Immunoactive cannabinoids: therapeutic prospects for marijuana constituents.

M the common name for Cannabis sativa, is a widely distributed hemp plant whose dried flowering tops and leaves have been used for medicinal purposes for 12,000 years by some estimates (1). The article by Malfait et al. (2) in this issue of PNAS is relevant to the question of whether such traditional uses of marijuana could be clinically justifiable today. Contemporary discussions of the medical value of marijuana must be undertaken within a larger cultural, legal, and political context (Workshop on the Medical Utility of Marijuana, National Institutes of Health, http:yywww.nih. govynewsymedmarijuanayMedicalMarijuana.htm). The perceived behavioral and addictive effects of marijuana led to its prohibition from nonmedical uses by most states, taxation at the federal level, and eventual removal from the U.S. Pharmacopoeia in the 1930s and 1940s. Nonetheless, smoking of marijuana cigarettes continued and became the recreational drug practice of choice as well as a virtual rite of passage for young people during the Vietnam era. Some people who suffered chronic debilitating illnesses observed that marijuana eased some of their symptoms. A movement grew to redefine marijuana as a neglected, but valuable, therapeutic tool. Today, that movement has been subsumed under a more general advocacy for a whole spectrum of complementary and alternative health approaches (3). Complementary and alternative medicine entails the use of unconventional diagnostic, preventative, and therapeutic approaches including acupuncture, chiropractic manipulation, homeopathy, and magnets, few of which have been tested according to rigorous scientific standards. Herbal and other botanical products are key components of many alternative health approaches. Numerous preparations are marketed in the United States as nutritional supplements with such promises as combating fatigue, restoring mental balance, warding off respiratory infections, losing weight, and relieving the pains of arthritis. Were botanical products merely inert food supplements or condiments, there would be little concern over their use. But the very discoveries that yielded aspirin, digoxin, vincristine, taxol, and many other valuable plant-based drugs informed us as well of their potential for harm. Despite the common belief that natural substances must be healthful, the media and scientific literature today are rife with reports of serious adverse effects of particular botanical supplements and unexpected interactions between some supplements and proprietary drugs. Thus, the public need for definitive preclinical and clinical testing of botanicals and other unconventional healing approaches led to the creation in 1999 of the National Center for Complementary and Alternative Medicine at the National Institutes of Health. With regard to marijuana, there are data to indicate that the plant, or at least some of its constituents, conveys some clinical benefits, but a number of risks as well. Comprehensive reviews of the medical utility of marijuana were undertaken by a National Institutes of Health workshop in 1997 and by the Institute of Medicine in 1999 (http: yywww.nih.govynewsy medmarijuanayMedicalMarijuana.htm and ref. 4). These reviews concluded that smoking marijuana reduces intraocular pressure in glaucoma and is claimed to ameliorate pain, cachexia, nausea, and other debilitating conditions. Unfortunately, large controlled trials have not been conducted to support the majority of such claims. Moreover, there are better, well-defined treatments for virtually all such indications. Far more certain than reports of the benefits of marijuana smoking, however, are the health risks it imposes. Studies have described its adverse psychological, cardiovascular, and pulmonary effects, and even raised the specter of an increased risk of cancer (5, 6). In contrast to the incomplete state of the science regarding use of the plant itself, the identity, pharmacology, and clinical effects of several of marijuana’s constituents are relatively well characterized (7, 8). Marijuana contains more than 60 distinct cannabinoids, of which a series of tetrahydrocannabinols (THC) and their metabolites are the primary psychoactive ingredients and best-known components (Fig. 1). D9-THC alleviates the nausea associated with cancer chemotherapy and AIDS wasting and is available for these indications as the prescription drug dronabinol. Even the nonpsychoactive cannabinoids have been shown to have cellular and physiologic effects that could prove of clinical value. The paper by Malfait et al. (2) summarizes in vitro and in vivo immunological studies of the marijuana constituent cannabidiol (CBD; Fig. 1) and its potential effects in the treatment of arthritis (1). Using a murine model in which arthritis is induced by immunization with type II collagen, the authors show that CBD