Pubdate: May 1998 Section: Volume XX No. 5 p. 75 Source: Oncology Times Contact: oncologytimes@compuserve.com Author: Peggy Eastman

NEW, IMPROVED MEDICAL MARIJUANA DRUG READIED FOR TESTING

Washington, DC - The company that makes Marinol - the only medicinal marijuana drug approved in the US - hopes to be in Phase I clinical trials of a new pharmaceutical form of marijuana by the second quarter of this year.

A new form of medicinal marijuana would be good news to the patients who say they prefer smoked marijuana to relieve their medical ailments rather than a pill. Some came here recently to the staid National Academy of Sciences building for a scientific workshop on medical marijuana - several in wheelchairs with companion dogs - to state their case. Except for eight patients grandfathered under the federal government's disbanded compassionate use program, smoked marijuana is illegal in every state except California.

Delta-9-tetrahydrocannabinol ( THC) is the most active ingredient of the marijuana plant and the one believed to have medicinal value for patients with cancer, AIDS, glaucoma, and a host of other illnesses and conditions.

"We are keenly interested in a new formulation for THC," said Robert E. Dudley, PhD, Senior Vice President of Unimed Pharmaceuticals, Inc., in Buffalo Grove, IL, speaking here at the last of three information-gathering workshops sponsored by the Institute of Medicine of the National Academy of Sciences. Marinol is taken orally in gel capsules. Dr. Dudley said the company wants to more nearly mimic inhaled marijuana, avoid the first pass through the liver that occurs with the oral formulation, and develop a faster-acting THC product. Drug delivery routes under consideration are sublingual, nasal aerosol, and pulmonary aerosol formulations.

Approved Form

Marinol was approved in 1985 as an antiemetic for cancer patients undergoing chemotherapy, and in 1992 it was approved for treatment of anorexia associated with weight loss in AIDS patients. Today, Dr. Dudley said in an interview, about 10 percent of Marinol sales are in oncology and about 90 percent in the HIV/AIDS treatment field. Sales data, he said, are strictly a function of how Marinol is marketed.

Considering how much controversy swirls around providing marijuana to patients legally, Dr. Dudley said, "I am always amazed when I meet physicians who don't know that an approved THC product has been on the market for 13 years." He added, "Oncologists don't know much about it; many don't use it much. We need more awareness about Marinol among oncologists."

Dr. Dudley said he believes that the fact that Marinol is a controlled substance has proved to be a hindrance to its acceptance by oncologists. In 1995 Unimed petitioned the US Drug Enforcement Administration to change Marinol from a Schedule II to a Schedule III drug, he said. The company is awaiting a US Department of Health and Human Services review of that petition and expects final US Drug Enforcement Administration action on its request this year. Rescheduling, said Dr. Dudley, would provide for improved patient access to Marinol, availability of prescription refills of the drug, increased pharmacy stocking, and a much higher comfort level among physicians.

"A lot of physicians are leery of prescribing Schedule I and II drugs," said Dr. Dudley. "They feel they're being watched by the feds. Schedule I and II drugs are viewed very differently from Schedule III drugs and non-scheduled drugs." ( Note by Tom Barrus, R.Ph., MBA - The DEA does not allow usual prescribing of schedule I drugs. However, Dr. Dudley is correct about feeling that, doctors who write prescriptions for schedule II drugs are being watched by the feds. The DEA is watching them and counting the kinds and numbers of pills they prescribe.)

He said the company knows Marinol is expensive ( about $200 a month for the average patient who uses it), but that there is coverage of the drug by third-party payors. The expense of the drug - along with the fact that some patients say smoked marijuana is more effective for them - is one reason consumer advocacy groups such as the Marijuana Policy Project believe patients who smoke marijuana for medicinal reasons should be allowed to do so without risking breaking the law.

The Institute of Medicine investigators studying medicinal uses of marijuana will produce a final report - expected to be finished by the end of this year - on the health benefits and risks of the plant. One of the issues they are examining is whether smoked marijuana is a "gateway drug" to other illegal drugs.

"There is a tremendous amount of new science" on the medical benefits of marijuana, said John A. Benson, Jr., MD, co-principal investigator of the Institute of Medicine study and Emeritus Professor and Dean at Oregon Health Sciences University. "My hope is that we'll go beyond asking for more research and that we might offer some specific suggestions for research," said Dr. Benson.

In an interview, Dr. Benson added, "In general, patients like the plant. They say, why bother [to do more research]? Or they say, 'Let us use the plant while you do your research.' But that's not up to Drs. Benson and Watson." Dr. Benson's co-principal investigator on the Institute of Medicine's marijuana study is Stanley J. Watson, Jr., MD, PhD, Co-Director and Senior Research Scientist at the University of Michigan's Mental Health Research Institute.

Difficult Drug to Study

The use of medical marijuana is so political and controversial that it has been hard to subject it to rigorous scientific scrutiny. In August, the National Institutes of Health released the report of a panel that met the previous February to review the scientific data on the potential therapeutic benefits of marijuana and the need for, and feasibility of, more research. The NIH panel concluded that the risks linked to marijuana, especially smoked marijuana, must be considered not only in terms of immediate adverse effects on the lung, but also in terms of long-lasting effects in patients with chronic diseases who might use it for long periods of time.

The NIH panel felt that frequent and prolonged marijuana use might reduce immune function ( especially in patients with compromised immune systems); they were also concerned about the dangerous combustion byproducts of smoked marijuana on patients with chronic diseases. Thus they favored the development of a smoke-free inhaled delivery system that could deliver purer forms of THC or related cannabinoid compounds.

NIH Director Harold Varmus, MD, said the NIH is open to receiving research grant applications for studies of the medical efficacy of marijuana, and will put applications through "our normal scientific review."

The National Institute on Drug Abuse maintains a contract with the University of Mississippi to grow marijuana for research purposes, according to Institute sources. The Institute also has a contract with Research Triangle Institute to package the product into cigarettes distributed for NIH-approved research to scientists who have an Investigational New Drug clearance from the Food and Drug Administration. A small portion of these cigarettes - which are made according to standardized specifications from marijuana of known origin and quality - go to eight patients legally supplied with marijuana under the government's compassionate use program, which has been discontinued.

At the Institute of Medicine workshop, speakers said marijuana's status as a controlled substance discourages scientists from attempting to study its therapeutic benefits. There is a "tremendous bureaucratic tangle to get a protocol approved," said J. Richard Crout, MD, a former FDA official who now runs Crout Consulting. He said that in addition to the constraints of the Drug Enforcement Administration, state agencies may also become involved in controlling marijuana trial protocols.

Nevertheless, other speakers said studies of cannabinoids are underway. David Pate, a senior technical officer with HortaPharm, BV, in Amsterdam, said his company is manufacturing a generic THC drug and that he is studying another cannabinoid-like drug that goes to the same receptor as THC.

Smokeless Cannabinoids

Phyllis I. Gardner, MD, a dean at Stanford University and a consultant to Alza Corporation in Palo Alto, CA, said if she had a choice, she would choose inhalation as her first choice of delivery because it seems to provide the most therapeutic benefit. She said Alza tried to make a cannabinoid transdermal patch in the 1970s, but "it didn't work." She cited transmucosal delivery as a promising route, noting that in general Americans accept nasal delivery but do not accept rectal suppositories as readily as Europeans do.

Reid M. Rubsamen, MD, Vice President for Medical Affairs of Aradigm Corporation in Hayward, CA, said he is working on a respiratory-tract drug delivery system for analgesics in which the patient holds a device with a light that tells him how to breathe; a liquid-formulated drug flows through the device in fine-particle, low-velocity aerosolized form. With this system, he noted, more of a given drug goes into the alveoli.

Mahmoud A. ElSohly, PhD, President of ElSohly Laboratories, Inc., in Oxford, MS, said he is studying delta-9-THC-hemisuccinate in suppository form as an alternative to oral and smoked THC. He is testing this formulation on patients with spasticity, and said he was "very encouraged" from preliminary results.

The Institute of Medicine carefully warned observers at the Washington workshop about the dangers of drawing inferences too hastily about what may be in the final report on medical use of marijuana. It stated that "observers who draw conclusions from the workshop about the Institute of Medicine study, will be doing so prematurely. The goal of this meeting is not to draw conclusions, but to listen to the evidence."