From: [h--rr--s] at [bhc.com] (Bob Harris)
Newsgroups: alt.drugs
Subject: MAPS Newletter Maijuana update
Date: Sun, 2 Jan 94 22:20:05 GMT



Medical Marijuana Research 

 After  about a decade's hiatus in the research into smoked marijuana's
medical uses,  the FDA has approved  a study comparing smoked marijuana to
the oral THC pill in the treatment of weight loss caused by the HIV-related
wasting syndrome.  The principle investigator in the study is Dr. Donald
Abrams of the San Francisco Community Consortium. Previous editions of the
MAPS newsletter have reported on this project, a
nd on the $50,000 pledge that MAPS received for the study from an individual
in the Netherlands.
 As a result of my work assisting Dr. Abrams with protocol development, I was
asked by officials at the FDA to prepare a Clinical Plan outlining the entire
research agenda for the development of the medical uses of marijuana (this
plan will be more fully discussed in the next issue of the MAPS newsletter).
This Clinical Plan formed the basis for  further discussions with the FDA.
These discussions focused on the sequence, size and design of  the studies
that the FDA will require to be successfully carried out  prior to  any 
approval of the prescription availability of marijuana for one or more
medical indicat
ions. 
 
PROTOCOL DESIGN ISSUES 
 The discussions with the FDA led to some very helpful suggestions about how
to design the marijuana research protocol. Unfortunately,  there are still
some major obstacles in the road ahead.  As a result of the work on the
Clinical Plan, a major protocol design issue has arisen which involves the
clash of differing sets of concerns, all of which have some valid
ity. The FDA requires at least two "adequate and well-controlled trials" 
demonstrating safety and efficacy before it will approve a drug for
prescription use.  Traditionally,  these studies  are designed in the
standard double-blind placebo-controlled manner. If a study is not
double-blind,  the
 FDA is not inclined to consider it  "well-controlled."   Given that a 
single medical marijuana study will probably take over a year to conduct and
cost over $150,000, it is essential  that t
he FDA will seriously consider the data it generates.
  Though the FDA has approved Dr. Abrams' s
tudy comparing smoked marijuana to Marinol,  it considered it a pilot study 
that was not   "wel
l-controlled."   The  rationale was that since the study design compares
smoked marijuana to oral THC capsules,  all the patients  could easily
determine which experimental treatment they were receiving simply by noticing
if their medicine is smoked or swallowed.  This knowledge in turn compromises
the double-blind. As a result,  bias  can be consciously or unconsciously
introduced into the experiment by  either the subjects, the researchers,  or
both.  Limiting the potential for bias to influence the results of the study
is the fact that patients suffering from the wasting syndrome are by
definition not able  to 
control their weight at will ( if they could they wouldn't be in the study).
Nevertheless, subjects would be able to alter their reports concerning their
appetite, an outcome variable that was goi
ng to be measured through patient self-reports.
 Despite everyone's best intentions, there is no known way to conduct
effectively a double-blind study with two psychoactive drugs like marijuana
and the oral THC capsule.   The best way to attempt to create a double-blind
experiment  with these two drugs is to give patients either active marijuana
and placebo THC,  or placebo marijuana and an active THC capsule.  Since the
pill takes about 45 minutes to take effect, the subjects would be asked to
first take th
e pill, wait about 45 minutes, and then smoke some marijuana. Even with the
attempt to confuse the patient about which drug was active,   patients would
still be able to tell which active drug they received. The rapid,  almost
instantaneous onset of the psychoactive effects of smoked marijuana  differs
dramatically from the slow onset of the THC capsule. Even the nature of the
subjective experience is 
different.  Furthermore,  the oral THC pill's absorption into the body is
quite variable fro
m day to day depending on diet and other factors. The pill's actual time of
onset could never be perfectly correlated with any standardized time
suggested to the patient about when to smoke the marijuana. After several
days in the study, at the longest,  all the patients would know which drug
they received, 
the active marijuana or the active pill.
 After some discussion, the FDA officials and I agreed that a  design
involving high dose marijuana (10% THC), medium dose marijuana (3-5% THC) and
placebo marijuana ( less than 1% THC) would come the closest to being a true
double-blind study. Such a study wo
uld be considered as one of the two required "adequate and well-controlled"
studies.  I therefore suggested to Dr. Donald Abrams that we redesign the
study by dropping the use of Marinol and adding a medium dose group and a
placebo marijuana group.  Dr. Abrams agreed to present the new study design
to the Scientific Advisory Board (SAC) of the Community Consortium at its
December 2, 1993 meeting. 
NO TO PLACEBO MARIJUANA 
 To my surprise, the SAC rejected the proposed protocol design
. The reasons for its decision  are valid, as is the FDA's competing need for
a "well-controlled
" study.  Some mutual accommodation will need to be developed.  While the SAC
approved of the use of high- and medium-dose marijuana, it refused to
administer placebo marijuana to its patients.  The rationale was that the
subjects would be exposed to the potentially harmful effects of smoking
without receiving any benefits. Furthermore,  after a few days in the study,
they would certainly be able to determine whether they were smoking active
marijuana or not,  thereby compromising the double-blind.  Since the
double-blind would not be effective anyway, the SAC saw no reason to go
through with an empty formality that carried even a slight degree of risk.
 I had also thought that patients  in the study would indeed be able to tell
if they had active or placebo marijuana.  However,  I thought a good-faith
effort at the double-blind would be worth it in order for the study as a whole
to be considered "well-controlled".  Furthermore, I considered the risk of
harm to the subjects
from the smoke from the placebo marijuana to be minimal,  especially since
there are simple ways to reduce the risk of smoking, for example with a water
pipe.  In deciding to recommend this design, I tried to weigh the
risk/benefit ratio for the subjects who would be randomly assigned to the
placebo marijuana group.  While I recognized that they would not benefit from
their three months in the study, and would  also be exposed to smoke without
therapeutic value,  I thought that their opportunity to obtain legal access
to smoked marijuana after the conclusion of the three month study period
might adequately compensate them for participating in
 the study in the placebo marijuana group.  
 The SAC  had one additional concern that even I could see was compelling. 
The SAC pointed out the ethical problem of not providing patients suffering
from the life-threatening wasting syndrome with some active  treatment,
especially since there already a
re two drugs approved by the FDA for this indication - Marinol and a new drug
called Megace.  When there are no FDA-approved drugs for an illness,  having
a placebo group is easily justified since there are no proven alternatives
that have been demonstrated to be safe and effective.  Indeed, given that all
drugs have some side-effects, administering a drug of unknown safety and
efficacy is probably har
der to justify than giving a placebo. 
 Though there are FDA-approved drugs for the wasting syndrome,  the SAC was
not enthusiastic about  the therapeutic value of either Marinol or Megace.
Marinol has only been demonstrated to increase appetite but not weight. 
While Megace has a small effect on weight gain, this may primarily be water
weight of little consequence to overall health. Despite their shortcomings,
the SAC preferred to administer one of these drugs  to the control group 
instead of placebo marijuana. Using either of these drugs, however, would
still not result in a double-blind study.  Furthermore,  using  an active
placebo with some therapeutic potential creates another problem.  When the
data  from  standard double-blind studies are analyzed,   the important
variable is the difference between the effect of the treatment and the effect
of the placebo.   The statistical probability that the observed effect of the
treatment is due to the treatment and not to chance depends in  part on how
large the difference is between the two groups. However, when the drug used
as a placebo has some therapeutic effecti
veness of its own, the true effect of the treatment is more difficult to
determine.
 
ONE PO
SSIBLE SOLUTION 
 Dr. Abrams, the SAC, the FDA and I  are all still trying to develop an
appropriate protocol design. My  preference is to use low-THC marijuana that 
still has some therapeutic effect, perhaps 2% marijuana.  The study design
would then be patterned on a standard dose-response study,  though without an
inactive placebo.    Using three groups with high-, medium- or low-THC
content at least maximizes the chance that patients and researchers will  be
blind as to which treatment group the patients are in.   The problem of
comparing the results  of the high and medium doses to an active placebo rema
ins to be addressed, but.there seems to be no way to avoid this. In any case,
isn't this why
 some people become statisticians?
 Some progress has resulted from all this struggle to craft the best design
for the experiment. The SAC decided that it would be a good idea to conduct a
small pilot study with whatever design we come up with, rather than enter
into a big trial without first testing out the methodology with a smaller
group of patients. Since we have already been pledged $50,000, we do have
enough funding for a pilot study. As soon as the  protocol design is
finalized and all the regulatory permissions are in hand, we can begin the
experiment instead of waiting until larger sums are available.  It should be
much easier to raise the remaining funds once the  pilot study is underway. 
At that time we would  have actually demonstrated that this project was not
just another pipe dream but instead was an actual study that could have
dramatic implications for the medical treatment of the wasting syndrome, and
for medical marijuana research in general.
FDA GRANT PROGRAM
In  a good-faith attempt to help the medical marijuana debate be resolved on
the scientific merits of research data,  an FDA official  who did not have to
do so nevertheless informed me about a grant program that I did not know
existed. This  grant program had the potential to provide  substantial
funding for the wasting syndrome study. This  gesture convinced me more than
ever that working with the FDA to conduct scientific research is an essential
partt of  breaking  the logjam concerning the medical use of marijuana. 
 The  grant I was shown 
was from FDA's Office of Orphan Products Development. These grants are for
research into the therapeutic potential of drugs intended for diseases which
afflict 200,000 people per year or less, such as the AIDS-related wasting
syndrome. I had erroneously assumed that marijuana would first need to be
formally approved by the FDA as an Orphan Drug before any funding proposals
would be considered. I  was told  instead that  researchers need only have an
approved protocol ,  which Dr.  Abrams already had. The grant application
deadline was December 27, 1993,  about a month and a half after I was
informed about the program. If there were no  unexpected problems,  it seemed
that there just might be enough lead time for Dr. Abrams and the Community
Consortium to prepare a grant application for the research study, and
possiblyf obtain funding support for the study directly from the FDA.
 The SAC's decision to reject the proposed protocol design with the placebo
marijuana group had one major unfortunate side-effect. In the absence of a
protocol design that the SAC was willing to implement and the FDA was willing
to consider well-controlled,  Dr. Abrams was not  able to prepare an
application for FDA funding for the study in time for the December 27, 1993
application date.  Since this grant program is on an annual cycle,  the
opportunity for FDA funding for medical marijuana research slipped through
our fingers for at least a year. While other sources of funding will probably
become available eventually, FDA funding would have been  particularly
appropriate for such a controversial drug at this stage in its development. 

NATIONAL
 MEDICAL MARIJUANA DAY 
 Another idea to help raise funds for medical marijuana research is to
initiate a National Medical Marijuana Day, perhaps in April or May  of 1994.
The idea would be to catalyze hundreds of small, local fundraising events all
synchronized to take place on the same day.  The events would ideally be
co-sponsored by local medical marijuana groups, NORML chapters, and the
Cannabis Action Network, some of the same groups that helped with the
symposium commemorating the 50th anniversary of LSD. In addition, we would
advise the local organizers to seek co-sponsorship of the events with their
local AIDS groups.  If each local event raised $500 and there were 100
events, $50,000 would be g
enerated.  
 The central organizers would need to assemble a "Local Organizers Starter
Packet"  composed of a video about the issue, some informational material,
and organizational tips.  This kit could be sold at a price that covers
costs, perhaps $25. It should also be possible to arrange a benefit concert
to take place in San Francisco on the same day with some very popular bands.
More on this idea later. If you would be interested in sponsoring a local
event, please contact MAPS.

Bob Harris
8 :-)