MAPS: Medical Marijuana Research: Request for Orphan Drug Designation for Smoked Marijuana in the Treatment of HIV-Associated Wasting Syndrome

Request for Orphan Drug Designation for Smoked Marijuana in the Treatment of HIV-Associated Wasting Syndrome

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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.

Nahlen (1993) describes the HIV-associatedwasting syndrome by noting that:

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.