Cannabis Has Potential as a Drug to Relieve the Side Effects of Cancer and Its Treatment

ABSTRACT: "From My Viewpoint" features essays from experts on vital issues in cancer care. This month, Donald I. Abrams, MD, professor of clinical medicine, University of California, San Francisco (UCSF), Comprehensive Cancer Center, and chief of hematology-oncology, San Francisco General Hospital, discusses the contentious issue of medical marijuana from his opinion and perspective as a physician and clinical trial researcher.

Cannabis has been used as a medicine for thousands of years. A body of evidence suggests that this plant, which contains hundreds of active compounds, has potential value for certain patients undergoing cancer treatment. However, largely due to nonscientific political issues, marijuana is still classified as a schedule I drug—an illegal substance having a "high potential for abuse" and "no currently accepted medical use in the United States." This classification, which has been repeatedly challenged, greatly complicates scientific research of this plant's medical potential.

Cannabis was first introduced into Western medicine in the 1840s to counteract pain, spasm, and inflammation. It found a place in the medical literature of the day as a treatment for a number of diverse conditions. In the early 1900s, as other pharmaceutical agents were developed for these indications, interest in marijuana began to fade. The first federal restriction on marijuana was the Marijuana Tax Act of 1937, which imposed cost-prohibitive taxes for the medical or recreational use of the drug.

At that time, the American Medical Association (AMA) opposed the restrictive tax, citing a lack of objective data regarding marijuana's purported harmful effects and fearing that further investigations into its efficacy would be impeded. Ultimately, marijuana was removed from the United States Pharmacopoeia (USP) in 1942.

About every 10 years since 1942, the federal government has commissioned a study group to evaluate the medical potential of cannabis. The most recent of these groups—the 1997 National Institutes of Health Workshop on the Medical Utility of Marijuana and the 1999 Institute of Medicine (IOM) report Marijuana and Medicine: Assessing the Science Base—identified several medical conditions in which marijuana warranted further research: appetite stimulation, nausea and vomiting, analgesia, and neurological and movement disorders. These potential benefits, which could also help relieve side effects of cancer or its treatment, are certainly relevant to the patients we treat.

The IOM report included caveats cautioning that although marijuana has shown some benefits, they are generally weak and other more potent agents are currently available, such as our potent antiemetic agents. The report also expressed concern about a smoked medicine and urged the development of smokeless delivery systems. One such system is already felt to exist in the form of synthetic delta-9-tetrahydrocannabinol (THC) (dronabinol), marketed as Marinol capsules. Marinol was approved by FDA in 1986 for the treatment of chemotherapy-induced nausea and vomiting.

So why should we study marijuana when we have an approved drug? For one, delta-9 THC—the single most psychoactive compound of the herb—has been on the market for 2 decades; therefore, it seems illogical from a scientific perspective not to study the properties of the whole plant if one of its constituent components has proven medicinal value.

In 1992, the indication for dronabinol was expanded to include the treatment of anorexia associated with the wasting syndrome in patients with AIDS. However, many patients taking dronabinol complained about being too heavily sedated for too long. Oral dronabinol has low bioavailability (6% to 20%) and a long half-life. Peak plasma concentrations occur within 1 to 6 hours and may remain elevated for several hours. On the other hand, patients who use smoked marijuana as an appetite stimulant seemed to enjoy more control over the drug's effects.

At that time, there were no effective treatments for HIV, and the associated wasting syndrome was ravaging the patient population. We noticed that our patients with HIV-induced anorexia who smoked marijuana showed an increase in appetite, relief of pain symptoms, and improved mood. Consequently, my colleagues and I decided a study was warranted looking at the efficacy of smoked marijuana as an appetite stimulant to counteract the devastating anorexia and weight loss in HIV-infected patients.

Our initial protocol design was approved by the FDA in 1994. This pilot study was designed to evaluate high-, medium-, and low-potency smoked marijuana vs dronabinol in stimulating appetite and reducing weight loss associated with HIV-related wasting syndrome. We submitted an application to obtain marijuana for the study to the National Institute on Drug Abuse (NIDA), which controls the supply of marijuana for research in the United States. After a protracted waiting period, NIDA rejected the study design on the grounds of insufficient scientific merit.

Over the next few years, a contentious series of exchanges with NIDA ensued, during which time we saw the development of potent antiretroviral agents that proved effective in controlling HIV infection and thus reducing the incidence and severity of AIDS wasting syndrome. However, given the potential for dangerous drug interactions between THC and the antiretrovirals, we redesigned a clinical trial to examine the safety of smoked marijuana in patients being administered protease inhibitors. In 1997, NIDA awarded our team a grant of $978,000 for a study comparing the safety of smoked marijuana, oral THC, and placebo in HIV patients receiving protease inhibitor-containing regimens.

Our findings were published in the Annals of Internal Medicine (139:258-266, 2003). We randomized 62 subjects to one of three groups receiving—three times a day before meals—a marijuana cigarette containing 3.95% THC, an oral tablet containing THC (2.5 mg oral dronabinol), or an oral placebo.

After analyzing an intense battery of virologic, immunologic, and pharmacokinetic studies in patients taking protease inhibitors, we found that smoking marijuana led to no changes in the levels of HIV in the blood or had any adverse effect on the immune system. We also found no clinically relevant pharmacokinetic interaction between smoked cannabis and protease inhibitors.

Growing Body of Evidence

Inspired by anecdote, history, and observational data, I started questioning whether cannabis was a viable medicinal agent back in 1992. After demonstrating safety in patients with HIV on protease inhibitors, we have gone on to demonstrate effectiveness against HIV-related painful peripheral neuropathy. A study in patients with chemotherapy-related neuropathy seems like a possible next trial. We have also evaluated a smokeless vaporization system to deliver cannabis that appears promising. We hope soon to commence a government-funded trial looking at the interaction of cannabinoids and opioids in patients with cancer-related pain. An increasing body of elegant investigation suggests that cannabinoids may actually have antitumor effects in a variety of in vitro and animal models.

Who Makes the Decision?

As previously mentioned, the IOM, which is a division of the National Academy of Sciences, has concluded after rigorous evaluation that the accumulated data indicate a potential therapeutic value for cannabinoid drugs—especially in pain relief, control of nausea and vomiting, and appetite stimulation. To me, that sounds like at least one august national body has acknowledged medical use of this drug in areas of particular concern to us as oncology professionals. And aren't the IOM and the National Academy of Sciences the appropriate organizations to make these decisions?

As a physician, I am concerned that medical decisions, which have historically been the charter of state medical boards, are being made through Congress and the Supreme Court. I should hope that one day there is evidence credible enough to sway these decisions makers in a more progressive direction, enabling us to study and use any viable option that will help us treat and reduce distress in our patients with cancer.