was
undertaken in late 1970s and early 1980s, the cannabinoids
have not been widely used therapeutically, nor have further
investigations been conducted along the lines suggested in
the positive evaluations made by the Institute of Medicine
(1982). This seems largely attributable to the fact that
clinical research on the therapeutic use of cannabinoids
has been discouraged by regulation and a lack of funding in
the United States, where most cannabis research has been
conducted. The discouragement of therapeutic research, in
turn, derives from the fact that THC, the most
therapeutically effective cannabinoid, has the psychoactive
effects sought by recreational users. In opposing the
therapeutic uses of cannabinoids, some researchers have
used double standards in appraising efficacy and safety,
setting unreasonably high standards in assessing the
evidence on the comparative therapeutic safety and efficacy
of cannabinoids and existing agents. The application of the
same demanding standards to existing agents for the
candidate diseases, and more generally, to existing
psychoactive drugs that are widely used in medical
practice, would denude the pharmacopoeia. The recent
discovery of the cannabinoid receptor may help to overcome
some of the resistance to research into the therapeutic
uses of cannabinoids, by holding out the prospect that the
psychoactive effects of the cannabinoids can be disengaged
from their other therapeutically desirable effects.
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