Walter Krampf, M.D., M.P.H., is a practicing physician and AIDS patient specialist in San Francisco, California.

 

Since July 1981, when the Centers for Disease Control (CDC) first described the disease known as acquired immune deficiency syndrome (AIDS), there have been approximately 513,000 reported cases in the United States and 320,000 deaths (as of March 31, 1996). The World Health Organization stated that as of late 1995 there have been 1,300,000 persons reported with AIDS worldwide and has estimated that there were probably 6 million cases. Furthermore, it estimated that as of 1995 there were probably 17 million people alive with HIV/AIDS. The epidemic is expanding rapidly, and the degree of morbidity associated with it is enormous. There are certain AIDS conditions for which the therapeutic use of cannabis has been found helpful. For the persons affected cannabis should be readily available and healthcare providers should be educated about the benefits of its use.

 

Definition of the Wasting Syndrome

 

One of the worst symptoms of AIDS is a condition known in the United States as the wasting syndrome. It is characterized by a significant (>10 percent) loss of body weight in a person who is HIV antibody positive and may be associated with fever and diarrhea. The presence of this syndrome alone, without any other conditions of AIDS, is sufficient to justify an AIDS diagnosis (CDC, 1987). In Africa the wasting syndrome is so prevalent it has been named "slim disease." It is the most common clinical manifestation of HIV infection in Africa and has been observed to be a precursor of death.

 

The wasting syndrome is very common. In one study of AIDS diagnoses, 17.8 percent of all AIDS patients were diagnosed with AIDS on the basis of having the wasting syndrome (Nahlen et al. 1993). Of those 17.8 percent, 7.1 percent had only the wasting syndrome and 10.7 percent had the wasting syndrome and one other AIDS condition. However, the wasting syndrome is even more prevalent than this data indicates. Persons with AIDS are reported to the Department of Public Health when a first diagnosis of AIDS occurs. Subsequent diagnoses are frequently not reported. Thus patients who develop the wasting syndrome after their first AIDS diagnosis will go unreported. Patients with only wasting syndrome as their AIDS diagnosis are more likely to be women, more likely to be black or Hispanic, and less likely to be homosexual men.

In addition to the classic wasting syndrome, where no apparent cause for weight loss is found except HIV itself, there are a number of gastrointestinal infections that can lead to severe diarrhea, vomiting, pain, and fever, all of which can be accompanied by weight loss. These include those caused by bacteria (shigella, salmonella, campylobacter), protozoa (cryptosporidia, microsporidia, amebiasis, giardiasis), mycobacteria (Mycobacterium avium complex), and viruses (cytomegalovirus). Weight loss itself is such a debilitating condition that it can quickly predispose the body to further infections, to significant weakness, and can render the patient unable to care for himself or herself. Death in AIDS patients can be predicted by the magnitude of body wasting (Grunfeld and Kotler 1992).

 

Another cause of wasting in AIDS is the patient's inability to eat due to a loss ofappetite. Ironically, many of the medications that persons with HIV take to treat or prevent specific illnesses have a loss of appetite or nausea as a side effect. Nausea is a common side effect of retrovir (AZT), the main antiretroviral drug used to treat HIV infection. Two malignancies are also frequently seen in persons with AIDS: non—Hodgkin's lymphoma and the much more prevalent Kaposi's sarcoma, both of which are often treated with chemotherapy. This treatment frequently causes further significant nausea and vomiting and appetite depression.

 

Current Treatments of Wasting and Appetite Stimulation

 

Because the consequences of wasting are so severe, nutritional interventions as well as medications have been tested to try to stop and reverse the loss of weight. Both oral and intravenous food preparations have been used. Among the different drugs studied have been various antinausea and antiemetic preparations, a synthetic progesterone called Megace, growth hormone, and cannabinoids.

 

Megace, a hormone used to treat inoperable breast cancer, was found to produce weight gain in a significant number of patients. This drug has also been studied in persons with AIDS, and a similar stimulation of appetite and subsequent weight gain has been observed (Tierney, Cuff and Kotler 1991; Von Roenn et al. 1991). Its appetite stimulation effect, however, seems to decrease over time. Megace is now available in a high-concentration, liquid suspension and is relatively easy to take. Cost of the recommended 800 mg daily dose is approximately $10.00 per day.

 

An old medication that was taken off the market because of severe teratogenic effects in pregnant women but is now being studied again is the sedative thalidomide. Due to its devastating effects on limb development in the fetus, it is no longer prescribable, but it has been shown to selectively inhibit tumor necrosis factor alpha, a factor implicated in the pathogenesis of wasting. Multiple studies are currently evaluating its effectiveness, and it seems promising (Klauser et al. 1994; Reyes-Teran et al. 1994). Side effects include sedation, neuropathy, and rash. Thalidomide is also being studied to treat aphthous ulcers, a common oral manifestation in persons with HIV that also interferes with eating because of pain.

 

Another drug under investigation to promote weight gain is recombinant human growth hormone (Schambelan et al. 1995). It generally produces an increase in lean body mass rather than just fat. Growth hormone is an already approved drug, but it has not been approved for this specific indication, that is, weight gain in persons with AIDS. Although this may ultimately prove to be an effective and useful medication, it needs to be injected daily, and its current cost to the patient is about $150.00 per day. This price makes it essentially unavailable to the vast majority of HIV-infected people.

 

Another modality for treating the wasting syndrome has been the use of intravenous nutritional supplements known as total parenteral nutrition (TPN). Large amounts of nutritional supplements (sugars, vitamins, minerals and electrolytes) are administered between 8 and 24 hours a day through an indwelling intravenous catheter. Not only are the nutritional supplements expensive (several hundred dollars per day), but the maintenance of this system is very costly, and requires skilled medical personnel, catheter installation, and blood tests to continually monitor the solutions given. Furthermore, the limitations of TPN in reversing the wasting syndrome are well known. Catheter infections are a constant threat, and the infusions are very disruptive. This intervention is not one that can be embarked upon lightly nor could it ever be suggested for large populations of affected individuals.

 

Studies of smoked cannabis in healthy volunteers to test its effects on appetite stimulation and weight gain have shown it to be effective (Foltin, Fischman and Byrne 1988). Most of the current research on the effectiveness of cannabinoids, however, is based on the studies with dronabinol (brand name Marinol), a synthetic preparation of delta-9-tetrahydrocannabinol (THC), the major psychoactive ingredient in cannabis (Gorter 1991; Gorter, Seefried and Volberding 1991; Plasse et al. 1991 and 1992; Struwe et al. 1992). Repeatedly, these studies have shown that dronabinol suppresses nausea, stimulates appetite, and prevents further weight loss or actually leads to weight gain. In addition, there are very few side effects, and if present, they are not life-threatening and reverse quickly when the drug is discontinued. The FDA has approved Marinol as both an antinausea and antivomiting agent for cancer chemotherapy, and more recently it has been approved for stimulating appetite and preventing weight loss in people with AIDS.

 

Dronabinol at 2.5 mg twice a day has been found useful in combating the wasting syndrome. In studies this dosage correlated with minimal side effects and maximal beneficial effects. Higher doses are generally needed for antinausea and antivomiting action to counteract the effects of chemotherapy. One major drawback to prescribed dronabinol is its cost. A 2.5 mg capsule retails for about $4.00, costing the patient $8.00 per day for this one medication alone if taken twice a day. Five milligram Marinol capsules retail between $7.00 and $8.00 per capsule. If the patient has health insurance that covers prescription medications, this cost is then passed on to the insurance company. Cannabis is a much cheaper alternative, but the current illegal status of the plant keeps the cost unnecessarily high. For persons without health insurance or without a policy covering drugs (such as Medicaid or MediCal), dronabinol becomes yet one more very expensive drug among a host of other very expensive AIDS drugs, and one for which an inexpensive alternative exists.

 

Adverse Effects

 

One of the major reasons presented against the use of cannabis in people with HIV infection is its supposed suppression of the immune system. At this time, this conclusion is unsubstantiated. The studies this conclusion is based on have been predominantly in vitro studies of cells exposed to very high concentrations of THC (Hollister 1992). The clinical significance of this data is not clear, but all current clinical and epidemiological studies have shown no difference in immune function between users and nonusers of cannabis (Dax et al. 1989; Dax et al. 1991; Hollister, 1992). Therefore, any immune suppressant effect must be quite small and does not compare to the potential gain from the positive effects of cannabis use in AIDS, particularly in counteracting the wasting syndrome. Epidemiological studies have shown that persons who use cannabis are no more likely than nonusers to progress to AIDS or to become HIV infected. Furthermore, starvation and malnutrition are themselves significantly immunosuppressive, much more so than any suppressive effects ascribed to cannabis. It is hard to overemphasize the severity of the debilitation and malnutrition accompanying the wasting syndrome or the need for good nutrition to maintain a functioning immune system. Methods that encourage a patient's own increased intake of food are to be endorsed and cannabis seems to do just that. That aspect of cannabis use greatly outweighs any clinical immunosuppressive effects ascribed to it that have yet to be demonstrated.

 

Among the more commonly described side effects of the use of dronabinol and cannabis are drowsiness or anxiety. For many users, these side effects pass with continued use although dose modifications may be required. Acute agitation and paranoia are much less frequently encountered symptoms, but some patients may not be able to tolerate cannabis at all. The description of Marinol that accompanies the drug, written by the manufacturer, lists feeling "high" as an adverse reaction that occurred in 24 percent of the persons enrolled in clinical trials of the drug. However, this adverse reaction could be seen as a beneficial effect, particularly in a patient who is feeling ill, depressed, or dysphoric, symptoms frequently encountered in people with AIDS. Incidentally, depression is a very common symptom in people with AIDS and is very frequently treated with antidepressant medications that often have significant side effects.

 

Smoking cannabis has concerned some physicians because of an infection called aspergillosis, caused by the fungus aspergillus. The spores of this fungus have been found on marijuana, and it is feared that persons with suppressed immune systems who inhale these fungi might be at risk for a pulmonary or systemic infection caused by it (Levitz and Diamond 1991; Sutton, Lum and Torti 1986). Aspergillosis has been described in persons with AIDS, but it is a very uncommon infection (particularly considering the numbers of persons believed to inhale marijuana). Baking cannabis in the oven prior to smoking will kill these spores as does baking it for eating. If a sterilized commercially prepared cannabis were legally available, this concern would be obviated.

 

Anecdotal Experience with Marinol and Cannabis

 

In the past 13 years, I have treated hundreds of people with HIV infection. Many patients had the severe weight loss that characterizes the wasting syndrome as well as the wasting that accompanies other AIDS-related infections and malignancies. I have found the use of dronabinol, and particularly the use of cannabis, to be beneficial.

 

I first started prescribing dronabinol to treat the nausea and vomiting associated with chemotherapy for AIDS-related malignancies and discovered that it was very well tolerated and effective. Patients often reported that they both smoked and ate cannabis. Many who had tried dronabinol preferred cannabis. They reported that with smoked cannabis they could much better control their dosage than with dronabinol. They could smoke a small amount, wait for the alleviation of symptoms or for appetite to increase, and smoke more if needed. They avoided the experience observed with oral medication: ingesting more than was needed and getting more side effects. Some patients remarked that although they preferred smoking cannabis, Marinol, being an approved drug, was covered on their health insurance plans. For financial reasons, they felt they had to choose the less desirable option.

 

One of the most positive effects of cannabis is the euphoria that accompanies the drug's other effects. For many patients who are severely debilitated by the disease, this effect was appreciated and should not be minimized or underestimated. Cannabis often has a tendency to make patients more philosophical about mortality and about the course of their illness. When the patient is in that state of mind, it can be beneficial for the healthcare provider and caretakers as well as for the patient.

 

Cannabis is used during chemotherapy for a short period of time, generally several weeks, during which a cycle of chemotherapy is given. Cannabis is used as needed during this treatment and then is stopped when chemotherapy is completed. In those patients who use cannabis to mitigate the wasting and loss of appetite accompanying advanced disease, cannabis could be used on g more extended or permanent basis. I have never seen any long-term negative effects from the use of either dronabinol or cannabis in treating people with HIV/AIDS, and considering the many and frequently severe side effects from drugs I routinely prescribe to treat AIDS and AIDS complications, this is quite remarkable.

 

Some patients using cannabis or dronabinol complain of drowsiness and occasionally of anxiety. These effects generally are more common among persons who were new to cannabis at the time when they first used it therapeutically, and it is well known that cannabis use requires a learning process to get the maximum benefit from its psychoactivity. It has been noted that among younger persons there is often less incidence of cannabis-related side effects presumably because this is a population that has had more cannabis experience. The major complaint from patients using dronabinol is drowsiness particularly for those who were still working or otherwise active. There are varieties of cannabis that are more sedating and others that are more stimulating, but most people cannot control the type of cannabis they purchase. If cannabis were legally available or people could grow their own plants, varying strains and potencies could be much more precisely adjusted to the individual patient's needs.

 

When I agreed to write this chapter for this book, I started to ask my patients during their regular appointments whether or not they had used cannabis in relation to their illness and to describe their experiences with it. Many of my patients reported using cannabis to stimulate appetite or to suppress nausea (frequently caused by other medications I was prescribing!). They reported that it was quite successful in treating these symptoms, and many felt they would have succumbed or sickened sooner if not for cannabis. One patient reported, "That's what's keeping me going." This information is anecdotal but indicates to me that many patients have discovered the use of cannabis is quite helpful and not harmful.

 

I was surprised at the number of my patients who indicated they had used cannabis to control their symptoms. Whether this reflects a patient population that was not new to cannabis, being urban (San Francisco) and young (mostly aged 25-50), or that information about the effectiveness of cannabis for these symptoms has become widely circulated, I cannot determine. It is true that the use of cannabis for treating chemotherapy-induced nausea and vomiting has received much publicity, particularly in local newspapers and on national television. In San Francisco there has been much coverage of the use of cannabis in AIDS both from a medical point of view as well as the much publicized legal case of Mary Rathbun, a 73-year-old woman who was arrested for baking marijuana brownies for people with AIDS. Due to much popular support, the charges against "Brownie Mary" were dropped. San Franciscans have voted on a city proposition to support the use of medical marijuana, and it was approved by 80 percent of the voters.

 

Furthermore, San Francisco (as do several other cities in the United States) has a Cannabis Buyers' Club (cBc) that specifically sells marijuana (the dried plant) and marijuana products (e.g., cookies, capsules, and tinctures) to patients. Patients are admitted to the club on the presentation of a letter from their physician indicating that they have HIV disease or another medical condition for which their physician would prescribe marijuana if it were legal. The San Francisco CBC has been in operation since 1993 under the direction of Dennis Peron, an activist who has been trying to get marijuana back into the formulary of the American physician. The CBC operates as a club as well as a supermarket, where patients can sit around and talk, smoke, and meet with other patients like themselves. The city of San Francisco has made the enforcement of anti-marijuana laws one of its lowest priorities. The legislature of the state of California also passed laws to allow the legal prescription of cannabis for medical reasons, but they were vetoed by Governor Wilson. In November of 1996, Proposition 215, an initiative which allows physicians to recommend marijuana for medicinal use, was passed by the people of the State of California by 56 percent. (A similar measure passed in Arizona by 67 percent.) Prior to the passage of Proposition 215 the San Francisco CBC was busted by state law enforcement agencies. Following the passage of the initiative the city's Superior Court judge ruled that the CBC be reopened and it did so in January of 1997 under the new name of the Cannabis Cultivators Club. Thus, there is much positive "lore" about the use of cannabis in AIDS that might account for this population's willingness to try it and find it helpful.

 

My patients' use of cannabis to treat their symptoms was also instructive in terms of how easily they determined how much and how frequently they needed to ingest it to obtain the desired effects. They did not need a physician to write a prescription and explain how to use it. In my experience, physicians are not needed to prescribe or otherwise control the use of cannabis for patients who are ill, and it would be desirable to minimize the amount of extra paperwork a physician must do to make this treatment available. The major role physicians could have would be to dispel years of misinformation about cannabis spread by the legal and medical professions as well as by prohibition activists. Accurate information from physicians can give patients who have concerns based on earlier misinformation permission to use the drug.

 

Two problems that my patients reported concerning cannabis were the difficulty of obtaining it and its current high price. Many of the patients who seemed to be most helped by cannabis were sicker, disabled and not working, and in poorer financial situations than others. The unnecessarily high prices for illicit cannabis were difficult for them to manage. In addition, because of their poor health, they themselves could not go out and buy it but had to get others to obtain it. This created much anxiety as they were getting more and more dependent on their family and friends and were now putting 'them also at legal risk for buying cannabis.

 

Further Research and Its Problems

 

Reading the medical and scientific literature and hearing the abundant anecdotal information available, one sees an obvious need for well-planned clinical trials of cannabis in persons with HIV/AIDS. That these studies have not yet been done is shameful and reveals the political nature of this research and that marijuana's controversial status interferes with good science (Grin-spoon, Bakalar and Doblin 1995; Voelker 1994). A professor of medicine at the University of California in San Francisco (ucsF), and chair of the Community Consortium of San Francisco (a group of community providers that has been conducting HIV research over the last ten years), Dr. Donald Abrams has been trying for over two years to pilot a study of the effects of various doses of inhaled cannabis versus Marinol in counteracting the symptoms of wasting (Abrams, Child and Mitche111995). This sophisticated and privately financed study was designed not only to look at the effects on wasting but also to measure pulmonary function, T-cells, and HIV levels. These are some of the many questions that should be answered but so far have remained unanswered. The study protocol has been approved by the California Research Advisory Panel, the UCSF Review Board, the Executive Board of the Community Consortium, and the FDA. The study has been stopped by the refusal of the DEA to permit the importation of marijuana for the study (cloned standardized cannabis is available in the Netherlands) and by the refusal of the NIDA to provide domestic marijuana. Each agency has taken many long months of inaction before denying the study protocol.

 

Many physicians feel that the only way to answer questions about cannabis is to do the appropriate controlled studies so they can advise their patients based on the best knowledge available. That these government agencies have chosen to delay and thereby prevent needed and meaningful studies, at no financial cost to them, can only be interpreted as a political decision. Such decisions are inappropriate for agencies that should be concerned with good science, with protecting public health—and that are supported by the taxpayers.

 

Conclusion

 

There is an obvious beneficial role for the use of cannabis in the treatment of HIV/AIDS. Marinol has been approved by the FDA to treat the wasting syndrome in people with AIDS. Many studies of cannabis itself have shown it to be well tolerated, to have a very wide therapeutic range, to not have a lethal dose, and it appears to be superior to Marinol. Few drugs are as well tolerated as it is. For many patients, cannabis is the medicine that makes the use of other medicines possible. Concerns about the immunosuppressive effects of cannabis are not supported by clinical data whereas the immunosuppressive effects of starvation and wasting are well documented. Cannabis has been used for centuries. Any further delay in making it widely available now, particularly to the ill, is both irrational and cruel.

 

References

 

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