I was training in oncology at UC San Francisco just as the first AIDS cases were reported. I helped found the AIDS program there and I've been participating in academic clinical research for over 20 years. More recently I've become an associate fellow of the Program in Integrative Medicine at the University of Arizona that was founded by Andrew Weil. This is a two-year program, mostly online, that is increasing my training and background in integrative medicine, including things like botanical medicine, manual medicine, and spirituality. It's been a stimulating experience so far and I'm really enjoying it.
I've been interested in complementary medicine since the very beginning of my career, so one of the reasons I'm doing the fellowship is to learn more that I can integrate into my own healthcare discussions with my patients. Of course another impetus is to see what other things we might want to do clinical research on. My intention is to continue to investigate the complementary and alternative approaches that our patients are using. We want to determine whether or not they may be beneficial, but also determine whether or not they may be harmful, particularly in how they interact with the conventional medications that patients are taking.
In the earliest days of AIDS we didn't have any treatment for this new disease; people were dying and everybody was frightened. Being here in San Francisco, we were near the Linus Pauling Research Institute in Palo Alto, so there were a number of people in the city who were proponents of high doses of Vitamin C. One of the first responses we saw in the early '80s were storefront clinics opening up where people went to receive intravenous injections of very high doses of Vitamin C. At that point in time we didn't even know that it was a virus causing the disease. So I used to go around on the lecture circuit with someone who would talk to audiences of concerned people who listened to him while hooked up to intravenous infusions of Vitamin C. Then I would speak as the academician who cautioned people that we really don't know if this is beneficial and there may be some dangers to being hooked up to intravenous vitamin C, and so on. Ultimately, this led to me to write a grant proposal in collaboration with the Linus Pauling Institute. It was right about the time we learned that HIV was the cause of AIDS so we wrote a proposal to the NIH to study the in vitro effects of Vitamin C on HIV. That grant didn't get funded.
In San Francisco at that time there were also a number of DNCB proponents. DNCB, dinitroclorobenzene, is actually a photographic chemical used for developing pictures, but it is also a skin sensitizer that had been used to test for delayed hypersensitivity reactions. There were people who believed that somehow it might be useful in restoring some of the T-cell immunity that patients with this new disease were lacking. So there were people who would paint themselves weekly or so with DNCB until they developed these skin reactions, thinking that the skin reaction was some sort of improved T-cell immune response that would help combat the virus. And again, seeing that people were using this and seeing that we really didn't have much else happening, I worked with some of the DNCB proponents, as well as some experts from the University of California -- I remember Jay Levy was involved, as was Marcus Conant and others -- and we wrote a protocol that we submitted to the FDA for funding. That also was rejected.
Around the time that AZT first became available in 1986, I went to a conference in Japan where I was introduced to some investigators from the Ueno Fine Chemicals company who told me that they had the cure for this disease. They said it was something that was very commonly used in Japan but they couldn't tell me about it until I signed a confidentiality agreement. That turned out to be dextran sulfate. Not long after I was going through the process of filing the paperwork to get approval from the FDA to do a phase I study of dextran sulfate in the United States when evidently some people heard about it. They realized that it was a product that was widely available in Japan -- I believe it was used for lowering cholesterol -- so they started an importation scheme similar to what had happened in earlier days with isoprinosine and ribavirin, which were brought across the Mexican border. But people had now become more sophisticated in their methods and began to import dextran sulfate from Japan to sell in the underground AIDS therapy market. I remember that activists stormed the offices of a Japanese drug distributor in New York for refusing to make dextran sulfate more widely available. Ultimately it became such a political issue that, even though my clinical trial here in San Francisco didn't show much benefit, Congress got involved and the AIDS Clinical Trial Group (ACTG) was asked to do a study of dextran sulfate through the NIH-funded mechanism. It turned out the drug was not even absorbed into the blood.
Another Japanese product I worked with was lentinin, which was an intravenously administered extract of shiitake mushroom. In Japan it was felt to be an immune booster for patients with cancer. Although it was being used by mainstream doctors in Japan, it was an alternative therapy here because it was not something that we had ever learned about or used in hospitals in the U.S. That's David Eisenberg's description of what an alternative therapy is -- that it's not taught about in medical schools or widely available in U.S. hospitals -- and certainly shiitake mushroom extracts qualified. Again, that's another study we did that had negative findings; there was no benefit to the intravenous infusions of lentinin. Since I've learned more about botanicals, it would seem to me that if there were immune enhancing benefits to shiitake mushrooms then they are more likely to be obtained by eating them rather than by injecting an extract intravenously.
During that time I was also involved with studies of conventional therapies. Even in the days of early AZT monotherapy, which I was not a big supporter of, I was involved in trying to put some evidence behind the claims of the proponents for these various agents. And since that time, I've had a constant history of investigating conventional therapies through the federally-funded CPCRA (Community Programs for Clinical Research on AIDS), and more recently through the ESPRIT study of interleukin 2, as well as in other, sometimes pharmaceutical industry-sponsored trials. But always ongoing with those studies, I've been involved with clinical trials of complementary and alternative interventions.
When we first became aware of immune thrombocytopenic purpora (ITP) in AIDS, I worked with a nurse who was very interested in therapeutic touch and we studied men with low platelet counts to see if therapeutic touch could decrease their stress and increase their platelet counts. That was another study that turned out to be fairly negative.
I then became interested in traditional Chinese medicine (TCM) and, in fact, one of the colleges of TCM here in San Francisco sent me to China in 1989 just to learn about Qigong (Chi Kung) -- that exercise that's felt to improve the immune system -- to see if it was something that I wanted to study here. Although I never studied Qigong I collaborated with Misha Cohen from the Quan Yin Healing Arts Center here in San Francisco. We did three studies of traditional Chinese herbal interventions for, first, symptomatic HIV, then for patients with diarrhea without a pathogenic source, and then another study for patients with anemia. The last two were hindered by the fact of being initiated about the time that HAART became available, so patients with diarrhea as well as anemia became scarce. There were also a lot of pills that needed to be taken in these Chinese herbal investigations and patients at that time were taking huge amounts of pills with their antiretroviral regimens, so the studies weren't very attractive. None of these studies had spectacular results and the anemia study was terminated for poor enrollment.
Have "soft endpoints" such as life satisfaction created a problem for designing and conducting credible studies?
The TCM herbal study that we published in 1996 investigated herbs versus placebo in symptomatic HIV infection. At the time of the study in 1993, we had patients with about 14 symptoms on average and we found that there was a significant decrease of symptoms in the herb-treated group -- they decreased from 14 to 12 -- whereas the other group still had 14 symptoms. We also found that they had improved "life satisfaction" which improved by a factor of +0.86 or thereabouts. Yet, if you look at the rest of the results, the Chinese herbal patients actually lost weight over 12 weeks compared to the placebo group, and their CD4 counts also dropped -- not statistically significant, but it was a trend. So that was an example of where their symptoms improved and their life satisfaction increased, but the parameters that we would normally look at to see if a patient is doing well (i.e., weight and CD4 count) went in the wrong direction. So, although I was also first author on a study that showed that epoetin alfa improves quality of life in HIV patients who are anemic, I'd have to say that a study whose main endpoint is quality of life is something I would find difficult to interpret.
The CPCRA actually did a large study of acupuncture for patients with HIV-related peripheral neuropathy that was published in JAMA. That was a landmark, having the NIH support an acupuncture study, although, again, it turned out to have negative results; acupuncture didn't appear to be effective in treating peripheral neuropathy.
About this time I began trying to study another botanical, which has consumed my efforts for the past decade, and that would be cannabis, or marijuana. Starting in 1992 I began proposing and developing clinical trials to investigate first the effectiveness -- but then I realized that that wasn't going to happen -- so subsequently, the safety of smoked marijuana in patients with HIV. We finally completed a study in the year 2000, that we hope will soon be published, that looked at the safety of marijuana in patients taking protease inhibitor regimens. And since that time we have obtained funding from the State of California that allows us now to conduct clinical trials to look at the potential effectiveness of smoked marijuana in patients with various syndromes. We have also just completed a pilot study in patients with HIV peripheral neuropathy, which allowed us to ascertain that there was some effectiveness of marijuana. But an open-label pilot study is not going to prove that, so we're now in the process of continuing on with a randomized, placebo controlled, double-blind trial in patients with HIV-related peripheral neuropathy. We're also doing marijuana studies in patients with cancer who have pain who are on opioid analgesics, and another study to look at the effect of smoked marijuana in patients who have delayed nausea and vomiting from breast cancer chemotherapy.
It was working with marijuana and all the problems that are inherent in studying a plant as a therapy that has led me to a broader interest in botanicals and the use of substances that come from nature as medicinal agents. Certainly, for thousands of years, people have depended primarily on these things. Whether or not they worked is unclear, but as an oncologist I know that many of my most potent chemotherapeutic agents were derived from plants. So right now we are waiting to hear if a protocol we submitted to the National Center for Complementary and Alternative Medicine (NCCAM) to investigate the lipid lowering effects of oyster mushrooms in patients on Kaletra is being funded. There's good evidence that mushrooms, including oyster mushrooms in particular, have some activity for lowering blood lipids and cholesterol.
We're also just finishing a three-year NCCAM grant studying the effects of DHEA, dehydroepiandrosterone, which is an over-the-counter adrenal steroid that people are taking for many reasons. We received a grant to investigate it as an antiviral and to see what impact it has on the immune system. Hopefully that data will be available by the end of the year and we will know if DHEA had any impact, positively or negatively, in our patients.
The goal, ultimately, would be to submit a center grant to the NCCAM, to allow us to establish a center here for the study of botanicals in HIV because there are still a number of herbal preparations and mushroom extracts that warrant further investigation for their potential benefit -- and to make sure that they're not harmful in our patients.
Safety keeps coming up again and again as one of the inarguable justifications for doing this research.
There's not a huge amount that we know about some of these botanical products and how they're metabolized, but there's probably more than people think. There are a number of textbooks available that talk about herb-drug interactions. That was the question in our marijuana study: is there an interaction between cannabinoids and protease inhibitors, which are both metabolized by cytochrome P450 enzymes in the liver, that may alter the activity of the protease inhibitors such that patients lose their viral suppression when they mix cannabis with their treatments? And in fact, in our article that was already published in AIDS, we saw no such effect. We've all heard about garlic and St. John's Wort and their interactions, and I think there are many other agents that we would like to study to make sure that they are not having significant interactions with protease inhibitors. We don't want people to either lose control of their viremia (through underdosing) or experience toxicity (through overdosing) because of antiretroviral concentrations that have been affected by herb-drug interactions.
You had to be enormously persistent to accomplish your marijuana study. In the current political climate, is it going to be more difficult to do marijuana studies?
I think we're blessed to live in the State of California, which is somewhat of a freestanding republic in and of itself. In 1996, the people of California voted to allow physicians to talk to their patients about the medicinal use of cannabis. Then, through the work of Senator John Vasconcellos, one of our state senators, appropriations were made to the University of California that established the Center for Medicinal Cannabis Research (www.cmcr.ucsd.edu). And that Center has had funds for the past three years that allows it to support clinical trials to investigate the use of marijuana for medicinal purposes. Whereas the NIH and NIDA, via their congressional mandate, could only give marijuana to clinical trials that show that it was harmful (they are the National Institute on Drug Abuse, not for Drug Abuse, as NIDA's director Alan Leshner always reminded me), they were not really able to provide us with marijuana to study the benefits. But now, they have modified their system so they can provide marijuana for peer reviewed clinical trials that will look at its effectiveness as a therapeutic agent -- as long as they are not funding it. So they have now created this ability for us to obtain government marijuana.
Is there a need to increase provider knowledge about these issues?
I think a part of the problem is a lack of communication from both sides. Patients don't really perceive that these substances are something that they need to tell their doctor about -- in fact many studies show they don't want to tell their doctor because they're afraid they're going to be reprimanded or told that they're wasting their money. And many physicians never even think about asking about these things as potential confounders or as things that are causing clinical symptoms. There also may be a variable of where in the country you are. I know many surveys show that we in the West have the highest percentage of people in the population who are using complementary and alternative interventions. So many of my colleagues here might be more familiar with how to ask the question and what to be looking for.
I remember once seeing a patient at our drop-in clinic who clearly had a drug rash. I looked through his chart -- this was when we had paper charts -- and he had a high CD4 count and a low viral load but he wasn't taking any medications.
So I said to the guy, "You're not taking any medications, huh?" And he said, "No."
"Are you taking any vitamins?" And he said, "Yeah."
So I asked him what he took and he listed about four or five vitamin preparations. Then I asked, "Do you take any herbs?" And he said, "Sure."
And so I listed the three or four herbal substances that he took.
"Do you take any minerals?" And he said, "Yeah."
By the time I finished I had a list of 12 different things he was taking.
So I asked, "Well, how come everybody else wrote down that you don't take anything?" And he said, "Well, nobody ever asked me before."
Back to the GMHC Treatment Issues June 2003 contents page.