The Cannarchist
05-15-2007, 08:38 PM
"On the future of cannabis as medicine."
Lester Grinspoon
Harvard Medical School, Wellesley, Massachusetts, USA
The recent publication by Abrams et al of a controlled
study using inhaled herbal marijuana for the treatment
of AIDS-related neuropathic pain has been greeted as a
landmark study because it demonstrated the efficacy of
cannabis in the treatment of this difficult-to-treat type
of pain [1]. However, this study deserves to be singled
out not so much for what it has newly revealed about
cannabis as an analgesic, but more for the extraordinary
perseverance of the research team in the face of a
variety of US government obstacles placed in the path
of those who wish to study herbal marijuana, including
the mandate to use government-produced marijuana of
inferior quality. Both AIDS patients and others suffering
from neuropathic pain, and open-minded, astute
clinicians have known for more than a decade that this
is arguably the most efficacious and least toxic way to
approach this difficult symptom; they know this from
their own clinical experience. Neuropathic pain is but
one of a large number of symptoms and syndromes
which emerge from a mountain of anecdotal data that
have long established herbal marijuana as a safe and
effective medicine. One might ask: given the enormously
enhanced interest in cannabis-related research,
why have there not been more controlled clinical studies
such as this? The answer is largely money.
Today drugs must undergo rigorous, expensive and
time-consuming tests to win approval by the appropriate
regulatory agency (the Food and Drug Administration
in the United States, FDA) for marketing as medicines.
The purpose of the testing is to protect the consumer
by establishing both safety and efficacy. Because
no drug is completely safe or always efficacious,
a drug approved by this agency as a medicine has presumably
satisfied a risk-benefit analysis. First, the
drug's safety (or rather, limited toxicity) is established
through animal and then human experiments. Next,
double-blind controlled studies are conducted to determine
whether the drug has more than a placebo
effect and is more useful than an available drug. As the
difference between drug and placebo may be small,
large numbers of patients are often needed in these
studies for a statistically significant effect. Medical and
governmental authorities sometimes insist that before
herbal marijuana is made legally available to patients,
this kind of study should be performed for each of the
indications for which it is believed to be useful. But it
is doubtful whether these regulatory rules should apply
to herbal marijuana. First, there is no question about its
safety. It has been used for thousands of years by millions
of people with no reported deaths and very little
evidence of significant toxicity. Similarly, no doubleblind
studies are needed to prove marijuana's efficacy.
Countless clinicians and patients the world around who
have had experience with the medicinal use of cannabis
have observed that it often provides better relief with
fewer serious side effects than conventionally prescribed
medicines. To impose this regulatory protocol
on herbal marijuana is tantamount to making the same
demand of aspirin, which was accepted as a medicine
more than 60 years before the advent of the doubleblind
controlled study. Many years of experience have
shown us that aspirin has many uses and limited toxicity,
yet today it could not be marshaled through the
FDA approval process. The patent has long since expired,
and with it the incentive to underwrite the substantial
cost of this modern seal of approval.
Ordinarily, pharmaceutical companies who own the
patent on a promising therapeutic are willing to invest
the large sums of money necessary to complete the
double blind controlled studies required by the FDA
for approval of the potential new medicine. Because
there is no possibility of acquiring a patent on herbal
marijuana, the drug companies have no direct interest
in it. The Abrams' study was financed by the State of
California; future controlled studies of the variety of
already obvious medicinal utilities of cannabis will
have to await funding from private or government
sources. Given that the official position of the US government
is that "marijuana is not a medicine", it is
highly unlikely that it will underwrite this large investment
to establish a "more scientific" refutation of
its position than that already provided by the compelling
body of anecdotal data.
Anecdotal evidence commands much less attention
than it once did, yet it is the source of much of our
knowledge of synthetic medicines as well as plant
derivatives. As Louis Lasagna has pointed out, controlled
experiments were not needed to recognize the
therapeutic potential of chloral hydrate, barbiturates,
aspirin, curare, insulin, or penicillin [2]. He asks why
regulators are now willing to accept the experience of
physicians and patients as evidence of adverse effects
but not as evidence of therapeutic effects. Anecdotes
present a problem that has always haunted medicine:
the anecdotal fallacy or the fallacy of the enumeration
of favorable circumstances (counting the hits and ignoring
the misses). If many people suffering from, say,
muscle spasms caused by multiple sclerosis take herbal
marijuana and only a few get much better relief than
they get from conventional drugs, those few patients
would stand out and come to our attention. They and
their physicians would understandably be enthusiastic
about cannabis and may proselyte for it. These people
are not dishonest, but they are not dispassionate observers.
Therefore, some may regard it as irresponsible
to suggest on the basis of anecdotes that herbal marijuana
may help people with a variety of disorders. That
might be a problem if marijuana were an especially
dangerous drug, but it is in fact remarkably safe. Even
in the unlikely event that only a few patients get the
kind of relief that many observant physicians have now
seen, it could be argued that it should be available to
them because the risks are so small and it costs so little
to produce.
While it is early in the history of the effort to "pharmaceuticalize"
cannabis, the few products that have so far
been developed do not measure up to the de facto gold
standard, herbal marijuana. Dronabinol (Marinol),
encapsulated THC in sesame oil, was introduced two
decades ago with expectations (particularly on the part
of the US government, which supported Unimed's
development of this pharmaceutical) that it would be
every bit as medically useful as marijuana and thereby
obviate the necessity to find a way to allow patients to
use herbal marijuana legally. However, Marinol has not
succeeded in displacing marijuana because it is not as
effective or useful as marijuana, whether ingested as a
food such as brownies or smoked. I have yet to know
of a patient who has had the opportunity to use both
marijuana and Marinol who prefers the latter. One
reason is that like the 19th century oral preparations of
cannabis indica, with their slow time of onset, the appropriate
dose of dronabinol is much more difficult to
titrate than smoked cannabis, whose therapeutic effects
are experienced within a few minutes. The most common
reason people who have an opportunity to choose
between these two forms of cannabis elect dronabinol
is because it is legal. Sativex, a more recent addition of
cannabinoid medicines which are meant to fly under
the legal radar, has been referred to as liquid marijuana.
It is a liquid formulation of two cannabinoids, tetrahydrocannabinol
and cannabidiol, extracted from marijuana.
It was developed as a means to make use of the
medicinal capacities of marijuana without exposing the
patient to the twin "dangers" of getting “high” and
smoking. There are many who now question both the
harmfulness of the "high" and whether the psychoactive
effects are always separable from those that are
therapeutic. While smoking anything may cause
chronic bronchitis, smoked marijuana has never been
demonstrated to have serious pulmonary consequences
[3], but in any case the technology to inhale these cannabinoids
without smoking cannabis already exists as
vaporizers that allow for smoke-free inhalation. Sativex
is administered as drops to be held under the tongue to
facilitate buccal mucosal absorption. However, in part
because it has such a disagreeable taste, some if not
most of it is swallowed. While the time of the onset of
that part of the dose absorbed by the buccal mucosa is
about 20 minutes, that part which is absorbed by the
gastrointestinal tract requires at least an hour and a half
and thus its capacity for titration is closer to that of
Marinol than to inhaled marijuana. It also shares with
Marinol a cost to the patient which is greater than that
of herbal marijuana, even with its heavy prohibition
tariff.
I have no doubt that the use of herbal marijuana as a
medicine is here to stay. Nor do I doubt that the present
effort directed at the "pharmaceuticalization" of cannabis
will eventually lead to some good cannabinoid
pharmaceuticals. However, I question how many of
them would be able to compete with herbal marijuana
on a level playing field, i.e. effectiveness, limited toxicity,
versatility, ease of titration of dose, expense and,
of course, legal access. Presently we are beginning to
see two powerful forces collide: the growing acceptance
of medical cannabis and the proscription against
any use of herbal marijuana, medical or non-medical.
There are few signs that we are moving away from
absolute prohibition to a regulatory system that would
allow responsible use of marijuana. As a result, we
appear to be heading toward two simultaneous distribution
systems for medical cannabis: the conventional
model of legal pharmacy-filled prescriptions for officially
approved medicines, and a model closer to the
distribution of alternative and herbal medicines, legal
or illegal.
References
1. Abrams DI, Jay CA, Shade SB,Vizoso H, Reda S,
Press ME, Kelly MC,Rowbotham MC, Peterson
KL. Cannabis and painful HIV-associated sensory
neuropathy: A randomized placebocontrolled
trial. Neurology 2007;68:515-21.
2. Hashibe M, Morgenstern H, Cui Y, Tashkin DP,
Zang ZF, Cozen W, Mack TM, Greenland S.
Marijuana use and the risk of lung and upper
aerodigestive tract cancers: results of a population-
based case-control study. Cancer Epidemiol
Biomarkers Prev 2006;15(10):1829-34.
3. Lasagna L. Clinical trials in the natural environment.
In: Stiechele C, Abshagen W, Koch-Weser
J, editors. Drugs between research and regulation.
New York: Springer-Verlag; 1985. p. 45-49.
Lester Grinspoon
Harvard Medical School, Wellesley, Massachusetts, USA
The recent publication by Abrams et al of a controlled
study using inhaled herbal marijuana for the treatment
of AIDS-related neuropathic pain has been greeted as a
landmark study because it demonstrated the efficacy of
cannabis in the treatment of this difficult-to-treat type
of pain [1]. However, this study deserves to be singled
out not so much for what it has newly revealed about
cannabis as an analgesic, but more for the extraordinary
perseverance of the research team in the face of a
variety of US government obstacles placed in the path
of those who wish to study herbal marijuana, including
the mandate to use government-produced marijuana of
inferior quality. Both AIDS patients and others suffering
from neuropathic pain, and open-minded, astute
clinicians have known for more than a decade that this
is arguably the most efficacious and least toxic way to
approach this difficult symptom; they know this from
their own clinical experience. Neuropathic pain is but
one of a large number of symptoms and syndromes
which emerge from a mountain of anecdotal data that
have long established herbal marijuana as a safe and
effective medicine. One might ask: given the enormously
enhanced interest in cannabis-related research,
why have there not been more controlled clinical studies
such as this? The answer is largely money.
Today drugs must undergo rigorous, expensive and
time-consuming tests to win approval by the appropriate
regulatory agency (the Food and Drug Administration
in the United States, FDA) for marketing as medicines.
The purpose of the testing is to protect the consumer
by establishing both safety and efficacy. Because
no drug is completely safe or always efficacious,
a drug approved by this agency as a medicine has presumably
satisfied a risk-benefit analysis. First, the
drug's safety (or rather, limited toxicity) is established
through animal and then human experiments. Next,
double-blind controlled studies are conducted to determine
whether the drug has more than a placebo
effect and is more useful than an available drug. As the
difference between drug and placebo may be small,
large numbers of patients are often needed in these
studies for a statistically significant effect. Medical and
governmental authorities sometimes insist that before
herbal marijuana is made legally available to patients,
this kind of study should be performed for each of the
indications for which it is believed to be useful. But it
is doubtful whether these regulatory rules should apply
to herbal marijuana. First, there is no question about its
safety. It has been used for thousands of years by millions
of people with no reported deaths and very little
evidence of significant toxicity. Similarly, no doubleblind
studies are needed to prove marijuana's efficacy.
Countless clinicians and patients the world around who
have had experience with the medicinal use of cannabis
have observed that it often provides better relief with
fewer serious side effects than conventionally prescribed
medicines. To impose this regulatory protocol
on herbal marijuana is tantamount to making the same
demand of aspirin, which was accepted as a medicine
more than 60 years before the advent of the doubleblind
controlled study. Many years of experience have
shown us that aspirin has many uses and limited toxicity,
yet today it could not be marshaled through the
FDA approval process. The patent has long since expired,
and with it the incentive to underwrite the substantial
cost of this modern seal of approval.
Ordinarily, pharmaceutical companies who own the
patent on a promising therapeutic are willing to invest
the large sums of money necessary to complete the
double blind controlled studies required by the FDA
for approval of the potential new medicine. Because
there is no possibility of acquiring a patent on herbal
marijuana, the drug companies have no direct interest
in it. The Abrams' study was financed by the State of
California; future controlled studies of the variety of
already obvious medicinal utilities of cannabis will
have to await funding from private or government
sources. Given that the official position of the US government
is that "marijuana is not a medicine", it is
highly unlikely that it will underwrite this large investment
to establish a "more scientific" refutation of
its position than that already provided by the compelling
body of anecdotal data.
Anecdotal evidence commands much less attention
than it once did, yet it is the source of much of our
knowledge of synthetic medicines as well as plant
derivatives. As Louis Lasagna has pointed out, controlled
experiments were not needed to recognize the
therapeutic potential of chloral hydrate, barbiturates,
aspirin, curare, insulin, or penicillin [2]. He asks why
regulators are now willing to accept the experience of
physicians and patients as evidence of adverse effects
but not as evidence of therapeutic effects. Anecdotes
present a problem that has always haunted medicine:
the anecdotal fallacy or the fallacy of the enumeration
of favorable circumstances (counting the hits and ignoring
the misses). If many people suffering from, say,
muscle spasms caused by multiple sclerosis take herbal
marijuana and only a few get much better relief than
they get from conventional drugs, those few patients
would stand out and come to our attention. They and
their physicians would understandably be enthusiastic
about cannabis and may proselyte for it. These people
are not dishonest, but they are not dispassionate observers.
Therefore, some may regard it as irresponsible
to suggest on the basis of anecdotes that herbal marijuana
may help people with a variety of disorders. That
might be a problem if marijuana were an especially
dangerous drug, but it is in fact remarkably safe. Even
in the unlikely event that only a few patients get the
kind of relief that many observant physicians have now
seen, it could be argued that it should be available to
them because the risks are so small and it costs so little
to produce.
While it is early in the history of the effort to "pharmaceuticalize"
cannabis, the few products that have so far
been developed do not measure up to the de facto gold
standard, herbal marijuana. Dronabinol (Marinol),
encapsulated THC in sesame oil, was introduced two
decades ago with expectations (particularly on the part
of the US government, which supported Unimed's
development of this pharmaceutical) that it would be
every bit as medically useful as marijuana and thereby
obviate the necessity to find a way to allow patients to
use herbal marijuana legally. However, Marinol has not
succeeded in displacing marijuana because it is not as
effective or useful as marijuana, whether ingested as a
food such as brownies or smoked. I have yet to know
of a patient who has had the opportunity to use both
marijuana and Marinol who prefers the latter. One
reason is that like the 19th century oral preparations of
cannabis indica, with their slow time of onset, the appropriate
dose of dronabinol is much more difficult to
titrate than smoked cannabis, whose therapeutic effects
are experienced within a few minutes. The most common
reason people who have an opportunity to choose
between these two forms of cannabis elect dronabinol
is because it is legal. Sativex, a more recent addition of
cannabinoid medicines which are meant to fly under
the legal radar, has been referred to as liquid marijuana.
It is a liquid formulation of two cannabinoids, tetrahydrocannabinol
and cannabidiol, extracted from marijuana.
It was developed as a means to make use of the
medicinal capacities of marijuana without exposing the
patient to the twin "dangers" of getting “high” and
smoking. There are many who now question both the
harmfulness of the "high" and whether the psychoactive
effects are always separable from those that are
therapeutic. While smoking anything may cause
chronic bronchitis, smoked marijuana has never been
demonstrated to have serious pulmonary consequences
[3], but in any case the technology to inhale these cannabinoids
without smoking cannabis already exists as
vaporizers that allow for smoke-free inhalation. Sativex
is administered as drops to be held under the tongue to
facilitate buccal mucosal absorption. However, in part
because it has such a disagreeable taste, some if not
most of it is swallowed. While the time of the onset of
that part of the dose absorbed by the buccal mucosa is
about 20 minutes, that part which is absorbed by the
gastrointestinal tract requires at least an hour and a half
and thus its capacity for titration is closer to that of
Marinol than to inhaled marijuana. It also shares with
Marinol a cost to the patient which is greater than that
of herbal marijuana, even with its heavy prohibition
tariff.
I have no doubt that the use of herbal marijuana as a
medicine is here to stay. Nor do I doubt that the present
effort directed at the "pharmaceuticalization" of cannabis
will eventually lead to some good cannabinoid
pharmaceuticals. However, I question how many of
them would be able to compete with herbal marijuana
on a level playing field, i.e. effectiveness, limited toxicity,
versatility, ease of titration of dose, expense and,
of course, legal access. Presently we are beginning to
see two powerful forces collide: the growing acceptance
of medical cannabis and the proscription against
any use of herbal marijuana, medical or non-medical.
There are few signs that we are moving away from
absolute prohibition to a regulatory system that would
allow responsible use of marijuana. As a result, we
appear to be heading toward two simultaneous distribution
systems for medical cannabis: the conventional
model of legal pharmacy-filled prescriptions for officially
approved medicines, and a model closer to the
distribution of alternative and herbal medicines, legal
or illegal.
References
1. Abrams DI, Jay CA, Shade SB,Vizoso H, Reda S,
Press ME, Kelly MC,Rowbotham MC, Peterson
KL. Cannabis and painful HIV-associated sensory
neuropathy: A randomized placebocontrolled
trial. Neurology 2007;68:515-21.
2. Hashibe M, Morgenstern H, Cui Y, Tashkin DP,
Zang ZF, Cozen W, Mack TM, Greenland S.
Marijuana use and the risk of lung and upper
aerodigestive tract cancers: results of a population-
based case-control study. Cancer Epidemiol
Biomarkers Prev 2006;15(10):1829-34.
3. Lasagna L. Clinical trials in the natural environment.
In: Stiechele C, Abshagen W, Koch-Weser
J, editors. Drugs between research and regulation.
New York: Springer-Verlag; 1985. p. 45-49.