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Submitted to the Food and Drug Administration Pursuant to 21 CFR Part 316.14 (b)
Federal Register 62076 V.57,
# 250 (Tuesday, December 29, 1992)
Submitted by The Multidisciplinary Association for Psychedelic Studies, Inc. (MAPS), an
IRS-approved 501 (c) (3) research and educational corporation
Click to view Application Cover Letter
April 24, 1997
- MAPS requests Orphan Drug designation for smoked marijuana in the treatment of HIV-
associated wasting syndrome. The definition of HIV-associated wasting syndrome for
which
MAPS wishes to obtain an orphan drug designation shall be as follows, "profound
involuntary
weight loss >5% of baseline body weight in the presence of HIV infection."
The Center for Disease Control (CDC) AIDS surveillance case definition of HIV-associated
wasting is defined as "profound involuntary weight loss >10% of baseline body weight plus
either
chronic diarrhea (at least two loose stools per day >30 days) or chronic weakness and
documented
fever (for >30 days, intermittent or constant) in the absence of a concurrent illness or
condition
other than HIV infection that could explain the findings (e.g., cancer, tuberculosis,
cryptosporidiosis, or other specific enteritis)."
MAPS proposes to modify the CDC AIDS surveillance case definition of HIV-associated
wasting syndrome per suggestions from Dr. Richard Selik, Medical Epidemiologist, CDC
(Selik
1997) and Kathleen Mulligan, Ph.D., UC San Francisco, an expert on HIV-related wasting
who
presented a report at the February 19-20, 1997 NIH Workshop on the Medical Utility of
Marijuana
(Mulligan 1997). Dr. Selik noted that, "The HIV wasting syndrome was defined to mean an
entity
caused by HIV (otherwise unexplained), not caused by an opportunistic infection or
cancer, as far
as can be determined... You probably want to include weight loss due to opportunistic
infection or
cancer." Dr. Mulligan suggested that advances in the understanding and treatment of HIV-
related
opportunistic infections had resulted in a situation whereby many patients who suffer
from
involuntary weight loss are able to avoid fevers and diarrhea. As a result of these
suggestions,
MAPS is defining HIV wasting syndrome solely in terms of involuntary weight loss in the
presence of HIV infection.
The definition used by MAPS specifies a "profound involuntary weight loss >5% of
baseline
body weight" instead of the CDC definition of a "profound involuntary weight loss >10% of
baseline body weight." The lower limit of "profound involuntary weight loss >5% of
baseline
body weight" is used so that treatment might be initiated in the early stages of the
disease.
According to Dr. Mulligan, clinical treatment is frequently initiated when involuntary
weight loss
exceeds 5% of baseline body weight. In addition, it is anticipated that the clinical trials
to be
conducted into the use of smoked marijuana in the treatment of HIV-associated wasting
will use
"profound involuntary weight loss >5% of baseline body weight" as part of the inclusion
criteria.
It therefore seems appropriate to define the disease to conform to the data that will be
gathered.
On April 7, 1997, the American Medical Association published an official editorial in
the
American Medical News endorsing research into the potential medical uses of marijuana
(AMA
News, 1997). The editorial noted that "Since there is no patent potential, no drug company
will be
willing to underwrite the research." By designating marijuana an Orphan Drug for the
treatment of
HIV associated wasting syndrome, FDA could play a major role in facilitating medical
marijuana
research by remedying the lack of patent protection for the development of one of
marijuana's
potential medical uses. This action would also communicate to the pharmaceutical
industry that
other potential uses of marijuana that meet the Orphan Drug criteria could obtain patent
protection.
- Sponsor: Multidisciplinary Association for Psychedelic Studies, Inc.
Address: 2121 Commonwealth Avenue, Suite 220-A
Charlotte, North Carolina, 28205
Phone: (704) 334-1798, fax (704) 334-1799
Email: sylvia@maps.org
Primary Contact: Rick Doblin, MAPS President
Address: 2121 Commonwealth Avenue, Suite 220-A
Charlotte, North Carolina, 28205
Phone: (704) 358-0138
Email: rick@maps.org
Generic Names: marijuana, cannabis
Source of the Drug: National Institute on Drug Abuse (NIDA)
- Nahlen (1993) describes the HIV-associatedwasting syndrome by noting that:
Progressive involuntary weight loss is a fundamental feature of HIV infection.
This process of body wasting may be due to a number of factors related to HIV
disease, acting either alone or in combination. Such factors include an inadequate
oral intake, an altered metabolic state, and/or malabsorption.
The morbidity of severe weight loss plays a major role in the decreased quality of
life of AIDS patients, and the malnutrition associated with marked depletion of
body cell mass may contribute to further reduction of cell-mediated immunity. The
weight loss observed in AIDS patients differs from cancer-related cachexia by its
occurrence early in the clinical course and by its rapid progression and severity,
frequently exceeding 20% of baseline body weight. In contrast to weight loss seen
in starvation, HIV-related cachexia results in profound tissue depletion that does not
respond readily to nutritional therapy.
The proposed indication will be for use in the promotion of weight gain in
patients diagnosed with HIV wasting syndrome. Such therapy is needed because
patients with HIV wasting syndrome and >20% baseline weight loss have
significantly decreased survival (Chlebowski 1989), and the extent of weight loss is
related to the timing of death (Kotler 1989).
Dr. Donald Abrams describes the need for therapy of HIV-associated wasting syndrome
in the
context of a 1996 NIH grant application to study the use of smoked marijuana in the
treatment of
HIV-associated anorexia and wasting (Abrams 1996). He wrote:
The prognostic significance of weight loss in HIV infection has long been
recognized. Early antiretroviral therapy trials used weight gain as an efficacy
parameter. Despite an increased armamentarium of licensed antiretroviral agents,
weight loss and wasting continue to be problematic for patients with advanced HIV
disease. A Community Programs for Clinical Research on AIDS (CPCRA) analysis
of opportunistic events occurring within the 6 months prior to death in a cohort of
1883 HIV-infected individuals showed that the wasting syndrome and
Mycobacterium avium Complex share second place behind Pneumocystis carinii
pneumonia as the most frequent premorbid diagnoses (Chan 1995). The 6-month
cumulative mortality in another CPCRA cohort of HIV-infected individuals
diagnosed with wasting syndrome was 41.7 percent, for a relative risk of 2.5
(Neaton 1995).
Wasting syndrome is also a frequent initial disease progression diagnosis in
patients with HIV disease. In an analysis of another CPCRA cohort comparing
outcomes by gender, 11 percent of the 768 women and 12 percent of the 3779 men
developed wasting as their first progression-of-disease event after 15 months of
followup (Melnick 1994). Other analyses of this cohort found relationships among
baseline weight, percent weight change, disease progression, and survival. For
instance, Gibert examined a cohort of 2,076 persons with CD4+ cell counts of
<500/mm[3] and found weight and percent weight change to be important
predictors of mortality independent of CD4+ cell count (Gibert 1995). Similarly,
Wheeler analyzed the same cohort and showed that a decrease in body weight over
4 months correlated with an increased risk of opportunistic complications during the
same 4-month period (Wheeler 1995). Moreover, a decrease in weight over 4
months was associated with the occurrence of an opportunistic complication in the
subsequent year, independent of CD4+ cell count.
Loss of lean body mass has likewise been identified as an important predictor of
negative outcome in patients with advanced HIV infection. Kotler (1989) analyzed
depletion of body cell mass (nonadipose cellular mass, predominantly muscle and
viscera) in wasting AIDS patients. The investigators noted that body cell mass
values at death were 54 percent of normal and suggested that there is a critical level
of body cell mass needed to support life. They postulated that HIV disease-related
complications might cause depletion below the critical body cell mass limit, and that
interventions that successfully maintain body cell mass may prolong survival.
A recent analysis by Suttmann (1995) suggests that loss of body cell mass is a
more significant predictor of negative outcome than a drop in CD4+ cell count to
less than 50/mm[3]. Measuring body cell mass by bioelectrical impedance analysis
(BIA) in 39 AIDS patients, significant differences in survival were noted. Patients
with body cell mass less than 30 percent of body weight at entry into the study
survived 335 days compared to 527 days for patients with greater body cell mass
(p<0.05). Data suggest that decreased energy intake is probably the most important
contributor to wasting (Macallan 1995; Grunfeld 1992).
- Marijuana is comprised of the flowering buds and leaves of the cannabis plant. The primary therapeutic ingredient in marijuana is considered to be the cannabinoid molecule, 9- tetrahydrocannabinol (THC), although marijuana contains a variety of other cannabinoids (cannabidiol, CBD; cannabinol, CBN) and hundreds of other compounds. Marijuana can be prepared in a variety of potencies, standardized as to the percentage of 9- tetrahydrocannabinol (THC). The potency or potencies of marijuana to be used in the treatment of HIV-associated wasting syndrome will be determined in clinical trials.
A more specific description of the drug can be obtained from NIDA, the proposed
supplier of the
drug to clinical investigators. If marijuana is eventually approved by the FDA for
prescription use
in the treatment of HIV-associated wasting syndrome, MAPS will establish an alternative,
non-
NIDA source of marijuana with approvals and licenses from FDA and DEA.
The scientific rationale for the use of smoked marijuana in the treatment of HIV-
associated
wasting syndrome is based in part on the clinical trials conducted into the use of oral THC
(Marinol, dronabinol) in the treatment of HIV-associated wasting syndrome (Beal 1995;
Gorter
1992; Struwe 1993). These clinical trials demonstrated that THC, the main active
ingredient in
marijuana, promoted a significant increase in appetite and a trend toward weight gain that
failed to
reach significance. On the strength of data from these clinical trials, the FDA approved
the oral
THC capsule for marketing for treatment of HIV-associated wasting syndrome.
The scientific rationale for the use of smoked marijuana in the treatment of HIV-
associated
wasting syndrome is based in part on data demonstrating that the route of administration
of smoked
marijuana offers some scientifically documented advantages over the oral route of
administration.
Abrams (1996) noted:
The experience of patients using dronabinol has been mixed. Variable absorption
after oral ingestion is well recognized, leaving some patients with a minimal drug
effect. Smoking is a more efficient route of delivery with a more desirable
pharmacokinetic pattern for patients seeking to maximize any potential appetite-
stimulating effect (Agurell 1986). The smoking curve tends to parallel the effects of
intravenous administration at about half the concentration. Plasma drug levels and
heart rate peak within 15 minutes of an inhaled dose and rapidly decline. Oral THC
increases heart rate to a lesser extent than smoked marijuana with a peak occurring
two to three hours after ingestion (Chait 1992). Heart rate remained elevated four
hours after ingestion. It is the combination of these features - delayed onset,
prolonged duration and less ability to titrate the effect - that has led patients with
HIV infection to turn in increasing numbers to utilization of smoked marijuana as a
self-medication for this condition.
A recent report describes a number of small related trials comparing different
routes of THC administration for their effects on appetite stimulation (Mattes 1994).
Eleven subjects received single doses by oral, sublingual and inhaled routes. In
another component of the trial, a 2.5 mg dose was administered twice daily for
three days by oral and rectal suppository routes. There was a high level of
variability in plasma drug levels, particularly in subjects with oral drug
administration. Two of the 11 (18%) subjects in the oral trial of the multiroute study
and 18/57 (32%) of subjects in the larger, acute oral study showed no detectable
plasma THC or metabolite level in the four hours following ingestion of the active
drug. For patients receiving oral THC in this study, the time course of peak levels
and the concentration area under the curve (AUC) values were highly variable
across subjects. The suppository led to the highest AUC, followed by inhalation.
The metabolite AUC was highest for the oral and lowest following inhalation. Mean
energy intake after inhalation of THC was 2719 +/- 359 kcal; 481 kcal more than
after oral dosing and 603 kcal greater than sublingual dosing effects. (This analysis
eliminates two inhalation subjects who experienced "highs" that caused them to
sleep through lunch and had the lowest daily intakes.) The investigators conclude
that inhalation of THC led to more consistent elevations of plasma drug
concentration and tended to promote intake, although due to the sample size the
results were not statistically significant. They note, as well, that "because this form
of delivery requires smoking the drug and is not currently legal, it is objectionable
to many patients." It is evident that patients with HIV infection are risking potential
legal consequences in hopes of reversing the devastation of the wasting syndrome,
and that they and their health care providers would clearly benefit from concrete
information on the potential risks and benefits of this controversial treatment
modality.
The scientific rationale for the use of smoked marijuana in the treatment of HIV-
associated
wasting syndrome is also based on studies of cannabinoids and appetite stimulation.
Abrams
(1996) wrote:
An extensive literature regarding the impact of smoked marijuana on appetite has
accumulated, although much of it was published 20 to 50 years ago. Anecdotal
accounts of increased food intake have always been reported by marijuana smokers.
A study evaluating body weight and caloric intake in 12 "casual" and 15 "heavy"
marijuana users reported weight gains of 2.8 and 3.7 pounds respectively during
the first five days of a 21 day smoking trial (Greenberg 1976). Control subjects,
without access to marijuana or other drugs but otherwise exposed to the identical
ward experimental conditions, gained only 0.2 pounds during the same time
interval. Despite the absence of sophisticated body composition analysis
technologies (such as BIA or DEXA), the investigators believed that water retention
was not a major factor in the weight gain, contradicting an earlier report by a
member of our group (Benowitz 1975). An increase in caloric intake accompanied
the initial weight gain; however, caloric intake was noted to decrease subsequently
during the remainder of the 21 day trial.
Foltin has investigated the impact of smoking marijuana on food intake in men
confined in residential laboratories under various conditions (Foltin 1986). He
reported that smoking marijuana compared to placebo was more likely to lead to
increased food intake during social access periods when the subject interacted with
others as opposed to when the marijuana was smoked in isolation. The average
mean caloric daily intake increased by 758 kcal (p<0.001) across the nine subjects
under active marijuana as compared to placebo conditions during social access
periods. The increased intake was noted to be consumed between meals as snack
foods. In a subsequent study of six subjects confined to the residential laboratory
for 13 days, smoked active marijuana significantly increased total daily caloric
intake by 40%, with increased food intake evident during both private and social
periods (Foltin 1988). The increase was again noted to be confined to between meal
snacks as a consequence of an increased number of snacking occasions, principally
in the sweet, solid item category. The investigators noted that during this short trial,
smoking active marijuana significantly increased body weight. Weight increased an
average of 3 kg over the three day active smoking periods and decreased
subsequently by nearly the same amount over the three day placebo smoking
periods. In their experience, smoking marijuana led to reduced physical activity
levels and increased sleeping time which could explain why increases in body
weight during periods of active marijuana smoking were greater than predicted by
caloric intake alone.
SAFETY
As reported by Dr. Abrams in his soon-to-be-submitted 1997 NIH grant application to
study the
use of smoked marijuana in the treatment of HIV-associated wasting syndrome:
A recently published evaluation of clinical information from the large Kaiser
Permanente health maintenance organization patient database sheds further light on
the question of the overall safety of marijuana. In an article entitled "Marijuana Use
and Mortality," Sidney et al (1997) report on a study population of 65,171 HMO
patients aged 15-49 undergoing multiphasic health checkup examinations between
1979 and 1985. Questionnaires about smoking habits, including marijuana use,
were completed as part of the routine exam during those years. Mortality follow-up
was conducted through 1991. The Kaiser HMO has extensive computerization of
records and excellent follow-up of their members, allowing for meaningful research
to be conducted in this retrospective review fashion. The study subjects consisted
of 37,090 women and 28,081 men. The cohort comprised 38% nonusers of
smoked marijuana, 20% experimenters (ever smoked 1-6 marijuana cigarettes),
20% former users ( none now, but >6 times in past), and 22% current users. The
percentage of ever users ( current + former) was highest in the 20-29 year old age
group and more common in men and whites. Never-married men and women were
twice as likely to be ever users as their married counterparts. Compared with non-
use or experimentation, current marijuana use was not associated with a
significantly increased risk of non-AIDS mortality in men (RR=1.12 [0.89, 1.39]
or of total mortality rate in women (RR=1.09 [0.80,1.49]. Current marijuana use
was found to be associated with an increased risk of AIDS mortality in men with a
relative risk of 1.90 [1.33-2.73]; however the authors attribute this to uncontrolled
confounding by male homosexual behavior and not to a causal relationship. This
interpretation was supported by an analysis of a separate cohort of 214 men in the
Kaiser Permanente Medical Care Program AIDS Database. The diagnosis of AIDS
was subsequent to the determination of their marijuana use status. The prevalence
of marijuana use in this AIDS cohort was 56%, significantly higher that the 38%
prevalence in the unmarried men in the larger study cohort. Interestingly, for these
214 AIDS patients, current use of marijuana was associated with a nonsignificant
decrease in relative risk for total mortality (RR=0.78 [0.47,1.30] and for AIDS
mortality (RR=0.71 [0.41,1.23]. These findings are quite provocative, albeit
limited by the retrospective methodology. Regardless, the impact of marijuana on
specific body systems warrants a prospective evaluation.
Abrams (1996) summarized the literature concerning the safety of the use of smoked
marijuana in
the treatment of HIV-associated wasting syndrome as follows:
Safety Concerns
The potential detrimental effects of marijuana smoking in patients without HIV
infection are numerous. Interestingly, most of the literature is at least twenty years
old and often conflicting reports can be found, occasionally by the same author.
With regard to patients with HIV infection, the impact of smoked marijuana on
immune function, pulmonary function, gonadal function and neuropsychiatric
status have not yet been described and would seem to be particularly critical safety
parameters to examine.
Immune Function
Studies of the effect of marijuana on immunity have been contradictory, and,
when viewed in the aggregate, difficult to interpret. On the one hand, the major
psychoactive component of marijuana, delta-9-tetrahydrocannabinol (THC), has
been reported to suppress immune functions such as lymphocyte proliferation,
antibody production, natural killer cell activity and macrophage function; to
dysregulate production of such pro-inflammatory cytokines as interferon and tumor
necrosis factor (TNF) (Friedman 1995); and to confer altered susceptibility in vivo
to infection with intracellular organisms such as Legionella pneumophilia (Klein
1994; Klein 1995) and in vivo to herpes simplex virus type-1 infected cells (Cabral
1992; Fischer-Stenger 1992). With Munro's discovery of a new type of
cannabinoid receptor present not in the brain but only in peripheral tissues
(particularly reticuloendothelial tissues), the potential for interactions of THC with
the immune system was further validated. In a commentary on the discovery of the
receptor, an industry pharmacologist poses the question, "Is the second
cannabinoid receptor only in the spleen? The level of expression, probably high in
the active macrophages, in a region where the outside world meets the immune
system, suggests a possible role in inflammatory and immune responses to
infection or other foreign antigens." (Iverson 1993).
It has been hypothesized that these effects may be related to THC-induced shifts in
the balance of "Thl" and "Th2" cells (Newton 1994). In contrast, and as reviewed
by Hollister (Hollister 1992), many of the effects so documented for THC have
been observed in conditions, both in vivo and in vitro, in which supraphysiologic
doses of the compound are used and/or without inclusion of controls which have
similar lipophilic properties. Even relatively simple observations (e.g., that
phytohemagglutinin and mixed lymphocyte culture responses are suppressed in
young, chronic marijuana smokers) (Nahas 1974), have been difficult to reproduce
(White 1975; Lau 1976). More recently, conflicting reports have been generated
regarding the impact of THC on levels of TNF-alpha. Whereas some investigators
report THC inhibition of TNF (Friedman 1995), another study utilizing ELISA
(enzyme-linked immunoabsorbant assay) techniques demonstrated decreased
interleukin-6, but increased TNF levels in a mouse macrophage system (Shivers
1994). As these cytokines, particularly TNF, have been implicated in the
pathogenesis of HIV-related wasting, determining the impact of THC on levels of
TNF and related cytokines in human subjects smoking marijuana would be a
significant contribution.
No controlled investigations of the impact of marijuana on immune function in
patients with HIV infection have been conducted to date; however, information
suggesting impaired cellular immune function is certainly worrisome. Interestingly,
suggestions of B lymphocyte modulation and TNF inhibition could, in fact, have
potential beneficial effects in patients with HIV-induced immune dysregulation over
the long term. Whether a stimulant or suppressant of immune function, marijuana
could potentially lead to increased viral burden. This potential effect, as well, has
never been investigated in a prospective, controlled fashion. Retrospective analyses
from the Multicenter AIDS Cohort Study evaluating outcomes in 1662 seropositive
users of psychoactive drugs found that none of the drugs used by participants was
associated with enhanced clinical or immunologic expression of HIV infection
(Kaslow 1989). Of note, use of marijuana in the preceding two years was reported
by 89% of the seropositive men in the cohort. This confirmed a previous
observation from our San Francisco General Hospital experience (Roland 1987).
The disparate results on the effects of THC on the immune system may be related
to differences in study populations, drug composition, drug concentration, or assay
conditions. Taking a conservative approach, it is perhaps reasonable at this juncture
to assume that marijuana can exert immunosuppressive effects under certain
experimental conditions.
Pulmonary Effects
Much of the work on the pulmonary effects of smoked marijuana has been done
by Tashkin and his group at the University of California Los Angeles. Again, the
published data are less than crystal clear. Tashkin wrote in 1987 that "evidence
regarding the potential long-term pulmonary consequences of regular marijuana
smoking is mixed. Several studies conducted during the past decade on whole
animals and isolated cell systems exposed to marijuana smoke, as well as some
clinical observations, suggest that marijuana can be harmful to the lung.
Conversely, human studies carried out abroad have failed to find any evidence of
respiratory dysfunction or disease in long-term heavy users of marijuana" (Tashkin
1987). However, when comparing effects in tobacco and marijuana smokers,
Tashkin has demonstrated that marijuana smoke can be harmful to the lungs. In a
chronic smoking experiment, young healthy volunteers developed decreases in
forced expiratory volume in one second (FEV1), in maximal mid-expiratory flow
rate, in plethysomographic specific airway conductance and diffusing capacity
(Tashkin 1976)."
In a recent paper, however, heavy habitual marijuana smoking did not cause an
accelerated
decline in FEV1 with age (Tashkin 1997). Dr. Abrams continues:
In subsequent studies comparing the effects of marijuana smoke to tobacco, his
group has reported that marijuana users have significant pulmonary symptoms
(cough, sputum, wheeze, bronchitis episodes); detrimental effects on specific
airway conductance and resistance (Tashkin 1987); an inconsistent effect on
nonspecific airway hyperresponsiveness (Tashkin 1993); a high prevalence of
abnormal airway appearance and histologic findings including squamous metaplasia
and dysplasia (Tashkin 1987); an increased alveolar cellular response composed
predominantly of alveolar macrophages (Tashkin 1987); a substantially greater
respiratory burden of carbon monoxide and tar than those smoking a similar
quantity of tobacco (Wu 1988); and a trend towards increased alveolar macrophage
DNA damage (Sherman 1995). In a recent report, Tashkin's group defines a
differential effect of tobacco and marijuana on lower respiratory tract and circulating
T-lymphocyte subpopulations (Wallace 1994). Tobacco was found to have a
significant effect toward decreasing percentages of bronchoalveolar CD4 cells and
increasing CD8 cells, thus yielding lower CD4:CD8 ratios, whereas marijuana use
decreased the percentage of bronchoalveolar CD8 cells. Both tobacco and marijuana
increased bronchoalveolar B-lymphocyte populations. In the peripheral blood,
marijuana (but not tobacco use) was associated with increased percentages of CD4
cells, decreased CD8 lymphocytes and an elevated CD4:CD8 ratio - effects
frequently sought through therapeutic intervention in patients with HIV infection.
Concerns about the potential risk of sinopulmonary infection from smoking
marijuana have been longstanding. Aspergillus contamination of marijuana has been
noted and presumed to be the cause of possible clinical infection (Kagen 1981;
Schwartz 1985). More recent studies have demonstrated decreased ability of
pulmonary alveolar macrophages to destroy Candida albicans (Sherman 1991) and
suppressed resistance to Legionella pneumophilia secondary to THC (Klein 1994,
Klein 1995). These findings would be of concern with regard to an increased
possibility of pulmonary infectious processes in patients with acquired immune
deficiency utilizing smoked marijuana. No prospective analysis of such risk has
been conducted, although a retrospective review examining risk factors for the first
episode of bacterial pneumonia among HIV positive injection drug users with a
prior history of Pneumocystis carinii pneumonia found that "smoking illicit drugs"
was a significant risk (Caiaffa 1994). Unfortunately, marijuana was included
together with cocaine and crack smoking in this analysis. In addition, virtually all of
the injection drug users evaluated also smoked cigarettes, further confounding the
analysis. Despite the statistical significance and the higher prevalence of marijuana
use (88%) compared to cocaine (26%) and crack (9%) smoking, the data
supporting the claim that smoking illicit drugs had the strongest effect on the risk of
bacterial pneumonia in this narrow subpopulation of AIDS patients would be
strengthened if the individual smoked agents had been analyzed separately.
Endocrine Effects
It has been demonstrated that men with HIV infection may become hypogonadal
during the course of their disease (Dobs 1988; Croxson 1989; Raffi 1991; Christeff
1992). It is conceivable that agents such as marijuana may have an impact on
changes in male sex hormones. Testosterone synthesis in rats is decreased by THC.
In a four week exposure study in men conducted in the 1970's, a decrease in
luteinizing hormone (LH) occurred first, followed by decreases in testosterone and
follicle-stimulating hormone (FSH). A more recent evaluation in ten chronic
marijuana users demonstrated that basal and stimulated levels of LH were reduced
in comparison to age-matched controls, with no difference in FSH and prolactin
levels and responses (Vescovi 1992). The authors postulate that chronic marijuana
use may selectively impair the hypothalamic mechanism regulating LH secretion. In
the current study, this information is relevant as hypogonadism has been associated
with AIDS-related wasting (Coodley 1994). Marijuana smoking could precipitate or
exacerbate the hypogonadal state necessitating testosterone replacement therapy.
Neuropsychiatric Effects
The question of the acute neuropsychological effects of marijuana intoxication on
healthy subjects has been addressed in several studies in recent years. Research
indicates that acute cognitive effects do exist. They may vary based on the amount
of prior exposure to marijuana (Marks 1989), and may (Solowij 1995; Block 1993;
Solowij 1991; Varma 1988) or may not be confounded by chronic cognitive effects
of long term, heavy exposure to the substance (Lundquist, 1995; Carlin 1977;
Weckowicz 1977; Weckowicz 1973).
Research has generally found that cognitive impairment covaries with the amount
of marijuana exposure and plasma THC levels. Most studies indicate that this
impairment may last anywhere from 65 minutes (Heishman 1989) to 24 hours
(Leirer 1991; Heishman 1990) after exposure. Heishman (1990) found that on the
day of exposure subjects exhibited decreased performance on a serial
addition/subtraction task. Their performance returned to baseline the following day.
Frank (1976) noted a slight acute effect, but no significant difference between
marijuana exposed and control group patients over time on an unnamed
"computation" task. Research is conflicting regarding the acute effects of marijuana
on tho Digit Symbol Subtest of the Wechsler Adult Intelligence Scale - Revised
(WAIS-R) (1981), a task of visual-motor speed and novel learning. Some studies
indicate that impairment is present (Azorlosa 1992; Heishman 1989), and others
report a normal performance in marijuana-exposed subjects (Chait 1990; Chait
1985; Jones 1976). On an unnamed complex visual matching task, Jones (1976)
found a pattern of slowing of response time during initial THC exposure followed
by a return to baseline performance, despite continued THC exposure. In addition,
several subjects (3 of 12) showed no impairment in performance on the task during
the thirty day study. This suggests both acclimation to THC, as well as a possible
practice effect on the measure. While one study found no effect of marijuana on a
computerized task of divided attention (Heishman 1989), others who have explored
this cognitive domain have found impairment in subcomponents of the task
(Azorlosa 1992; Barnett 1985; Chait 1990). Frank (1976) gave their subjects the
Trail Making Test, another measure of executive functioning, on three occasions
during a 36 day hospital admission. They found no significant differences between
marijuana-exposed and control subjects, but noted a slight practice effect on the
test.Studies using a computerized program for central and peripheral light reaction
time (Heishman 1990; Marks 1989) both found impairment with acute marijuana
exposure. Research indicates that acute marijuana exposure impairs ability to
accurately judge brief time intervals (Chait 1990; Chait 1985; Ferraro 1980), and to
rapidly sort cards into complex (by suit), and simple (equal stacks, face down)
categories. In addition Chait (1992) found that marijuana significantly decreased the
number of words generated on a free recall task.
Other measures have been employed in the investigation of the present topic. Each
of these has been explored by one investigator, who has found no significant
difference between baseline and acute marijuana exposure performances: a
computerized version of The Buschke Selective Reminding Task (Chait 1990), an
unidentified task of auditory memory (Jones 1976), a task of logical reasoning and
a "two letter search" (Heishman 1990).
There are shortcomings in the methodology of the studies cited above. A number
of the measures outlined above are presented in a non-standardized manner. Each of
the above mentioned studies of marijuana use also addressed the use of other drugs
and alcohol in the sample. Still, subjects often varied within studies on the amount
of alcohol and other substances consumed, both by history, and at the time of
research. Finally, studies which did not require subjects to remain in a controlled
setting during the course of the research may also have allowed exposure to
substances/events which could have skewed results.
Most studies cited above attempted to carefully screen out for medical illness or
conditions which may contribute to cognitive impairment. No study as yet has
addressed the cognitive effects of the use of marijuana in a population of HIV-
positive patients who are using the substance to control symptoms of their illness.
Tumors
The National Toxicology Program conducted a two-year study of male and female rats and
mice
(NTP Technical Report, 1996). Compared to control animals, rodents who received large
doses of
delta-9 THC by gavage had fewer malignant tumors and survived significantly longer than
the
controls.
- MAPS seeks orphan-drug designation for smoked marijuana. This is a different drug
with a
different route of administration than oral THC. Smoked marijuana contains numerous
other
cannabinoids and other ingredients that are absent from the oral THC preparation.
Whether any of
these other cannabinoids and/or the smoking route of administration are therapeutically
advantageous in the treatment of HIV-associated wasting syndrome has yet to be confirmed
in
scientific studies. The extent to which the extraneous plant materials will result in
clinically relevant
side effects is also unknown at this time.
A survey of 123 people with HIV infection in Hawaii revealed that 37% had used
marijuana in the
treatment of their HIV/AIDS (Wesner 1996). Of those who had used both marijuana and
prescription anti-emetics, marijuana was preferred by 80%. The ability to titrate the
onset and
intensity of drug effect and the shorter overall duration of effects are most often cited as
reasons for
the preference for smoked marijuana compared to oral THC.
- The CDC has determined that the diagnosis of HIV-associated wasting syndrome is
medically
plausible and has created a specific definition for this syndrome. The modifications of the
CDC
diagnostic criteria proposed by MAPS have either been suggested by staff of the CDC, by
researchers expert in the study and treatment of HIV-associated wasting syndrome, or
conform to
the proposed inclusion criteria of the clinical trials that will hopefully be conducted.
- The medical use of marijuana in a variety of dosage forms, including smoked, was legal
in the
United States until the 1937 Marijuana Tax Act. From 1937 to the present, the medical use
of
smoked marijuana by prescription has not been officially permitted in the United States.
At the time
of this application, smoked marijuana is not a legally prescribed medicine anywhere in
the world.
Eight patients in the United States do currently receive legal supplies of smoked
marijuana from
NIDA under an FDA Compassionate IND program that was closed to new applicants in
1992.
The medical use of smoked marijuana, when recommended or approved by a physician, is
legal
under state law in California pursuant to the passage of a 1996 initiative. The issue of
state versus
federal jurisdiction over the medical use of marijuana is currently the subject of
controversy and
two class action lawsuits.
Numerous juries across the United States have recognized a "medical necessity defense"
that
applies to some medical uses of marijuana and have found that some patients who use
marijuana
for medical purposes are innocent of a criminal offense.
There have been no studies in the United States in over a decade into the medical use of
smoked
marijuana in a patient population. Previous studies conducted from the late 1970's to the
early
1980's examined the use of smoked marijuana and oral THC in the treatment of nausea and
vomiting associated with cancer chemotherapy. The outcome of these studies was FDA
approval of
the oral THC capsule, Marinol, for prescription use in the treatment of nausea and
vomiting
associated with cancer chemotherapy. After FDA approval of Marinol, no further research
was
conducted into the use of smoked marijuana in the treatment of nausea and vomiting
associated
with chemotherapy. Subsequent research with the use of THC capsules in the treatment of
HIV-
related wasting syndrome resulted in their approval for that use in 1992.
Dr. Abrams and associates, with support from MAPS, have been trying for over four years
to
obtain permission to study the use of smoked marijuana in the treatment of HIV-associated
anorexia and wasting syndrome. Abrams (1996) reports:
We proceeded in 1993 to develop a pilot study comparing three different strengths
of inhaled marijuana to the licensed tetrahydrocannabinol preparation, dronabinol,
which is approved for treatment of anorexia associated with HIV-associated
wasting. The 12-week pilot study was to be conducted as an outpatient study and
would include body composition measurements as well as evaluations of
pulmonary function, endocrine function and HIV viral load. The study was
designed with constructive input from the Pilot Drug Evaluation Staff at the FDA,
from whom an IND was obtained (#43,542). The pilot study was also approved by
the Committee on Human Research at the University of California at San Francisco,
and received conditional approval from the California Research Advisory Panel
(which reviews all clinical trials involving controlled substances), pending
identification of a legal source of marijuana. Multiple complications ensued over the
next three years regarding obtaining a legal supply of marijuana to use in the study
(Voelker 1994; Kingman 1995; Lehrman 1995; Grinspoon 1995; Abrams 1995;
Steele 1995).
In the summer of 1995, Dr. Alan Lesher, Director of NIDA, announced a new policy
regarding
the provision of NIDA marijuana for research into its medical uses; only projects that were
approved by the NIH peer-review process would receive marijuana. Since NIDA has a
monopoly
on the supply of marijuana legal for research, Dr. Abrams and associates, with support
from
MAPS, submitted an NIH grant application in May 1996 for a redesigned, intensive, Phase
I/II
study comparing smoked marijuana versus placebo in an inpatient setting. In August
1996, this
grant application was rejected by peer-review at the National Institute of Allergy and
Infectious
Diseases (NIAID).
Dr. Abrams and associates, with support from MAPS, are preparing to submit yet another
redesigned NIH grant application in May 1997. Dr. Abrams' new protocol will be
submitted to a
NIDA study section. The new design was prepared in consultation with Dr. Robert Temple
and
Dr. Curtis Wright of the FDA, and followed the suggestions on protocol design that Dr.
Temple
outlined at the February 19-20, 1997 NIH Workshop on the Medical Utility of Marijuana.
At the
conclusion of that meeting, Dr. Leshner indicated that he was of the opinion that Dr.
Abrams' next
grant application stood a very good chance of being approved. Whether Dr. Leshner was
correct
about the likelihood of approval for Dr. Abrams' study will be determined when the
results of the
upcoming NIDA peer-review are announced around August 1997.
If MAPS is granted its request for Orphan Drug Designation for smoked marijuana for
HIV-
associated wasting syndrome, it intends to request a grant from the Orphan Drug
Development
program. This grant program includes a peer-review process that would probably meet
NIDA
requirements for the provision of its marijuana to a research project.
After research with smoked marijuana is approved, MAPS intends to begin seeking
permission to
establish its own production facility to replace NIDA supplies with material determined
by FDA to
be equivalent or better to that supplied by NIDA. If smoked marijuana is approved for
marketing,
MAPS will need to have developed an alternative production facility in order to supply
pharmacies
because NIDA is only authorized to supply marijuana for research purposes.
- HIV-associated wasting syndrome or AIDS-associated catabolism/weight loss has
already been
designated an orphan disease in the context of orphan-drug designation for sermoelin
acetate
(2/13/90), oxandrolone (9/6/91), dronabinol (1/15/91, approved for marketing
12/22/92),
somatropin (11/15/91, approved for marketing 8/23/96), testosterone (2/5/96),
dihydrotestosterone
(2/5/96), and thalidomide (3/11/96).
In order to determine if there are still fewer than 200,000 people suffering from HIV-
associated
wasting syndrome at the time of this application, it is necessary to estimate the total
number of
people with AIDS at the time of this application and then estimate the total number of
people with
AIDS at the time of this application who also have wasting syndrome.
In the calculations detailed below, there are an estimated maximum of 275,000 people
living with
AIDS as of the end of April 1997, slightly after the time of this application. Of that
number, it is
estimated that a maximum of 31% suffer from HIV-associated wasting syndrome. These
calculations result in an estimated maximum number of people suffering from the HIV-
associated
wasting syndrome of about 82,250. Under all reasonable sets of assumptions, there are
fewer than
200,000 people suffering from HIV-associated wasting syndrome at the time of this
application.
ESTIMATED PREVALENCE OF AIDS AS OF JUNE 1996
According to the CDC's February 1997 report on HIV-AIDS trends, as of June 30, 1996,
the
latest date for which specific numbers are available, the estimated prevalence of AIDS was
223,000
U.S. residents aged 13 years or older (MMWR, February 28, 1997). The HIV/AIDS
Surveillance
Report (March 1997) noted that there were 3,207 children under 13 living with AIDS as of
December 31, 1996. Thus, 223,000 is a slight underestimate for the total number of people
of all
ages with AIDS as of June 1996. For purposes of this application, the number of people of
all ages
living with AIDS as of June 1996 will be assumed to be 227,000.
ESTIMATED PREVALENCE OF AIDS FROM JULY 1, 1996 TO APRIL 30, 1997
One method of estimating the prevalence of AIDS as of the end of April 1997, shortly
after the
date of this application, is to estimate the number of new AIDS cases reported from mid-
1996 to
the end of April 1997 and then to subtract from that number the estimated death rate from
AIDS
from mid-1996 to the end of April 1997. If the estimates used are of a "reasonable
maximum"
number of new cases and a "reasonable minimum" number of deaths, the end result will be
an
estimate that probably overstates rather than understates the prevalence of AIDS as of
April 1997.
According to the CDC, the total number of new AIDS cases reported in 1996 (January 1-
December 31, 1996) was 69,151 (68,473 adults and adolescents „13 years of age and 678
pediatric cases <13 years of age). The annual number of new AIDS cases has been declining
since
1993. However, the annual number of new cases of AIDS with opportunistic infections
(AIDS-OI)
has been growing slightly at around 2%. According to the CDC, "Between 1994 and 1995,
the
estimated number of people diagnosed with AIDS (AIDS incidence) [The MMWR report
indicates
that these numbers refer to the incidence of diagnoses of AIDS with opportunistic
infections]
increased 2%, from 61,200 to 62,200. These estimates reflect a slowing in the growth of
the
epidemic, with an average of 15,200 diagnosed each quarter between January 1994 and
June
1996. Hopefully, with a combined strategy to prevent new infections and provide early
diagnosis
and treatment for people who are infected, AIDS incidence will soon begin to decline (CDC
Update, February 1997)."
To estimate a reasonable maximum for the increased number of cases of AIDS from mid-
1996 to
the end of the first quarter of 1997,the larger number of reported AIDS cases will be used
instead
of the smaller number of reported diagnoses of AIDS-OI. It will also be assumed that there
is no
continuation in the reduction in the rate of reported AIDS cases. Since there were 69,151
total
reported AIDS cases in 1996 (down from 72,967 >13 yrs in 1995), it should be a slight
overestimate to assume that half of the cases for 1996, or 34,876, took place in the second
half of
1996. It should similarly be a slight overestimate to assume that there were 23,248 new
cases (2/3
of 34,237) from January to the end of April 1997. These assumptions result in an
estimated total of
58,124 new cases from mid-1996 to the end of April 1997. For the sake of simplicity, the
number
of new cases to be used in this calculation will be rounded up from 58,124 to 60,000.
According to the CDC (MMWR, Feb. 28, 1997), the estimated numbers of deaths of people
who
had AIDS during the first two quarters of 1996 was 22,000. This was 13% less than the
estimated
number of deaths during the first two quarters of 1995. This trend marked the first
decline in AIDS
deaths in the history of the epidemic. According to HIV/AIDS Surveillance Report (Vol. 8,
No. 2),
the total number of AIDS deaths for the first two quarters of 1996 (as reported by
December 1996)
was 18,169, certain to be an underestimate due to delayed reporting. As of December
1996, there
were 7,526 deaths reported in the second half of 1996, certain to be an underestimate due
to
delayed reporting.
Given the remarkable claims that are being made about the therapeutic effects of protease
inhibitors, it is difficult to estimate with any degree of confidence what the actual death
rates have
been from July 1996 to the end of April 1997. What is certain is that the death rates are
continuing
to fall from a minimum of 18,169 in the first half of 1996.
At the lowest limit, there were no deaths from AIDS in 1997 and only 7,526 deaths in the
second
half of 1996. A more reasonable minimum estimate would be 9,000 deaths in the second
half of
1996 (this would represent at least a 50% decline in death rates from the first half of
1996), and
3,000 deaths from January through April 1997 (this would represent another 50% decline
in death
rates from the rate in the second half of 1996). Thus, a reasonable minimum number of
deaths
from July 1996 through April 1997 is 12,000.
Subtracting the reasonable minimum estimate of 12,000 new deaths from mid-1996 to the
end of
April 1997 from the reasonable maximum of 60,000 new AIDS cases from mid-1996 to the
end of
April 1997 yields a net increase of 48,000 more people living with AIDS at the end of
April 1997.
Adding the previously estimated 227,000 people living with AIDS as of mid-1996 to the
reasonable maximum of 48,000 new people living with AIDS at the end of April 1997 leads
to an
estimate of 275,000 people living with AIDS at the end of April 1997.
REASONABLE MAXIMUM ESTIMATED PREVALENCE AS OF APRIL 30, 1997
It can be estimated with a substantial degree of confidence that there will be no more
than 275,000
people living with AIDS at the end of April 1997, when this request for orphan-drug
designation is
filed.
ESTIMATED PREVALENCE OF HIV-ASSOCIATED WASTING SYNDROME
There are two basic approaches to estimating the prevalence of HIV-associated wasting
syndrome
in the population of people living with AIDS. One approach involves a review of the data
from
AIDS cases reported to the CDC. Another approach involves a review of data from death
certificates.
ESTIMATED PREVALENCE OF HIV-ASSOCIATED WASTING - CDC REPORTS
A close inspection of HIV-associated wasting cases reported to the CDC suggests that
many do
not meet the formal diagnostic criteria established by the CDC. As a result, estimates
based on
CDC surveillance data may overestimate the prevalence of a narrowly defined wasting
syndrome.
Nwanyanwu (1993) reported that "Medical charts were available for review for 165
(82.5%) of
200 patients. Of these, 148 (89.7) had documented evidence of weight loss, 117 (70.9%)
weakness, 68 (44.8%) diarrhea, 91 (55.2%) fever, and 9 (5.5%) had no documented criteria
for
WS in their medical charts. Overall, 74 (44.9%) had complete documentation of diagnostic
criteria
of WS in the charts, and 91 (55.2%) has incomplete documentation of WS. Of the 91
patients who
did not meet the surveillance criteria, 63 (69.2%) missed one clinical manifestation, 19
(20.9%)
missed two clinical manifestations, and 9 (9.9%) had no documentation of WS criteria."
However,
since the definition of HIV-associated wasting syndrome proposed by MAPS is less
narrowly
defined than the CDC definition, a reasonable estimate of the prevalence of HIV-associated
wasting
can still be made using the number of cases reported to the CDC.
Nahlen (1993) examined the records for all 147,225 individuals reported to the CDC with
AIDS
from September 1, 1987 to August 31, 1991. He reported that "a total of 10,525 (7.1%) had
wasting syndrome as the only AIDS indicator condition and 15,726 (10.7%) had wasting
syndrome plus at least one other AIDS-indicator system." Thus, 17.8% of all AIDS
patients had
AIDS wasting syndrome. He also noted that "The true cumulative incidence of wasting
syndrome
is probably much greater than this, since many diseases that occur after diagnosis of the
initial
AIDS-indicator disease are not reported CDC."
According to the CDC's HIV Surveillance Report (Vo. 8, No 2), HIV-associated wasting
syndrome was an AIDS-indicator condition in 19% of the new adult/adolescent AIDS cases
reported in 1996, and in 15% of the new pediatric AIDS cases. These estimates are likely
to be
underestimates due to a lack of reporting of the development of new conditions.
The highest estimate of the prevalence of HIV-associated wasting ever reported in the
scientific
literarure was 31%, out of a sample of 26 patients at the Naval Medical Center in San
Diego, in
1992 (Weiss 1993). Due to its small sample size, this study cannot be assumed to be
represenative
of the entire population of AIDS patients. A study involving 844 men in whom AIDS was
diagnosed found that the incidence of HIV-associated wasting syndome was 18.4% (Hoover
1993).
ESTIMATED PREVALENCE OF HIV-ASSOCIATED WASTING SYNDROME-DEATHS
Another approach to estimating the prevalence of HIV-associated wasting syndrome is to
review
death certificates for cause of death. Selik and Ward (1996) reported that "the percentage
of
documented HIV-related deaths associated with any of these conditions [wasting-
nutritional
marasmus, severe calorie deficiency, severe malnutrition not otherwise specified,
unspecified
protein-calorie malnutrition, abnormal weight loss, and cachexia] has more than doubled
from
3.9% (394 of 10001) in 1987 to 10.8% (2618 of 24,230) in 1992." Selik's unpublished
data
indicates that the percentage of patient deaths from wasting syndrome rose to 11.7% in
1993 and
13.4% in 1994 (Selik, 1997).
Complicating the use of death certificates to determine the number of AIDS wasting
patients is
that fact that death certificates may underestimate the prevalence of wasting syndrome.
Seligman
and Gross (1996) reported that many "diagnoses reflecting weight loss are frequently
omitted from
death certificates."
According to Selik (1997), " A figure [for the prevalence of AIDS wasting in AIDS
patients]
closer to the truth might be the 22% found for persons with HIV infection who were
followed until
they died during 1991-1994 (from CDC's "Adult and Adolescent Spectrum of Disease
Project,"
unpublished data, Jeffrey L. Jones, MD.)
An even higher estimate of 25% for the prevalence of HIV-associated wasting was
reported by
Chan (1995) in a study of 1883 individuals who died from AIDS. The study combined
medical
history data obtained at the time of follow-up, new events that occurred during follow-up,
and
causes of death.
SUMMARY
The increasing use of protease inhibitors is dramatically reducing the incidence of HIV-
associated
wasting syndrome. The extent to which this is true will not be quantified for some time. In
the
context of this application for Orphan Drug designation, the most conservative approach is
to use
the highest estimate of the prevalence of HIV-associated wasting syndrome obtained from
any
source, that being the estimate of 31% obtained by Weiss (1993) in 1992 from a sample of
26
patients at the Naval Medical Center in San Diego.
Combining the estimate that a maximum of 31% of all AIDS patients have wasting
syndrome with
the previous "reasonable maximum" prevalence estimate of 275,000 AIDS patients as of
the end of
April 1997, results in an estimate of a maximum of 82, 250 people with wasting syndrome.
For the number of AIDS patients with wasting syndrome to exceed 200,000, 72.8% of the
estimated maximum of 275,000 AIDS patients would need to have wasting syndrome. It
therefore
seems certain that the number of patients with HIV-associated wasting syndrome number
less than
200,000.
- MAPS is the real party in interest in the development of the medical use of smoked
marijuana in
the treatment of the HIV-associated wasting syndrome.
The intended production and sales of marijuana cannot be estimated with any degree of
accuracy.
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