Marijuana Ruling Exempts Federally Funded Research

"In the case of the Controlled Substances Act, the statute reflects a determination that marijuana has no medical benefits worthy of an exception (outside the confines of a government-approved research project)." -Justice Clarence Thomas1 The Supreme Court's recent ruling against manufacturing and distributing medicinal cannabis does not appear to have had any immediate impact on either basic or clinical research studies under way. Some investigators, however, remain leery about the potential for research being compromised in the future. The ruling comes at a time when research into cannabis, and its active ingredient delta-9-tetrahydrocannabinol (THC), is booming. Just last year, the nation's first Center for Medicinal Cannabis Research (CMCR) opened at the University of California, San Diego, and more projects involving the infamous weed have been approved in the last couple of years than ever before. But it's been a long time coming, and "it hasn't been easy," says University of California, San Francisco physician-researcher and professor Donald Abrams, who spent five years getting his first study on smoked marijuana funded. Government officials have been reluctant to discuss the issue in any detail. The National Institute on Drug Abuse (NIDA), the agency that retains sole authority to supply marijuana for research, has been referring calls to National Institutes of Health headquarters. There, a spokesperson, who requested to remain nameless, said simply: "The Supreme Court's decision will have no impact on [cannabis] research." Quoting from an NIH Web site, she added "the NIH will review grant applications on the medical utility of marijuana ... that meet accepted standards of scientific design."2 The case-U.S. v. Oakland Cannabis Buyer's Cooperative-began with a 1998 federal injunction to prevent an outlet in Oakland, Calif., and five other state-regulated centers, from distributing marijuana. The cooperatives opened following the passage of California's Proposition 215 in 1996, which legalized cannabis for patients with doctor's recommendations. Seven other states have since legalized medical marijuana, and other distribution centers opened. The Controlled Substances Act, a federal law enacted by Congress in 1970, lists cannabis, or marijuana, as a Schedule I drug, meaning that it has no medical value, so it is illegal to possess and/or distribute. The Supreme Court's recent ruling affirms the existing federal law. Medical cannabis dispensaries, wherever they are located in the United States, the majority held, are illegal under federal law regardless of state laws allowing for medicinal cannabis use. Since the ruling was handed down, Thomas' frequently quoted summary comment has proved to be the most incendiary, igniting discussions within the cannabis research community. Ruling aside, it's what the justices chose not to consider or say that had many researchers on both the basic and clinical fronts collectively wincing. "That its decision should be based on such an outdated body of knowledge is amazing," states Daniele Piomelli, professor of pharmacology at University of California, Irvine. "The Court did not acknowledge that an increasing number of studies indicate the medicinal benefits of cannabis for a number of disorders and ailments, while basic science studies are now opening the window on the natural cannabinoid system in the human body, something that will increase knowledge on many fronts," elaborates Montana physician Ethan Russo. The Court had access to any number of government-generated documents, as well as science journals and other articles detailing new as well as old, recovered research. In recent years, reports issued by the Institute of Medicine and the NIH concluded cannabis does appear to have therapeutic benefit for some people with various conditions and encouraged research.3,4 On other fronts, the community now has its own Journal of Cannabis Therapeutics, and an increasing number of studies are being published in mainstream science journals. Cannabis also has quite an extensive pharmaceutical history. Between 1842 and 1942, it was a standard medical treatment in Western Europe and the United States, readily available as an extract and used extensively in pain treatment, including migraines.5 According to Russo it was also used to treat addictions to alcohol or narcotics. Cannabis was used regularly until 1937 when the Tax Act made it, essentially, unavailable. There are very different cultural attributes given to recreational drugs, Piomelli explains. "Cannabis-marijuana-has for decades suffered from a negative social image, and even as a research drug, cannabis is not considered as serious as cocaine or even nicotine." Now, he says, "the Supreme Court has opened the door ¼ to an interpretation that is potentially dangerous for science. The risk is if [the ruling] is interpreted to mean there is no actual value in the investigating of the medicinal properties of marijuana because the law is explicitly stating there are no such properties. This could create an intellectual atmosphere of 'let's try to stay away from cannabis because it's a problem.' And that is exactly the atmosphere that has delayed tremendously our understanding of cannabis pharmacology," concludes Piomelli, who is currently working under grants from NIDA and CMCR for basic research on THC. Those who have been on the cannabis research front lines have experienced extreme difficulty in getting projects funded. "It has been an uphill battle at the very best, and impossible at worst, to get research funded, particularly for projects involving smoked marijuana," says Russo. No one knows that better than Abrams. After four years of grant applications and revisions on a protocol to test the therapeutics of smoked cannabis as an appetite stimulant on AIDS wasting syndrome, he finally conceded to shifting his focus from efficacy to safety to get his first study approved, investigating the impact of smoked marijuana on the immune system in AIDS patients taking protease inhibitor drugs. In his study (recently submitted to a medical journal), Abrams reports that cannabis did not produce immune problems in people taking protease inhibitor drugs and did lead to weight gain. Russo hasn't been as lucky. He first applied to the Food and Drug Administration in 1997 for an Investigational New Drug application to test cannabis on acute migraines. He says he was put through "a classic bureaucratic runaround" between the FDA and the NIH. In 1999, he finally hooked up with FDA ombudsman Jim Morrison. "He led me to understand that the FDA had not been following its own procedures, and indicated things would be different from then on," Russo recalls. By September of that year, he had finally secured approval from both the FDA and NIDA. "Then, NIDA changed its policy and ultimately rejected my grant application for a variety of reasons, including the requirement that participants be exposed to marijuana only once." Russo has now aligned with GW Pharmaceuticals of the United Kingdom, the only company in the world that produces cannabis for research. The company, he says, "is currently in negotiation with the FDA and the [Drug Enforcement Administration] and if they get approved for trials, my migraine project may finally see the light of day." For now, investigators are cautiously optimistic that their research will continue on track and that cannabis is-at least in scientific circles-beginning to rise above its troubled past. "I think the trend at the federal level, at the NIH, is that this is an area worthy of scientific study," says physician-researcher Igor Grant, CMCR director. "I think there's a kind pressure building scientifically and medically that we need to get some answers." Still, the fact that NIDA is the sole official and legal distributor of marijuana for research may portend more stormy days ahead. Given NIDA's prime objective, says Russo, "I just don't know if the agency could ever look favorably on a study that indicated medicinal benefit from smoked marijuana." And, he says, such studies exist already. "In one recent report, material gathered by several state commissions back in the late 1970s and 1980s on trials involving smoked cannabis versus synthetic THC versus standard medicines found in many of the cases people had 100 percent response rate to smoked cannabis in preventing nausea and vomiting with chemotherapy, with lesser degrees of relief from the synthetic versions and other medications."6 "The use of marijuana per se [in its organic form] as an analgesic for the greater population-not in the compassionate sense of a particular cancer patient-I don't think [will] be possible," says Piomelli. "This system that cannabis is disclosing for us offers enormous opportunities for drug discovery-new drugs-not necessarily THC [derived]-but drugs that have higher selectivity and effects that are more suitable to a medicine." To that end, more research is needed. "This is one of the most exciting areas in neuropharmacology and the neurosciences at large right now," says Piomelli. "But you have to be extremely persistent and have dogged determination," cautions Russo. "And you have to have a high tolerance for frustration," adds Abrams, who is going through the regulatory hoops for his next two studies that will investigate the effect of smoked cannabis on patients suffering from peripheral neuropathy and pain from bone metastases caused by breast and prostate cancer. "Even now, with the research we're trying to do, we need to go through seven regulatory reviews, each one making their own comments and suggestions on how to change it, so it's very hard to keep track of your revised protocol in this field." For researchers considering investigating cannabis, Piomelli advises, don't think about the politics, "think about the science." A.J.S. Rayl (ajsrayl@loop.com) is a contributing editor for The Scientist. References 1. C. Thomas, et al., Majority Opinion, U.S. v. Oakland Cannabis Buyer's Cooperative, U.S. Supreme Court, May 2001, online at supct.law.cornell.edu/supct/html/00-151.ZO.html 2. www.nih.gov/news/medmarijuana/hhsfact.htm 3. J.E. Joy et al., editors, "Marijuana and Medicine: Assessing the Science Base," Institute of Medicine, National Academy Press, 1999. 4. NIH Workshop. August 1997 5. E. Russo, "Hemp for headaches: an in-depth historical and scientific review of cannabis in migraine treatment," Journal of Cannabis Therapeutics, 1:21-92, 2001. 6. R.E. Musty, R. Rossi, "Effects of smoked cannabis and oral tetrahydrocannabinal on nausea and emesis after cancer chemotherapy: a review of state clinical trials, Journal of Cannabis Therapeutics, 1:29-41, 2001. Focusing on Endocannabinoid By Ricki Lewis Much of the current research on medicinal marijuana focuses on anandamide, the human body's version of delta-9-tetrahydrocannabinol (THC), the major active ingredient in marijuana. Understanding the molecular choreography between this endocannabinoid and its receptor is clarifying the control of neurotransmission while revealing targets for novel therapeutics. "Nature has always been the best inventor of new drugs. Scientists take their cues from nature," says Sumner Burstein, a natural products chemist at the University of Massachusetts Medical Center in Worcester and inventor of a THC analog now in clinical trials. Although THC is widely regarded as the component that gives the plant its kick, the overall effect of smoking marijuana is definitely a whole-is-more-than-the-sum-of-the-parts phenomenon. Marijuana smoke contains more than 400 different chemical compounds, including about 80 interacting cannabinoids. "Smoke exposes other cannabinoids, and we can't rule out the possibility that other compounds contribute to the medicinal effects. We need more research directly aimed at answering these questions," says Burstein. Perhaps the way to optimize the healing powers of marijuana is to identify combinations of cannabinoids that treat certain conditions, because smoke introduces dangerous tar compounds. "We recommended in an Institute of Medicine report in 1999 that using the whole plant is not a great idea for chronic use, because of the serious potential for damage, such as cancer," says Stanley J. Watson Jr., Raphael Professor of Neuroscience in Psychiatry at the Mental Health Research Institute of the University of Michigan.1 The key to making the most of marijuana requires understanding the signaling pathways in the human body with which plant cannabinoids interact. For THC to affect a human, it must bind to receptors. And if there are such receptors, then the body must produce its own version of THC, an endocannabinoid.2,3 "THC binds to receptors for the fatty acid derivative anandamide that is normally produced in the body. This situation is analogous to the opioid receptors that are activated by endorphins that are also normally produced in the body. In both cases, plant products that are quite different chemically from the endogenous agonists bind to and activate these receptors," says Herbert Schuel, a professor of anatomy and cell biology at the University at Buffalo in New York, who discovered cannabinoid receptors on sperm. Anandamide binds two types of receptors. "CB1 receptors are predominantly expressed in the brain, but they are also present at lower levels in peripheral tissues and immune and smooth muscle cells. CB2 receptors are mostly expressed in immune system cells," explains Daniele Piomelli, a professor of pharmacology at the University of California, Irvine. Binding of anandamide to a receptor modulates many signal transduction pathways in a way that regulates how cells respond to stimulation, Schuel says. This mechanism occurs in all animals as well as protista, indicating an ancient origin. "Anandamide signaling at least predates the appearance of multicellular animals more than 600 million years ago," Schuel adds. A trio of recent reports probes the tango between anandamide and CB1 receptors in the brain. Postsynaptic neurons produce the homegrown cannabinoid in response to calcium influx. Anandamide molecules then diffuse back toward the presynaptic neuron, where they bind receptors that temporarily shut down neurotransmission. "Endogenous cannabinoids don't seem to act as classic neurotransmitters, but as local mediators. They are released in a receptor- and activity-dependent manner and act near their site of synthesis," explains Piomelli. Adding a whiff of plant cannabinoids might shake up this system. "Effective operation of an endogenous signal system depends on the rapid on-demand release and subsequent removal of the signal molecule, anandamide. Exogenous cannabinoids derived from marijuana smoke persist for long periods of time in the body. They may produce adverse effects by flooding the endogenous anandamide-signal system," explains Schuel. Interestingly, all three groups that reported anandamide's backward action were not studying cannabinoids, but a hypothesized "retrograde messenger" that dampens a sending cell's activity. Rachel Wilson, a graduate student in the laboratory of Roger Nicoll in the department of cellular and molecular pharmacology and physiology at the University of California, San Francisco, worked with rat hippocampus slices.4 She noted release of a retrograde messenger that was not packaged into vesicles, a characteristic of anandamide. So, she blocked CB1 receptors, which inhibited the presynaptic cell's activity. Anandamide, therefore, is the retrograde messenger. Professor of neurobiology Wade Regehr and graduate student Anatol Kreitzer did similar work on cerebellum tissue at Harvard Medical School, and Takako Ohno-Shosaku and Masanobu Kano at Kanazawa University in Japan simultaneously reported evidence in hippocampus tissue.5,6 Beyond the Brain Since it's well known that marijuana exerts its most obvious effects on the central nervous system, it wasn't surprising that receptors for a human version of THC would turn up there. But research is shifting to include endocannabinoid signaling in other places. Piomelli's group, for example, investigated the role of anandamide in the respiratory system by puffing pepper spray, containing the irritant capsaicin, at guinea pigs. Normally, the animals cough violently in response. Not only does giving anandamide before the puff subdue the cough, but blocking CB1 receptors in airway neurons stops this effect.7 "These findings have considerable potential for the development of peripherally acting cough-suppressant drugs," Piomelli notes. Elsewhere, research is revealing the basis for the decades-old observation that marijuana lowers sperm counts. Schuel, Piomelli, and others reported at the annual meeting of the American Society for Cell Biology in San Francisco in December 2000, that changing the levels of a synthetic analog of anandamide in sperm cells in culture alters their swimming rate and ability to fertilize. Both the analog and THC prevent changes in the acrosome (the enzyme-containing tip of the sperm) that are necessary for capacitation, the readying of the cell for fertilization. "Our work suggests that anandamide signaling normally regulates sperm function in humans. This information provides new insights into normal human reproductive physiology, may account for certain types of human infertility, and may eventually provide the basis for the development of novel drugs for reproductive medicine," Schuel says. A little later in development, precise levels of anandamide and its receptor open a window of time when a preimplantation embryo can nestle into the uterine lining. Sudhansu Dey, a professor of molecular and integrative physiology at the University of Kansas Medical Center in Kansas City, tracked changing levels. "We found that CB1 is expressed very early in development, in the preimplantation embryo, 25-fold more than in brain. We also found anandamide level is very high in the mouse uterus," he explains. In pregnancies that proceed, levels of anandamide and its receptor stay low. "But when the embryo doesn't implant, both go up," he adds. When they hiked anandamide levels in early mouse embryos growing in culture, only 36 percent continued development, compared to 90 percent of unperturbed embryos. And mice doubly knocked out for the CB1 and CB2 genes lose embryos at the implantation stage. Dey hypothesizes that anandamide-receptor signaling provides quality control for preventing implantation under certain unknown conditions. Additional evidence of a role for anandamide and other cannabinoids in human reproduction comes from epidemiology - one study linked disrupted levels of the enzyme that dismantles anandamide with recurrent miscarriage.9 Adds Schuel, "Marijuana smoke and cannabinoids adversely [affect] a wide range of reproductive processes in humans and other mammals." These include secretion of gonadotropic hormones from the pituitary gland and steroids from the ovary and testis, sperm production and ovulation. Concludes Dey, "Everyone is paying so much attention to the brain, but a whole new area of the role of THC in fertility and early development is opening up." And that may be just the beginning. Ricki Lewis (rickilewis@nasw.org) is a contributing editor for The Scientist. References 1. Institute of Medicine, "Marijuana and Medicine: Assessing the Science Base. www4.nationalacademies.org/news.nsf. See also, P. Gwynne, "Medical Marijuana: Will IOM report encourage clinical trials?" The Scientist, 13[10]:1, May 10, 1999. 2. L.A. Matsuda et al., "Structure of a cannabinoid receptor and functional expression of the cloned cDNA." Nature, 346:561-4, 1990. 3. W.A. Devane et al., "Isolation and structure of a brain constituent that binds to the cannabinoid receptor." Science, 258:1946-9, 1992. 4. R.I. Wilson, R. A Nicoll, "Endogenous cannabinoids mediate retrograde signaling at hippocampal synapses." Nature, 410:588-91, March 29, 2001. 5. A.C. Kreitzer and W.G. Regehr. "Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses into Purkinje cells." Neuron, 29:717-727, March 2001. 6. T. Ohno-Shosaku et al. "Endogenous cannabinoids mediate retrograde signals from depolarized postysynaptic neurons to presynaptic terminals. Neuron, 29:729-738, March 2001. 7. A. Calignano et al., "Bidirectional control of airway responsiveness by endogenous cannabinoids," Nature, 08:96-101, 2000. 8. B.C. Paria et al., "Dysregulated cannabinoid signaling disrupts uterine receptivity for embryo implantation," Journal of Biological Chemistry, March 8, 2001, online version. 9. M. Maccarrone et al., "Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage," The Lancet, 355:1326-9, 2000. CT-3: A Variation on the THC Theme The idea to isolate compounds from Cannabis sativa for therapeutic use isn't new. The Food and Drug Administration approved Marinol (dronabinol) from Unimed Pharmaceuticals Inc. in 1985 to alleviate nausea and vomiting in cancer patients undergoing chemotherapy, and in 1992 to treat AIDS-related anorexia. Then in 1999, the U.S. Drug Enforcement Administration downgraded Marinol from schedule II to III, acknowledging its low abuse and addiction potential. But because many users report better results from smoked marijuana, research into medicinal uses of Cannabis components hasn't stopped with Marinol. One promising THC stand-in being developed by Atlantic Technology Ventures Inc. in New York City is known for now as CT-3. But to its inventor, natural products chemist at the University of Massachusetts Medical Center in Worcester Sumner Burstein, it is ajulemic acid, a shortened version of what he says is a two-line chemical name. The new drug has an interesting history. "Ajulemic acid came about from 30 years of basic research in which I accidentally discovered one principal metabolite in marijuana that is not psychoactive, but retains many desirable properties.1 I used that natural metabolite as a template to synthesize ajulemic acid," says Burstein. In 1985, his team started looking at the compound's biological properties, and were soon encouraged that they were indeed on the trail of a potential new analgesic and anti-inflammatory agent.2 The university was unable to back commercialization, so Burstein sought a partner. He didn't have enough human data to interest big pharma. "For an academic such as myself, it was a revealing education. I thought you had to have a good idea and data, and that's it. But it doesn't work that way," he recalls. But then he received, and nearly ignored, an offer. "The banking firm behind Atlantic Technology Ventures contacted me, and I almost threw the letter out because it looked like an offer for a credit card. This was the early 1990s, when venture capital was looking frantically for new technology. They had probably picked up my patent application." So far CT-3 is looking good. "Its analgesic properties are of equal potency to morphine, but with no respiratory depression or withdrawal symptoms. It doesn't wreak havoc on the gastrointestinal tract or cause kidney problems, as do non-steroidal anti-inflammatory drugs [NSAIDs, such as aspirin and ibuprofen]," Burstein says. Adds Michael Ferrari, vice president of business development at Atlantic, "Phase I clinical trials showed no side effects. We are extending Phase I testing to use a higher dose. FDA first approved 10 milligrams, and now we are up to 120 milligrams." Nonhuman animals received four times that dose with no ill effects. Next, the U.S. Army Medical Research Institute of Chemical Defense is conducting further trials of CT-3 as an alternative to NSAIDs. And that might not be all. Robert Zurier, also at the University of Massachusetts, has shown in rats that CT-3 treats rheumatoid arthritis without the bone destruction associated with other drugs.3 Meanwhile, Burstein sees a bigger picture. "I hope that CT-3 will prove to be the political and medical resolution to the problem of legalizing medicinal marijuana. It is hard to speak of one without the other." -Ricki Lewis References 1. S. Burstein et al., "Isolation and characterization of two major urinary metabolites of s1-tetrahydroacannabinol," Science, 176:422, 1972. 2. S. H. Burstein et al., "Synthetic non-psychotropic cannabinoids with potent anti-inflammatory, analgesic and leukocyte antiadhesion activities," Journal of Medicinal Chemistry, 35:3135-41, 1992. 3. R.B. Zurier et al., "Dimethylheptyl-THC-11 oic acid: a nonpsychoactive anti-inflammatory agent with a cannabinoid template structure," Arthritis and Rheumatism, 41:163-70, 1998.

Marijuana Ruling Exempts Federally Funded Research

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